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Lee E, Lee Y, Yang S, Gong EJ, Kim J, Ha NC, Jo DG, Mattson MP, Lee J. Akt-activated GSK3β inhibitory peptide effectively blocks tau hyperphosphorylation. Arch Pharm Res 2024; 47:812-828. [PMID: 39325351 DOI: 10.1007/s12272-024-01513-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 09/12/2024] [Indexed: 09/27/2024]
Abstract
Tau hyperphosphorylation and accumulation in neurofibrillary tangles are closely associated with cognitive deficits in Alzheimer's disease (AD). Glycogen synthase kinase 3β (GSK3β) overexpression has been implicated in tau hyperphosphorylation, and many GSK3β inhibitors have been developed as potential therapeutic candidates for AD. However, the potent GSK3β inhibitors produced are prone to side effects because they can interfere with the basic functions of GSK3β. We previously found that when the phosphorylated PPPSPxS motifs in Wnt coreceptor LRP6 can directly inhibit GSK3β, and thus, we produced a novel GSK3β inhibitory peptide (GIP), specifically activated by Akt, by combining the PPPSPxS motif of LRP6 and the Akt targeted sequence (RxRxxS) of GSK3β. GIP effectively blocked GSK3β-induced tau phosphorylation in hippocampal homogenates and, when fused with a cell-permeable sequence, attenuated Aβ-induced tau phosphorylation in human neuroblastoma cells and inhibited cell death. An in vivo study using a 3 × Tg-AD mouse model revealed that intravenous GIP significantly reduced tau phosphorylation in the hippocampus without affecting Aβ plaque levels or neuroinflammation and ameliorated memory defects. The study provides a novel neuroprotective drug development strategy targeting tau hyperphosphorylation in AD.
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Affiliation(s)
- Eunjin Lee
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea
| | - Yujeong Lee
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea
| | - Seonguk Yang
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea
| | - Eun Ji Gong
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea
| | - Jaehoon Kim
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea
| | - Nam-Chul Ha
- Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Dong-Gyu Jo
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Mark P Mattson
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Jaewon Lee
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea.
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Zhao Z, Yuan Y, Li S, Wang X, Yang X. Natural compounds from herbs and nutraceuticals as glycogen synthase kinase-3β inhibitors in Alzheimer's disease treatment. CNS Neurosci Ther 2024; 30:e14885. [PMID: 39129397 PMCID: PMC11317746 DOI: 10.1111/cns.14885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 06/21/2024] [Accepted: 07/09/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) pathogenesis is complex. The pathophysiology is not fully understood, and safe and effective treatments are needed. Glycogen synthase kinase 3β (GSK-3β) mediates AD progression through several signaling pathways. Recently, several studies have found that various natural compounds from herbs and nutraceuticals can significantly improve AD symptoms. AIMS This review aims to provide a comprehensive summary of the potential neuroprotective impacts of natural compounds as inhibitors of GSK-3β in the treatment of AD. MATERIALS AND METHODS We conducted a systematic literature search on PubMed, ScienceDirect, Web of Science, and Google Scholar, focusing on in vitro and in vivo studies that investigated natural compounds as inhibitors of GSK-3β in the treatment of AD. RESULTS The mechanism may be related to GSK-3β activation inhibition to regulate amyloid beta production, tau protein hyperphosphorylation, cell apoptosis, and cellular inflammation. By reviewing recent studies on GSK-3β inhibition in phytochemicals and AD intervention, flavonoids including oxyphylla A, quercetin, morin, icariin, linarin, genipin, and isoorientin were reported as potent GSK-3β inhibitors for AD treatment. Polyphenols such as schisandrin B, magnolol, and dieckol have inhibitory effects on GSK-3β in AD models, including in vivo models. Sulforaphene, ginsenoside Rd, gypenoside XVII, falcarindiol, epibrassinolides, 1,8-Cineole, and andrographolide are promising GSK-3β inhibitors. CONCLUSIONS Natural compounds from herbs and nutraceuticals are potential candidates for AD treatment. They may qualify as derivatives for development as promising compounds that provide enhanced pharmacological characteristics.
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Affiliation(s)
- Zheng Zhao
- Department of Emergency MedicineShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Ye Yuan
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Shuang Li
- Department of Emergency MedicineShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Xiaofeng Wang
- Department of Emergency MedicineShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Xue Yang
- Department of NeurologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
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Shen Y, Zhao M, Zhao P, Meng L, Zhang Y, Zhang G, Taishi Y, Sun L. Molecular mechanisms and therapeutic potential of lithium in Alzheimer's disease: repurposing an old class of drugs. Front Pharmacol 2024; 15:1408462. [PMID: 39055498 PMCID: PMC11269163 DOI: 10.3389/fphar.2024.1408462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Despite advances in understanding the pathophysiological mechanisms of AD, effective treatments remain scarce. Lithium salts, recognized as mood stabilizers in bipolar disorder, have been extensively studied for their neuroprotective effects. Several studies indicate that lithium may be a disease-modifying agent in the treatment of AD. Lithium's neuroprotective properties in AD by acting on multiple neuropathological targets, such as reducing amyloid deposition and tau phosphorylation, enhancing autophagy, neurogenesis, and synaptic plasticity, regulating cholinergic and glucose metabolism, inhibiting neuroinflammation, oxidative stress, and apoptosis, while preserving mitochondrial function. Clinical trials have demonstrated that lithium therapy can improve cognitive function in patients with AD. In particular, meta-analyses have shown that lithium may be a more effective and safer treatment than the recently FDA-approved aducanumab for improving cognitive function in patients with AD. The affordability and therapeutic efficacy of lithium have prompted a reassessment of its use. However, the use of lithium may lead to potential side effects and safety issues, which may limit its clinical application. Currently, several new lithium formulations are undergoing clinical trials to improve safety and efficacy. This review focuses on lithium's mechanism of action in treating AD, highlighting the latest advances in preclinical studies and clinical trials. It also explores the side effects of lithium therapy and coping strategies, offering a potential therapeutic strategy for patients with AD.
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Affiliation(s)
- Yanxin Shen
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Meng Zhao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Panpan Zhao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Lingjie Meng
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Yan Zhang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Guimei Zhang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Yezi Taishi
- Department of Cadre Ward, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Li Sun
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
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Zhao J, Wei M, Guo M, Wang M, Niu H, Xu T, Zhou Y. GSK3: A potential target and pending issues for treatment of Alzheimer's disease. CNS Neurosci Ther 2024; 30:e14818. [PMID: 38946682 PMCID: PMC11215492 DOI: 10.1111/cns.14818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/21/2024] [Accepted: 05/27/2024] [Indexed: 07/02/2024] Open
Abstract
Glycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aβ aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aβ formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity-driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles.
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Affiliation(s)
- Jiahui Zhao
- School of Basic Medical SciencesZhejiang Chinese Medical UniversityHangzhouChina
| | - Mengying Wei
- College of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- Future Health Laboratory, Innovation Center of Yangtze River DeltaZhejiang UniversityJiaxingChina
| | - Minsong Guo
- College of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- Cangnan County Qiushi Innovation Research Institute of Traditional Chinese MedicineWenzhouChina
| | - Mengyao Wang
- School of Basic Medical SciencesZhejiang Chinese Medical UniversityHangzhouChina
| | - Hongxia Niu
- School of Basic Medical SciencesZhejiang Chinese Medical UniversityHangzhouChina
- Key Laboratory of Blood‐stasis‐toxin Syndrome of Zhejiang ProvinceHangzhouChina
| | - Tengfei Xu
- College of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- Cangnan County Qiushi Innovation Research Institute of Traditional Chinese MedicineWenzhouChina
| | - Yuan Zhou
- School of Basic Medical SciencesZhejiang Chinese Medical UniversityHangzhouChina
- Key Laboratory of Blood‐stasis‐toxin Syndrome of Zhejiang ProvinceHangzhouChina
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Zhang X, Zhao G, Yang F, Li C, Lin W, Dai H, Zhai L, Xi X, Yuan Q, Huo J. Transcriptional Regulation Analysis Provides Insight into the Function of GSK3β Gene in Diannan Small-Ear Pig Spermatogenesis. Genes (Basel) 2024; 15:655. [PMID: 38927591 PMCID: PMC11203124 DOI: 10.3390/genes15060655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/17/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Glycogen synthase kinase-3β (GSK3β) not only plays a crucial role in regulating sperm maturation but also is pivotal in orchestrating the acrosome reaction. Here, we integrated single-molecule long-read and short-read sequencing to comprehensively examine GSK3β expression patterns in adult Diannan small-ear pig (DSE) testes. We identified the most important transcript ENSSSCT00000039364 of GSK3β, obtaining its full-length coding sequence (CDS) spanning 1263 bp. Gene structure analysis located GSK3β on pig chromosome 13 with 12 exons. Protein structure analysis reflected that GSK3β consisted of 420 amino acids containing PKc-like conserved domains. Phylogenetic analysis underscored the evolutionary conservation and homology of GSK3β across different mammalian species. The evaluation of the protein interaction network, KEGG, and GO pathways implied that GSK3β interacted with 50 proteins, predominantly involved in the Wnt signaling pathway, papillomavirus infection, hippo signaling pathway, hepatocellular carcinoma, gastric cancer, colorectal cancer, breast cancer, endometrial cancer, basal cell carcinoma, and Alzheimer's disease. Functional annotation identified that GSK3β was involved in thirteen GOs, including six molecular functions and seven biological processes. ceRNA network analysis suggested that DSE GSK3β was regulated by 11 miRNA targets. Furthermore, qPCR expression analysis across 15 tissues highlighted that GSK3β was highly expressed in the testis. Subcellular localization analysis indicated that the majority of the GSK3β protein was located in the cytoplasm of ST (swine testis) cells, with a small amount detected in the nucleus. Overall, our findings shed new light on GSK3β's role in DSE reproduction, providing a foundation for further functional studies of GSK3β function.
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Affiliation(s)
- Xia Zhang
- Department of Biological and Food Engineering, Lyuliang University, Lvliang 033001, China;
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Guiying Zhao
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Fuhua Yang
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Changyao Li
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Wan Lin
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Hongmei Dai
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Lan Zhai
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Xuemin Xi
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Qingting Yuan
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
| | - Jinlong Huo
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (G.Z.); (F.Y.); (C.L.); (W.L.); (H.D.); (L.Z.); (X.X.); (Q.Y.)
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Shim SS, Berglund K, Yu SP. Lithium: An Old Drug for New Therapeutic Strategy for Alzheimer's Disease and Related Dementia. NEURODEGENER DIS 2023; 23:1-12. [PMID: 37666228 DOI: 10.1159/000533797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 08/23/2023] [Indexed: 09/06/2023] Open
Abstract
BACKGROUND Although Alzheimer's disease (AD) is the most common form of dementia, the effective treatment of AD is not available currently. Multiple trials of drugs, which were developed based on the amyloid hypothesis of AD, have not been highly successful to improve cognitive and other symptoms in AD patients, suggesting that it is necessary to explore additional and alternative approaches for the disease-modifying treatment of AD. The diverse lines of evidence have revealed that lithium reduces amyloid and tau pathology, attenuates neuronal loss, enhances synaptic plasticity, and improves cognitive function. Clinical studies have shown that lithium reduces the risk of AD and deters the progress of mild cognitive impairment and early AD. SUMMARY Our recent study has revealed that lithium stabilizes disruptive calcium homeostasis, and subsequently, attenuates the downstream neuropathogenic processes of AD. Through these therapeutic actions, lithium produces therapeutic effects on AD with potential to modify the disease process. This review critically analyzed the preclinical and clinical studies for the therapeutic effects of lithium on AD. We suggest that disruptive calcium homeostasis is likely to be the early neuropathological mechanism of AD, and the stabilization of disruptive calcium homeostasis by lithium would be associated with its therapeutic effects on neuropathology and cognitive deficits in AD. KEY MESSAGES Lithium is likely to be efficacious for AD as a disease-modifying drug by acting on multiple neuropathological targets including disruptive calcium homeostasis.
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Affiliation(s)
- Seong Sool Shim
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
- Mental Health Service Line, Department of Veteran's Affair, Atlanta VA Medical Center, Decatur, Georgia, USA
- Department of Veteran's Affair, Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, Georgia, USA
| | - Ken Berglund
- Department of Veteran's Affair, Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, Georgia, USA
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Shan Ping Yu
- Department of Veteran's Affair, Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, Georgia, USA
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia, USA
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Fronza MG, Alves D, Praticò D, Savegnago L. The neurobiology and therapeutic potential of multi-targeting β-secretase, glycogen synthase kinase 3β and acetylcholinesterase in Alzheimer's disease. Ageing Res Rev 2023; 90:102033. [PMID: 37595640 DOI: 10.1016/j.arr.2023.102033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/04/2023] [Accepted: 08/14/2023] [Indexed: 08/20/2023]
Abstract
Alzheimer's Disease (AD) is the most common form of dementia, affecting almost 50 million of people around the world, characterized by a complex and age-related progressive pathology with projections to duplicate its incidence by the end of 2050. AD pathology has two major hallmarks, the amyloid beta (Aβ) peptides accumulation and tau hyperphosphorylation, alongside with several sub pathologies including neuroinflammation, oxidative stress, loss of neurogenesis and synaptic dysfunction. In recent years, extensive research pointed out several therapeutic targets which have shown promising effects on modifying the course of the disease in preclinical models of AD but with substantial failure when transposed to clinic trials, suggesting that modulating just an isolated feature of the pathology might not be sufficient to improve brain function and enhance cognition. In line with this, there is a growing consensus that an ideal disease modifying drug should address more than one feature of the pathology. Considering these evidence, β-secretase (BACE1), Glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE) has emerged as interesting therapeutic targets. BACE1 is the rate-limiting step in the Aβ production, GSK-3β is considered the main kinase responsible for Tau hyperphosphorylation, and AChE play an important role in modulating memory formation and learning. However, the effects underlying the modulation of these enzymes are not limited by its primarily functions, showing interesting effects in a wide range of impaired events secondary to AD pathology. In this sense, this review will summarize the involvement of BACE1, GSK-3β and AChE on synaptic function, neuroplasticity, neuroinflammation and oxidative stress. Additionally, we will present and discuss new perspectives on the modulation of these pathways on AD pathology and future directions on the development of drugs that concomitantly target these enzymes.
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Affiliation(s)
- Mariana G Fronza
- Neurobiotechnology Research Group (GPN) - Centre for Technology Development CDTec, Federal University of Pelotas (UFPel), Pelotas, RS, Brazil
| | - Diego Alves
- Laboratory of Clean Organic Synthesis (LASOL), Center for Chemical, Pharmaceutical and Food Sciences (CCQFA), UFPel, RS, Brazil
| | - Domenico Praticò
- Alzheimer's Center at Temple - ACT, Temple University, Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Lucielli Savegnago
- Neurobiotechnology Research Group (GPN) - Centre for Technology Development CDTec, Federal University of Pelotas (UFPel), Pelotas, RS, Brazil.
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Wencel PL, Blecharz-Klin K, Piechal A, Pyrzanowska J, Mirowska-Guzel D, Strosznajder RP. Fingolimod Modulates the Gene Expression of Proteins Engaged in Inflammation and Amyloid-Beta Metabolism and Improves Exploratory and Anxiety-Like Behavior in Obese Mice. Neurotherapeutics 2023; 20:1388-1404. [PMID: 37432552 PMCID: PMC10480137 DOI: 10.1007/s13311-023-01403-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2023] [Indexed: 07/12/2023] Open
Abstract
Obesity is considered a risk factor for type 2 diabetes mellitus, which has become one of the most important health problems, and is also linked with memory and executive function decline. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that regulates cell death/survival and the inflammatory response via its specific receptors (S1PRs). Since the role of S1P and S1PRs in obesity is rather obscure, we examined the effect of fingolimod (an S1PR modulator) on the expression profile of genes encoding S1PRs, sphingosine kinase 1 (Sphk1), proteins engaged in amyloid-beta (Aβ) generation (ADAM10, BACE1, PSEN2), GSK3β, proapoptotic Bax, and proinflammatory cytokines in the cortex and hippocampus of obese/prediabetic mouse brains. In addition, we observed behavioral changes. Our results revealed significantly elevated mRNA levels of Bace1, Psen2, Gsk3b, Sphk1, Bax, and proinflammatory cytokines, which were accompanied by downregulation of S1pr1 and sirtuin 1 in obese mice. Moreover, locomotor activity, spatially guided exploratory behavior, and object recognition were impaired. Simultaneously, fingolimod reversed alterations in the expressions of the cytokines, Bace1, Psen2, and Gsk3b that occurred in the brain, elevated S1pr3 mRNA levels, restored normal cognition-related behavior patterns, and exerted anxiolytic effects. The improvement in episodic and recognition memory observed in this animal model of obesity may suggest a beneficial effect of fingolimod on central nervous system function.
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Affiliation(s)
- P L Wencel
- Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02106, Warsaw, Poland.
| | - K Blecharz-Klin
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 1B Banacha St., 02097, Warsaw, Poland
| | - A Piechal
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 1B Banacha St., 02097, Warsaw, Poland
| | - J Pyrzanowska
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 1B Banacha St., 02097, Warsaw, Poland
| | - D Mirowska-Guzel
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 1B Banacha St., 02097, Warsaw, Poland
| | - R P Strosznajder
- Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02106, Warsaw, Poland
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Chuang WH, Chou YT, Chen YH, Kuo TH, Liaw WF, Lu TT, Kao CF, Wang YM. Neuroprotective Effect of NO-Delivery Dinitrosyl Iron Complexes (DNICs) on Amyloid Pathology in the Alzheimer's Disease Cell Model. ACS Chem Neurosci 2023; 14:2922-2934. [PMID: 37533298 DOI: 10.1021/acschemneuro.3c00348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment, memory loss, and behavioral deficits. β-amyloid1-42 (Aβ1-42) aggregation is a significant cause of the pathogenesis in AD. Despite the numerous types of research, the current treatment efficacy remains insufficient. Hence, a novel therapeutic strategy is required. Nitric oxide (NO) is a multifunctional gaseous molecule. NO displays a neuroprotective role in the central nervous system by inhibiting the Aβ aggregation and rescuing memory and learning deficit through the NO signaling pathway. Targeting the NO pathway might be a therapeutic option; however, NO has a limited half-life under the biological system. To address this issue, a biomimetic dinitrosyl iron complex [(NO)2Fe(μ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) that could stably deliver NO was explored in the current study. To determine whether DNIC-COOH exerts anti-AD efficacy, DNIC-COOH was added to neuron-like cells and primary cortical neurons along with Aβ1-42. This study found that DNIC-COOH protected neuronal cells from Aβ-induced cytotoxicity, potentiated neuronal functions, and facilitated Aβ1-42 degradation through the NO-sGC-cGMP-AKT-GSK3β-CREB/MMP-9 pathway.
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Affiliation(s)
- Wen-Han Chuang
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Yu-Ting Chou
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Yi-Hong Chen
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan
| | - Ting-Han Kuo
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Wen-Feng Liaw
- Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
| | - Tsai-Te Lu
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan
- Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
- Department of Chemistry, Chung Yuan Christian University, Taoyuan 32023, Taiwan
| | - Chih-Fei Kao
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Yun-Ming Wang
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- Department of Biomedical Science and Environmental Biology, Department of Dentistry, Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Wiseman AL, Briggs CA, Peritt A, Kapecki N, Peterson DA, Shim SS, Stutzmann GE. Lithium Provides Broad Therapeutic Benefits in an Alzheimer's Disease Mouse Model. J Alzheimers Dis 2023; 91:273-290. [PMID: 36442195 DOI: 10.3233/jad-220758] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is a chronic neurodegenerative disorder with a progressive loss of cognitive function. Currently, no effective treatment regimen is available. Lithium, a mood stabilizer for bipolar disorder, exerts broad neuroprotective and neurotrophic actions and improves cognitive function. OBJECTIVE The study investigated if lithium stabilizes Ca2+ signaling abnormalities in hippocampal neurons and subsequently normalize downstream effects on AD neuropathology and synaptic plasticity in young AD mice. METHODS Four-month-old 3xTg-AD mice were treated with a LiCl diet chow for 30 days. At the end of the lithium treatment, a combination of two-photon Ca2+ imaging, electrophysiology, and immunohistochemistry assays were used to assess the effects of the LiCl treatment on inositol trisphosphate receptor (IP3R)-dependent endoplasmic reticulum (ER) Ca2+ and voltage-gated Ca2+ channel (VGCC)-mediated Ca2+ signaling in CA1 neurons, neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels and synaptic plasticity in the hippocampus and overlying cortex from 3xTg-ADmice. RESULTS Thirty-day LiCl treatment reduced aberrant IP3R-dependent ER Ca2+ and VGCC-mediated Ca2+ signaling in CA1 pyramidal neurons from 3xTg-AD mice and restored neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels to control levels in the hippocampal subfields and overlying cortex. The LiCl treatment enhanced post-tetanic potentiation (PTP), a form of short-term plasticity in the hippocampus. CONCLUSION The study found that lithium exerts therapeutic effects across several AD-associated early neuronal signaling abnormalities including aberrant Ca2+ signaling, nNOS, and p-tau formation and enhances short-term synaptic plasticity. Lithium could serve as an effective treatment or co-therapeutic for AD.
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Affiliation(s)
- Alyssa L Wiseman
- Discipline of Neuroscience, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA.,School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL, USA
| | - Clark A Briggs
- Discipline of Neuroscience, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA
| | - Ariel Peritt
- Discipline of Neuroscience, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA.,Sackler School of Medicine, New York State/American Program of Tel Aviv University, Tel Aviv, Israel
| | - Nicolas Kapecki
- Discipline of Neuroscience, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA
| | - Daniel A Peterson
- Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University, North Chicago, IL, USA.,Discipline of Neuroscience, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA.,School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL, USA
| | - Seong S Shim
- Discipline of Psychiatry and Behavioral Sciences, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA.,Captain James A. Lovell Federal Health Care Center, Mental Health, North Chicago, IL, USA
| | - Grace E Stutzmann
- Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University, North Chicago, IL, USA.,Discipline of Neuroscience, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA.,School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL, USA
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11
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Khan SS, Khatik GL, Datusalia AK. Strategies for Treatment of Disease-Associated Dementia Beyond Alzheimer's Disease: An Update. Curr Neuropharmacol 2023; 21:309-339. [PMID: 35410602 PMCID: PMC10190146 DOI: 10.2174/1570159x20666220411083922] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/27/2022] [Accepted: 04/03/2022] [Indexed: 11/22/2022] Open
Abstract
Memory, cognition, dementia, and neurodegeneration are complexly interlinked processes with various mechanistic pathways, leading to a range of clinical outcomes. They are strongly associated with pathological conditions like Alzheimer's disease, Parkinson's disease, schizophrenia, and stroke and are a growing concern for their timely diagnosis and management. Several cognitionenhancing interventions for management include non-pharmacological interventions like diet, exercise, and physical activity, while pharmacological interventions include medicinal agents, herbal agents, and nutritional supplements. This review critically analyzed and discussed the currently available agents under different drug development phases designed to target the molecular targets, including cholinergic receptor, glutamatergic system, GABAergic targets, glycine site, serotonergic targets, histamine receptors, etc. Understanding memory formation and pathways involved therein aids in opening the new gateways to treating cognitive disorders. However, clinical studies suggest that there is still a dearth of knowledge about the pathological mechanism involved in neurological conditions, making the dropouts of agents from the initial phases of the clinical trial. Hence, a better understanding of the disease biology, mode of drug action, and interlinked mechanistic pathways at a molecular level is required.
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Affiliation(s)
- Sabiya Samim Khan
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow (UP) India
| | - Gopal L. Khatik
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow (UP) India
| | - Ashok K. Datusalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow (UP) India
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow (UP) India
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12
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Lu LP, Chang WH, Huang JJ, Tan P, Tsai GE. Lithium Benzoate Exerts Neuroprotective Effect by Improving Mitochondrial Function, Attenuating Reactive Oxygen Species, and Protecting Cognition and Memory in an Animal Model of Alzheimer’s Disease. J Alzheimers Dis Rep 2022; 6:557-575. [PMID: 36275418 PMCID: PMC9535606 DOI: 10.3233/adr-220025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/09/2022] [Indexed: 11/15/2022] Open
Abstract
Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease affecting many cellular pathways, including protein aggregation, mitochondrial dysfunction, oxidative stress (OS), and neuroinflammation. Currently, no effective treatment for AD exists. Objective: We aim to determine the effect of lithium benzoate (LiBen) in protecting neurons from amyloid-β (Aβ) or other neurotoxin insults. Methods: Primary rat cortical neurons co-treated with neurotoxins and LiBen were used to examine its effect in cell viability, reactive oxygen species (ROS) clearance, and mitochondrial functions by MTT, CellRox fluorescence staining, and seahorse assay. Then, Barnes maze and prepulse inhibition test were performed in APP/PS1 mice that received chronic LiBen treatment to assess its effect on cognitive protection. Oral bioavailability of LiBen was also assessed by pharmacokinetic study in rat plasma. Results: In this study, we discovered that LiBen can attenuate cellular ROS level, improve mitochondrial function, increase cell viability against multiple different insults of mitochondrial dysfunction, Aβ accumulation, and neuroinflammation, and promote neurogenesis. We demonstrated that LiBen has advantages over lithium or sodium benzoate alone as LiBen displays superior neuroprotective efficacy and oral bioavailability than the other two agents when being applied either alone or in combination. Furthermore, chronic administration of LiBen showed protection for cognition as well as spatial memory and reduced the senile plaque deposition in brains of AD animal models. Conclusion: LiBen stands as a promising therapeutic agent for improving cognition and delaying the progression of AD.
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Affiliation(s)
- Lu-Ping Lu
- Department of Research and Development, SyneuRx International (Taiwan) Corp., New Taipei, Taiwan
| | - Wei-Hua Chang
- Department of Research and Development, SyneuRx International (Taiwan) Corp., New Taipei, Taiwan
| | - Jing-Jia Huang
- Department of Research and Development, SyneuRx International (Taiwan) Corp., New Taipei, Taiwan
| | - Peng Tan
- Department of Research and Development, SyneuRx International (Taiwan) Corp., New Taipei, Taiwan
| | - Guochuan Emil Tsai
- Department of Research and Development, SyneuRx International (Taiwan) Corp., New Taipei, Taiwan
- UCLA School of Medicine, Los Angeles, CA, USA
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13
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Zhai Z, Xie D, Qin T, Zhong Y, Xu Y, Sun T. Effect and Mechanism of Exogenous Melatonin on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic review and Meta-analysis. Neuroscience 2022; 505:91-110. [PMID: 36116555 DOI: 10.1016/j.neuroscience.2022.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/05/2022] [Accepted: 09/08/2022] [Indexed: 12/09/2022]
Abstract
Melatonin (MT) has been reported to control and prevent Alzheimer's disease (AD) in the clinic; however, the effect and mechanism of MT on AD have not been specifically described. Therefore, the main purpose of this meta-analysis was to explore the effect and mechanism of MT on AD models by studying behavioural indicators and pathological features. Seven databases were searched and 583 articles were retrieved. Finally, nine studies (13 analyses, 294 animals) were included according to pre-set criteria. Three authors independently judged the selected literature and the methodological quality. Meta-analysis showed that MT markedly ameliorated the learning ability by reducing the escape latency (EL), and the memory deficit was significantly corrected by increasing the dwell time in the target quadrant and crossings over the platform location in the Morris Water Maze (MWM). Among the pathological features, subgroup analysis found that MT may ease the symptoms of AD mainly by reducing the deposition of Aβ40 and Aβ42 in the cortex. In addition, MT exerted a superior effect on ameliorating the learning ability of senescence-related and metabolic AD models, and corrected the memory deficit of the toxin-induced AD model. The study was registered at PROSPERO (CRD42021226594).
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Affiliation(s)
- Zhenwei Zhai
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Danni Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Tao Qin
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yanmei Zhong
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Ying Xu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Tao Sun
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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14
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The Anti-Inflammatory Effect of Preventive Intervention with Ketogenic Diet Mediated by the Histone Acetylation of mGluR5 Promotor Region in Rat Parkinson’s Disease Model: A Dual-Tracer PET Study. PARKINSON'S DISEASE 2022; 2022:3506213. [PMID: 36105302 PMCID: PMC9467749 DOI: 10.1155/2022/3506213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/05/2022] [Indexed: 11/24/2022]
Abstract
Materials and Methods The neuroprotective effect of ketosis state prior to the onset of PD (preventive KD, KDp) was compared with that receiving KD after the onset (therapeutic KD, KDt) in the lipopolysaccharide- (LPS-) induced rat PD model. A total of 100 rats were randomly assigned to the following 4 groups: sham, LPS, LPS + KDp, and LPS + KDt groups. Results Significant dopamine deficient behaviors (rotational behavior and contralateral forelimb akinesia), upregulation of proinflammatory mediators (TNF-α, IL-1β, and IL-6), loss of dopaminergic neurons, reduction of mGluR5+ microglia cells, increase of TSPO+ microglia cells, reduction of H3K9 acetylation in the mGluR5 promoter region and mGluR5 mRNA expression, and decline in the phosphorylation levels of Akt/GSK-3β/CREB pathway were observed after the intervention of LPS (P < 0.01). TSPO and DAT PET imaging revealed the increased uptake of 18F-DPA-714 in substantia nigra and decreased uptake of 18F-FP-CIT in substantia nigra and striatum in LPS-treated rats (P < 0.001). These impairments were alleviated by the dietary intervention of KD, especially with the strategy of KDp (P < 0.05). Conclusions The anti-inflammatory effect of KD on PD was supposed to be related to the modulation of Akt/GSK-3β/CREB signaling pathway mediated by the histone acetylation of mGluR5 promotor region. The KD intervention should be initiated prior to the PD onset in high-risk population to achieve a more favorable outcome.
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15
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Sen S, Lagas S, Roy A, Kumar H. Cytoskeleton saga: Its regulation in normal physiology and modulation in neurodegenerative disorders. Eur J Pharmacol 2022; 925:175001. [PMID: 35525310 DOI: 10.1016/j.ejphar.2022.175001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/31/2022] [Accepted: 04/29/2022] [Indexed: 11/25/2022]
Abstract
Cells are fundamental units of life. To ensure the maintenance of homeostasis, integrity of structural and functional counterparts is needed to be essentially balanced. The cytoskeleton plays a vital role in regulating the cellular morphology, signalling and other factors involved in pathological conditions. Microtubules, actin (microfilaments), intermediate filaments (IF) and their interactions are required for these activities. Various proteins associated with these components are primary requirements for directing their functions. Disruption of this organization due to faulty genetics, oxidative stress or impaired transport mechanisms are the major causes of dysregulated signalling cascades leading to various pathological conditions like Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP) or any traumatic injury like spinal cord injury (SCI). Novel or conventional therapeutic approaches may be specific or non-specific, targeting either three basic components of the cytoskeleton or various cascades that serve as a cue to numerous pathways like ROCK signalling or the GSK-3β pathway. An enormous number of drugs have been redirected for modulating the cytoskeletal dynamics and thereby may pave the way for inhibiting the progression of these diseases and their complications.
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Affiliation(s)
- Santimoy Sen
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India
| | - Sheetal Lagas
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India
| | - Abhishek Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India.
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16
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Kazemi Shariat Panahi H, Dehhaghi M, Heng B, Lane DJR, Bush AI, Guillemin GJ, Tan VX. Neuropathological Mechanisms of β-N-Methylamino-L-Alanine (BMAA) with a Focus on Iron Overload and Ferroptosis. Neurotox Res 2022; 40:614-635. [PMID: 35023054 DOI: 10.1007/s12640-021-00455-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 11/22/2021] [Accepted: 11/30/2021] [Indexed: 02/08/2023]
Abstract
The incidence of neurodegenerative diseases and cyanobacterial blooms is concomitantly increasing worldwide. The cyanotoxin β-N-methylamino-L-alanine (BMAA) is produced by most of the Cyanobacteria spp. This cyanotoxin is described as a potential environmental etiology factor for some sporadic neurodegenerative diseases. Climate change and eutrophication significantly increase the frequency and intensity of cyanobacterial bloom in water bodies. This review evaluates different neuropathological mechanisms of BMAA at molecular and cellular levels and compares the related studies to provide some useful recommendations. Additionally, the structure and properties of BMAA as well as its microbial origin, especially by gut bacteria, are also briefly covered. Unlike previous reviews, we hypothesize the possible neurotoxic mechanism of BMAA through iron overload. We also discuss the involvement of BMAA in excitotoxicity, TAR DNA-binding protein 43 (TDP-43) translocation and accumulation, tauopathy, and other protein misincorporation and misfolding.
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Affiliation(s)
- Hamed Kazemi Shariat Panahi
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mona Dehhaghi
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
- PANDIS.Org, Bendigo, Australia
- Department of Microbial Biotechnology, School of Biology and Centre of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
| | - Benjamin Heng
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Ashley I Bush
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Gilles J Guillemin
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
- PANDIS.Org, Bendigo, Australia.
| | - Vanessa X Tan
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
- PANDIS.Org, Bendigo, Australia
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17
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Lee Y, Bortolotto ZA, Bradley CA, Sanderson TM, Zhuo M, Kaang BK, Collingridge GL. The GSK-3 Inhibitor CT99021 Enhances the Acquisition of Spatial Learning and the Accuracy of Spatial Memory. Front Mol Neurosci 2022; 14:804130. [PMID: 35153671 PMCID: PMC8829050 DOI: 10.3389/fnmol.2021.804130] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/30/2021] [Indexed: 11/13/2022] Open
Abstract
Glycogen synthase kinase 3 (GSK-3) is a Ser/Thr protein kinase that regulates many cellular processes, including synaptic plasticity. Previously, we reported that inhibition of GSK-3 prevents the induction of one of the major forms of synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD), in hippocampal slices. In the present study, we have investigated the effects of inhibiting GSK-3 on learning and memory in healthy naïve animals. Systemic administration of a highly selective GSK-3 inhibitor, CT99021, reversibly blocked NMDAR-dependent LTD in the CA1 region of the hippocampus in anesthetized adult mice. In behavioral tasks, CT99021 had no effect on locomotor activity, anxiety, hippocampus-dependent contextual fear memory, and hippocampus-dependent reversal learning. However, CT99021 facilitated the rate of learning in the Morris water maze (MWM) and T-maze and enhanced the accuracy of long-term spatial memory in the MWM. These findings suggest that GSK-3 regulates the accuracy of spatial memory acquisition and recall.
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Affiliation(s)
- Yeseul Lee
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea
- Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Zuner A. Bortolotto
- Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
| | - Clarrisa A. Bradley
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea
- Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
- Genes and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Thomas M. Sanderson
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea
- Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Min Zhuo
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Bong-Kiun Kaang
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea
- *Correspondence: Bong-Kiun Kaang,
| | - Graham L. Collingridge
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea
- Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
- Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, Canada
- Graham L. Collingridge,
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Gupta S, Singh V, Ganesh S, Singhal NK, Sandhir R. siRNA Mediated GSK3β Knockdown Targets Insulin Signaling Pathway and Rescues Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies. ACS APPLIED MATERIALS & INTERFACES 2022; 14:69-93. [PMID: 34967205 DOI: 10.1021/acsami.1c15305] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Sporadic Alzheimer's disease (sAD) is a progressive neurodegenerative disorder with dysfunctional insulin signaling and energy metabolism. Emerging evidence suggests impairments in brain insulin responsiveness, glucose utilization, and energy metabolism may be major causes of amyloid precursor protein mishandling. The support for this notion comes from the studies wherein streptozotocin (STZ) induced brain insulin resistance in rodent model resulted in sAD-like neuropathology with cognitive decline. Our previous study showed a compromised insulin signaling pathway, glucose uptake, glucose metabolism, and energy homeostasis in STZ-induced glial-neuronal coculture and in vivo model of sAD. Various components of insulin signaling pathway were examined to understand the metabolic correlation, and GSK3β was selected for gene knockdown strategy to reverse sAD pathology based on the data. In the present study, we have synthesized carboxylated graphene oxide (GO) nanosheets functionalized with PEG and subsequently with polyethylenimine (PEI) to provide attachment sites for GSK3β siRNA. Our results showed that siRNA mediated knockdown of the GSK3β gene reduced expression of amyloid pathway genes (APP and BACE1), which was further confirmed by reduced amyloid beta (Aβ) levels in the in vitro STZ-induced sAD model. GSK3β knockdown also restored insulin signaling, AMPK and Mapk3 pathway by restoring the expression of corresponding candidate genes in these pathways (IR, Glut1/3, Prkaa1/2, Mapk3, BDNF) that reflected improved cellular energy homeostasis, neuronal proliferation, differentiation, maturation, and repair. Behavioral data from Morris water maze (MWM), open field (OF), novel object recognition (NOR), Y maze, and radial arm maze (RAM) tests showed that 0.5 μg nanoformulation (GOc-PP-siRNAGSK3β) intranasally for 7 days improved spatial memory, rescued anxiety like behavior, improved visual and working memory, and rescued exploratory behavior in STZ-induced sAD rats. GSK3β silencing resulted in decreased BACE1 expression and prevented accumulation of Aβ in the cortex and hippocampus. These molecular findings with improved behavioral performances were further correlated with reduced amyloid beta (Aβ) and neurofibrillary tangle (NFTs) formation in the cortex and hippocampus of GOc-PP-siRNAGSK3β administered sAD rats. Therefore, it is conceivable from the present study that nanoparticle-mediated targeting of GSK3β in the sAD appears to be a promising strategy to reverse sAD pathology.
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Affiliation(s)
- Smriti Gupta
- Department of Biochemistry, Panjab University, Chandigarh 160014, India
| | - Vishal Singh
- National Agri-Food Biotechnology Institute, Sector 81, S.A.S. Nagar, Mohali 140306, Punjab, India
| | - Subramaniam Ganesh
- Department of Biological Science and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Nitin K Singhal
- National Agri-Food Biotechnology Institute, Sector 81, S.A.S. Nagar, Mohali 140306, Punjab, India
| | - Rajat Sandhir
- Department of Biochemistry, Panjab University, Chandigarh 160014, India
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Yang J, Zhang W, Zhang S, Iyaswamy A, Sun J, Wang J, Yang C. Novel Insight into Functions of Transcription Factor EB (TFEB) in Alzheimer’s Disease and Parkinson’s Disease. Aging Dis 2022; 14:652-669. [PMID: 37191408 DOI: 10.14336/ad.2022.0927] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/27/2022] [Indexed: 03/31/2023] Open
Abstract
A key pathological feature of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is the accumulation of aggregated and misfolded protein aggregates with limited effective therapeutic agents. TFEB (transcription factor EB), a key regulator of lysosomal biogenesis and autophagy, plays a pivotal role in the degradation of protein aggregates and has thus been regarded as a promising therapeutic target for these NDs. Here, we systematically summarize the molecular mechanisms and function of TFEB regulation. We then discuss the roles of TFEB and autophagy-lysosome pathways in major neurodegenerative diseases including AD and PD. Finally, we illustrate small molecule TFEB activators with protective roles in NDs animal models, which show great potential for being further developed into novel anti-neurodegenerative agents. Overall, targeting TFEB for enhancing lysosomal biogenesis and autophagy may represent a promising opportunity for the discovery of disease-modifying therapeutics for neurodegenerative disorders though more in-depth basic and clinical studies are required in the future.
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20
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De-Paula VJ, Forlenza OV. Lithium modulates multiple tau kinases with distinct effects in cortical and hippocampal neurons according to concentration ranges. Naunyn Schmiedebergs Arch Pharmacol 2021; 395:105-113. [PMID: 34751792 DOI: 10.1007/s00210-021-02171-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 10/19/2021] [Indexed: 11/26/2022]
Abstract
The hyperphosphorylation of tau is a central mechanism in the pathogenesis of Alzheimer's disease (AD). Lithium is a potent inhibitor of glycogen synthase kinase-3beta (GSK3β), the most important tau kinase in neurons, and may also affect tau phosphorylation by modifying the expression and/or activity of other kinases, such as protein kinase A (PKA), Akt (PKB), and calcium calmodulin kinase-II (CaMKII). The aim of the present study is to determine the effect of chronic lithium treatment on the protein expression of tau and its major kinases in cortical and hippocampal neurons, at distinct working concentrations. Primary cultures of cortical and hippocampal neurons were treated with sub-therapeutic (0.02 mM and 0.2 mM) and therapeutic (2 mM) concentrations of lithium for 7 days. Protein expression of tau and tau-kinases was determined by immunoblotting. An indirect estimate of GSK3β activity was determined by the GSK3β ratio (rGSKβ). Statistically significant increments in the protein expression of tau and CaMKII were observed both in cortical and hippocampal neurons treated with subtherapeutic doses of lithium. GSK3β activity was increased in cortical, but decreased in hippocampal neurons. Distinct patterns of changes in the expression of the remaining tau tau-kinases were observed: in cortical neurons, lithium treatment was associated with consistent decrements in Akt and PKA, whereas hippocampal neurons displayed increased protein expression of Akt and decreased PKA. Our results suggest that chronic lithium treatment may yield distinct biological effects depending on the concentration range, with regional specificity. We further suggest that hippocampal neurons may be more sensitive to the effect of lithium, presenting with changes in the expression of tau-related proteins at subtherapeutic doses, which may not be mirrored by the effects observed in cortical neurons.
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Affiliation(s)
- V J De-Paula
- Laboratório de Neurociências (LIM-27), Departamento E Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
- Laboratório de Psicobiologia (LIM-23), Instituto de Psiquiatria, Hospital das Clinicas da Faculdade de Medicina da USP, Rua Dr. Ovídio Pires de Campos 785, São Paulo, SP, 05403-903, Brazil.
| | - O V Forlenza
- Laboratório de Neurociências (LIM-27), Departamento E Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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21
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Li Y, Chen L, Li Z, Song Y, Yuan Y, Liu T, Hong J, Wang Q, Chang H, Kuang Z, He J, Li Y, Mi X, Han D, Yang N, Guo X. Potential Serum Biomarkers for Postoperative Neurocognitive Disorders Based on Proteomic Analysis of Cognitive-Related Brain Regions. Front Aging Neurosci 2021; 13:741263. [PMID: 34658843 PMCID: PMC8511679 DOI: 10.3389/fnagi.2021.741263] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/03/2021] [Indexed: 12/14/2022] Open
Abstract
Postoperative neurocognitive disorders (po-NCD), including postoperative delirium (POD) and delayed neurocognitive recovery (dNCR), are common in geriatric surgical patients. However, the ideal diagnostic biomarkers to predict individual risks of po-NCDs have not been identified. In this study, proteomic analysis was used to detect dysregulated proteins in three cognitive-related brain regions, the hippocampus, prefrontal cortex, and temporal lobe, of aged dNCR rats. The common affected proteins in these three brain regions were further verified by real-time polymerase chain reaction and western blotting. Furthermore, serum samples from aged rats with dNCR and elderly hip fracture patients with POD were also assessed with enzyme linked immunosorbent assays to investigate the biomarker potential of these dysregulated proteins. The increased expression levels of haptoglobin, caseinolytic protease (ClpP), and alpha-2 macroglobulin (A2M) as well as decreased expression levels of 14-3-3β/α and biliverdin reductase-A (BVR-A) were validated by proteomic analysis in the hippocampus, prefrontal cortex, and temporal lobe of aged dNCR rats. The increased expression of haptoglobin and decreased expression of 14-3-3β/α were further demonstrated in the three brain regions by western blotting. Moreover, increased levels of S100A6 and BVR-A in the hippocampus, S100A6 in the prefrontal cortex, and A2M in the temporal lobe were also observed. More intriguingly, both decreased serum 14-3-3β/α and increased A2M in geriatric POD patients as well as decreased serum ClpP in aged dNCR rats were verified. These results not only indicate potential diagnostic biomarkers for po-NCD but also provide directions for further pathological investigations. Clinical Trial Registration:www.ClinicalTrials.gov, identifier [ChiCTR1900027393].
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Affiliation(s)
- Yitong Li
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Lei Chen
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Zhengqian Li
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Yanan Song
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Yi Yuan
- Department of Anesthesiology, Beijing Jishuitan Hospital, Beijing, China
| | - Taotao Liu
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Jingshu Hong
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Qian Wang
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Huixian Chang
- School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
| | - Zhongshen Kuang
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Jindan He
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Yue Li
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Xinning Mi
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Dengyang Han
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Ning Yang
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Xiangyang Guo
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
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22
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Song XJ, Zhou HY, Sun YY, Huang HC. Phosphorylation and Glycosylation of Amyloid-β Protein Precursor: The Relationship to Trafficking and Cleavage in Alzheimer's Disease. J Alzheimers Dis 2021; 84:937-957. [PMID: 34602469 DOI: 10.3233/jad-210337] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder in the central nervous system, and this disease is characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid-β (Aβ) peptide is the main constituent of senile plaques, and this peptide is derived from the amyloid-β protein precursor (AβPP) through the successive cleaving by β-site AβPP-cleavage enzyme 1 (BACE1) and γ-secretase. AβPP undergoes the progress of post-translational modifications, such as phosphorylation and glycosylation, which might affect the trafficking and the cleavage of AβPP. In the recent years, about 10 phosphorylation sites of AβPP were identified, and they play complex roles in glycosylation modification and cleavage of AβPP. In this article, we introduced the transport and the cleavage pathways of AβPP, then summarized the phosphorylation and glycosylation sites of AβPP, and further discussed the links and relationship between phosphorylation and glycosylation on the pathways of AβPP trafficking and cleavage in order to provide theoretical basis for AD research.
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Affiliation(s)
- Xi-Jun Song
- Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, China.,Research Institute of Functional Factors and Brain Science, Beijing Union University, Beijing, China
| | - He-Yan Zhou
- Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, China.,Research Institute of Functional Factors and Brain Science, Beijing Union University, Beijing, China
| | - Yu-Ying Sun
- Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, China.,Research Institute of Functional Factors and Brain Science, Beijing Union University, Beijing, China
| | - Han-Chang Huang
- Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, China.,Research Institute of Functional Factors and Brain Science, Beijing Union University, Beijing, China
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23
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On the Common Journey of Neural Cells through Ischemic Brain Injury and Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22189689. [PMID: 34575845 PMCID: PMC8472292 DOI: 10.3390/ijms22189689] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/19/2021] [Accepted: 09/03/2021] [Indexed: 01/09/2023] Open
Abstract
Ischemic brain injury and Alzheimer's disease (AD) both lead to cell death in the central nervous system (CNS) and thus negatively affect particularly the elderly population. Due to the lack of a definitive cure for brain ischemia and AD, it is advisable to carefully study, compare, and contrast the mechanisms that trigger, and are involved in, both neuropathologies. A deeper understanding of these mechanisms may help ameliorate, or even prevent, the destructive effects of neurodegenerative disorders. In this review, we deal with ischemic damage and AD, with the main emphasis on the common properties of these CNS disorders. Importantly, we discuss the Wnt signaling pathway as a significant factor in the cell fate determination and cell survival in the diseased adult CNS. Finally, we summarize the interesting findings that may improve or complement the current sparse and insufficient treatments for brain ischemia and AD, and we delineate prospective directions in regenerative medicine.
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24
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Melatonin protects against methamphetamine-induced Alzheimer's disease-like pathological changes in rat hippocampus. Neurochem Int 2021; 148:105121. [PMID: 34224806 DOI: 10.1016/j.neuint.2021.105121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 06/21/2021] [Accepted: 06/29/2021] [Indexed: 01/14/2023]
Abstract
Methamphetamine (METH) is a psychostimulant drug of abuse. METH use is associated with cognitive impairments and neurochemical abnormalities comparable to pathological changes observed in Alzheimer's disease (AD). These observations have stimulated the idea that METH abusers might be prone to develop AD-like signs and symptoms. Melatonin, the pineal hormone, is considered as a potential therapeutic intervention against AD. We thus conducted the present study to explore potential protective roles of melatonin against METH-induced deficits in learning and memory as well as in the appearance of AD-like pathological changes in METH-treated male Wistar rats. We found that melatonin ameliorated METH-induced cognitive impairments in those rats. Melatonin prevented METH-induced decrease in dopamine transporter (DAT) expression in rat hippocampus. Melatonin reversed METH-induced activation of β-arrestin2, reduction of phosphorylation of protein kinase B (Akt) and METH-induced excessive activity of glycogen synthase kinase-3β (GSK3β). Importantly, melatonin inhibited METH-induced changes in the expression of β-site APP cleaving enzyme (BACE1), disintegrin and metalloproteinase 10 (ADAM10), and presenilin 1 (PS1), as well as the reduction of amyloid beta (Aβ)42 production. Immunofluorescence double-labeling demonstrated that melatonin not only prevented the METH-induced loss of DAT but also prevented METH-induced Aβ42 overexpression in the dentate gyrus, CA1, and CA3. Furthermore, melatonin also suppressed METH-induced increase in phosphorylated tau. Significantly, melatonin attenuated METH-induced increase in N-methyl-D-aspartate receptor subtype 2 B (NR2B) protein expression and restored METH-induced reduction of Ca2+/calmodulin-dependent protein kinase II (CaMKII). This suggested that melatonin attenuated the toxic effect of METH on the hippocampus involving the amyloidogenic pathway. Taken together, our data suggest that METH abuse may be a predisposing risk factor for AD and that melatonin could serve as a potential therapeutic agent to prevent METH-induced AD like pathology.
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25
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When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease. Int J Mol Sci 2021; 22:ijms22115911. [PMID: 34072862 PMCID: PMC8199025 DOI: 10.3390/ijms22115911] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 01/18/2023] Open
Abstract
Alzheimer's disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington's disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.
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26
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Sambon M, Wins P, Bettendorff L. Neuroprotective Effects of Thiamine and Precursors with Higher Bioavailability: Focus on Benfotiamine and Dibenzoylthiamine. Int J Mol Sci 2021; 22:ijms22115418. [PMID: 34063830 PMCID: PMC8196556 DOI: 10.3390/ijms22115418] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/10/2021] [Accepted: 05/18/2021] [Indexed: 11/25/2022] Open
Abstract
Thiamine (vitamin B1) is essential for brain function because of the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. In order to compensate thiamine deficiency, several thiamine precursors with higher bioavailability were developed since the 1950s. Among these, the thioester benfotiamine (BFT) has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. BFT has no adverse effects and improves cognitive outcome in patients with mild Alzheimer’s disease (AD). Recent in vitro studies show that another thiamine thioester, dibenzoylthiamine (DBT) is even more efficient that BFT, especially with respect to its anti-inflammatory potency. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified metabolites in particular open thiazole ring derivatives. The identification of the active neuroprotective derivatives and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental and psychiatric conditions.
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27
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Jankowska A, Satała G, Bojarski AJ, Pawłowski M, Chłoń-Rzepa G. Multifunctional Ligands with Glycogen Synthase Kinase 3 Inhibitory Activity as a New Direction in Drug Research for Alzheimer's Disease. Curr Med Chem 2021; 28:1731-1745. [PMID: 32338201 DOI: 10.2174/0929867327666200427100453] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 11/22/2022]
Abstract
Alzheimer's disease (AD) belongs to the most common forms of dementia that causes a progressive loss of brain cells and leads to memory impairment and decline of other thinking skills. There is yet no effective treatment for AD; hence, the search for new drugs that could improve memory and other cognitive functions is one of the hot research topics worldwide. Scientific efforts are also directed toward combating behavioral and psychological symptoms of dementia, which are an integral part of the disease. Several studies have indicated that glycogen synthase kinase 3 beta (GSK3β) plays a crucial role in the pathogenesis of AD. Moreover, GSK3β inhibition provided beneficial effects on memory improvement in multiple animal models of AD. The present review aimed to update the most recent reports on the discovery of novel multifunctional ligands with GSK3β inhibitory activity as potential drugs for the symptomatic and disease-modifying therapy of AD. Compounds with GSK3β inhibitory activity seem to be an effective pharmacological approach for treating the causes and symptoms of AD as they reduced neuroinflammation and pathological hallmarks in animal models of AD and provided relief from cognitive and neuropsychiatric symptoms. These compounds have the potential to be used as drugs for the treatment of AD, but their precise pharmacological, pharmacokinetic, toxicological and clinical profiles need to be defined.
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Affiliation(s)
- Agnieszka Jankowska
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Grzegorz Satała
- Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland
| | - Andrzej J Bojarski
- Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland
| | - Maciej Pawłowski
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688 Krakow, Poland
| | - GraŻyna Chłoń-Rzepa
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688 Krakow, Poland
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28
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Vinuesa A, Pomilio C, Gregosa A, Bentivegna M, Presa J, Bellotto M, Saravia F, Beauquis J. Inflammation and Insulin Resistance as Risk Factors and Potential Therapeutic Targets for Alzheimer's Disease. Front Neurosci 2021; 15:653651. [PMID: 33967682 PMCID: PMC8102834 DOI: 10.3389/fnins.2021.653651] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/31/2021] [Indexed: 12/21/2022] Open
Abstract
Overnutrition and modern diets containing high proportions of saturated fat are among the major factors contributing to a low-grade state of inflammation, hyperglycemia and dyslipidemia. In the last decades, the global rise of type 2 diabetes and obesity prevalence has elicited a great interest in understanding how changes in metabolic function lead to an increased risk for premature brain aging and the development of neurodegenerative disorders such as Alzheimer's disease (AD). Cognitive impairment and decreased neurogenic capacity could be a consequence of metabolic disturbances. In these scenarios, the interplay between inflammation and insulin resistance could represent a potential therapeutic target to prevent or ameliorate neurodegeneration and cognitive impairment. The present review aims to provide an update on the impact of metabolic stress pathways on AD with a focus on inflammation and insulin resistance as risk factors and therapeutic targets.
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Affiliation(s)
- Angeles Vinuesa
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carlos Pomilio
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Amal Gregosa
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Melisa Bentivegna
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jessica Presa
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Melina Bellotto
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Flavia Saravia
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Beauquis
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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29
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Discovery of potent glycogen synthase kinase 3/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer’s disease. Bioorg Med Chem 2021; 30:115940. [DOI: 10.1016/j.bmc.2020.115940] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 12/02/2020] [Accepted: 12/06/2020] [Indexed: 01/02/2023]
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30
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Is There Justification to Treat Neurodegenerative Disorders by Repurposing Drugs? The Case of Alzheimer's Disease, Lithium, and Autophagy. Int J Mol Sci 2020; 22:ijms22010189. [PMID: 33375448 PMCID: PMC7795249 DOI: 10.3390/ijms22010189] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/16/2020] [Accepted: 12/23/2020] [Indexed: 12/11/2022] Open
Abstract
Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug's neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium's neuroprotective properties rely on its modulation of homeostatic mechanisms such as inflammation, mitochondrial function, oxidative stress, autophagy, and apoptosis. This myriad of intracellular responses are, possibly, consequences of the drug's inhibition of the enzymes inositol-monophosphatase (IMPase) and glycogen-synthase-kinase (GSK)-3. Here we review lithium's neurobiological properties as evidenced by its neurotrophic and neuroprotective properties, as well as translational studies in cells in culture, in animal models of Alzheimer's disease (AD) and in patients, discussing the rationale for the drug's use in the treatment of AD.
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31
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Toniolo S, Sen A, Husain M. Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer's Disease. Int J Mol Sci 2020; 21:E9318. [PMID: 33297460 PMCID: PMC7730926 DOI: 10.3390/ijms21239318] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/30/2020] [Accepted: 12/05/2020] [Indexed: 12/12/2022] Open
Abstract
People with Alzheimer's disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation of toxic proteins, and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. Several neurotransmitters participate in the initial hyperexcitable state, with increased synaptic glutamatergic tone and decreased GABAergic inhibition. These changes appear to activate excitotoxic pathways and, ultimately, cause reduced long-term potentiation, increased long-term depression, and increased GABAergic inhibitory remodelling at the network level. Brain hyperexcitability has therefore been identified as a potential target for therapeutic interventions aimed at enhancing cognition, and, possibly, disease modification in the longer term. Clinical trials are ongoing to evaluate the potential efficacy in targeting hyperexcitability in AD, with levetiracetam showing some encouraging effects. Newer compounds and techniques, such as gene editing via viral vectors or brain stimulation, also show promise. Diagnostic challenges include identifying best biomarkers for measuring sub-clinical epileptiform discharges. Determining the timing of any intervention is critical and future trials will need to carefully stratify participants with respect to the phase of disease pathology.
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Affiliation(s)
- Sofia Toniolo
- Cognitive Neurology Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK;
- Wellcome Trust Centre for Integrative Neuroimaging, Department of Experimental Psychology, University of Oxford, Oxford OX2 6AE, UK
| | - Arjune Sen
- Oxford Epilepsy Research Group, Nuffield Department Clinical Neurosciences, John Radcliffe Hospital, Oxford OX3 9DU, UK;
| | - Masud Husain
- Cognitive Neurology Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK;
- Wellcome Trust Centre for Integrative Neuroimaging, Department of Experimental Psychology, University of Oxford, Oxford OX2 6AE, UK
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32
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Jiang X, Zhou J, Wang Y, Chen L, Duan Y, Huang J, Liu C, Chen Y, Liu W, Sun H, Feng F, Qu W. Rational design and biological evaluation of a new class of thiazolopyridyl tetrahydroacridines as cholinesterase and GSK-3 dual inhibitors for Alzheimer’s disease. Eur J Med Chem 2020; 207:112751. [DOI: 10.1016/j.ejmech.2020.112751] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/06/2020] [Accepted: 08/09/2020] [Indexed: 12/28/2022]
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33
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Vignaux P, Minerali E, Foil DH, Puhl AC, Ekins S. Machine Learning for Discovery of GSK3β Inhibitors. ACS OMEGA 2020; 5:26551-26561. [PMID: 33110983 PMCID: PMC7581251 DOI: 10.1021/acsomega.0c03302] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/25/2020] [Indexed: 05/08/2023]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia, affecting approximately 35 million people worldwide. The current treatment options for people with AD consist of drugs designed to slow the rate of decline in memory and cognition, but these treatments are not curative, and patients eventually suffer complete cognitive injury. With the substantial amounts of published data on targets for this disease, we proposed that machine learning software could be used to find novel small-molecule treatments that can supplement the AD drugs currently on the market. In order to do this, we used publicly available data in ChEMBL to build and validate Bayesian machine learning models for AD target proteins. The first AD target that we have addressed with this method is the serine-threonine kinase glycogen synthase kinase 3 beta (GSK3β), which is a proline-directed serine-threonine kinase that phosphorylates the microtubule-stabilizing protein tau. This phosphorylation prompts tau to dissociate from the microtubule and form insoluble oligomers called paired helical filaments, which are one of the components of the neurofibrillary tangles found in AD brains. Using our Bayesian machine learning model for GSK3β consisting of 2368 molecules, this model produced a five-fold cross validation ROC of 0.905. This model was also used for virtual screening of large libraries of FDA-approved drugs and clinical candidates. Subsequent testing of selected compounds revealed a selective small-molecule inhibitor, ruboxistaurin, with activity against GSK3β (avg IC50 = 97.3 nM) and GSK3α (IC50 = 695.9 nM). Several other structurally diverse inhibitors were also identified. We are now applying this machine learning approach to additional AD targets to identify approved drugs or clinical trial candidates that can be repurposed as AD therapeutics. This represents a viable approach to accelerate drug discovery and do so at a fraction of the cost of traditional high throughput screening.
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Affiliation(s)
- Patricia
A. Vignaux
- Collaborations Pharmaceuticals,
Inc., 840 Main Campus
Drive, Lab 3510, Raleigh, North Carolina 27606, United States
| | - Eni Minerali
- Collaborations Pharmaceuticals,
Inc., 840 Main Campus
Drive, Lab 3510, Raleigh, North Carolina 27606, United States
| | - Daniel H. Foil
- Collaborations Pharmaceuticals,
Inc., 840 Main Campus
Drive, Lab 3510, Raleigh, North Carolina 27606, United States
| | - Ana C. Puhl
- Collaborations Pharmaceuticals,
Inc., 840 Main Campus
Drive, Lab 3510, Raleigh, North Carolina 27606, United States
| | - Sean Ekins
- Collaborations Pharmaceuticals,
Inc., 840 Main Campus
Drive, Lab 3510, Raleigh, North Carolina 27606, United States
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34
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Jankowska A, Wesołowska A, Pawłowski M, Chłoń-Rzepa G. Multifunctional Ligands Targeting Phosphodiesterase as the Future Strategy for the Symptomatic and Disease-Modifying Treatment of Alzheimer’s Disease. Curr Med Chem 2020; 27:5351-5373. [DOI: 10.2174/0929867326666190620095623] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 04/30/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023]
Abstract
Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive
impairments such as memory loss, decline in language skills, and disorientation that affects
over 46 million people worldwide. Patients with AD also suffer from behavioral and psychological
symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently
available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile
plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia.
A large body of evidence indicates that impaired signaling pathways of cyclic-3′,5′-
Adenosine Monophosphate (cAMP) and cyclic-3′,5′-guanosine Monophosphate (cGMP) may contribute
to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors,
commonly known as cAMP and/or cGMP modulators, were found to be involved in the phosphorylation
of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood,
and emotion processing. The purpose of this review was to update the most recent reports on the
development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic
and disease-modifying therapy of AD. This review collected the chemical structures of representative
multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies,
and current opinions regarding the potential utility of these compounds for the comprehensive
therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds
were calculated and discussed.
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Affiliation(s)
- Agnieszka Jankowska
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Anna Wesołowska
- Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Maciej Pawłowski
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Grażyna Chłoń-Rzepa
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
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Burdick KE, Millett CE, Russo M, Alda M, Alliey-Rodriguez N, Anand A, Balaraman Y, Berrettini W, Bertram H, Calabrese JR, Calkin C, Conroy C, Coryell W, DeModena A, Feeder S, Fisher C, Frazier N, Frye M, Gao K, Garnham J, Gershon ES, Glazer K, Goes FS, Goto T, Harrington GJ, Jakobsen P, Kamali M, Kelly M, Leckband S, Løberg EM, Lohoff FW, Maihofer AX, McCarthy MJ, McInnis M, Morken G, Nievergelt CM, Nurnberger J, Oedegaard KJ, Ortiz A, Ritchey M, Ryan K, Schinagle M, Schwebel C, Shaw M, Shilling P, Slaney C, Stapp E, Tarwater B, Zandi P, Kelsoe JR. The association between lithium use and neurocognitive performance in patients with bipolar disorder. Neuropsychopharmacology 2020; 45:1743-1749. [PMID: 32349118 PMCID: PMC7419515 DOI: 10.1038/s41386-020-0683-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 03/24/2020] [Accepted: 04/17/2020] [Indexed: 01/21/2023]
Abstract
Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1-5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.
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Affiliation(s)
- Katherine E. Burdick
- grid.62560.370000 0004 0378 8294Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA USA ,grid.38142.3c000000041936754XDepartment of Psychiatry, Harvard Medical School, Boston, MA USA ,James J Peters Veteran Administration (VA) Hospital, Bronx, NY USA
| | - Caitlin E. Millett
- grid.62560.370000 0004 0378 8294Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA USA ,grid.38142.3c000000041936754XDepartment of Psychiatry, Harvard Medical School, Boston, MA USA
| | - Manuela Russo
- grid.13097.3c0000 0001 2322 6764Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, UK
| | - Martin Alda
- grid.55602.340000 0004 1936 8200Department of Psychiatry, Dalhousie University Halifax, Halifax, NS B3H 2E2 Canada
| | | | - Amit Anand
- grid.411377.70000 0001 0790 959XIndiana University, Bloomington, IN USA
| | - Yokesh Balaraman
- grid.411377.70000 0001 0790 959XIndiana University, Bloomington, IN USA
| | - Wade Berrettini
- grid.25879.310000 0004 1936 8972Center for Neurobiology and Behavior, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA
| | - Holli Bertram
- grid.214458.e0000000086837370University of Michigan, Ann Arbor, MI USA
| | - Joseph R. Calabrese
- grid.67105.350000 0001 2164 3847Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106 USA
| | - Cynthia Calkin
- grid.55602.340000 0004 1936 8200Department of Psychiatry, Dalhousie University Halifax, Halifax, NS B3H 2E2 Canada
| | - Carla Conroy
- grid.67105.350000 0001 2164 3847Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106 USA
| | - William Coryell
- grid.214572.70000 0004 1936 8294University of Iowa, Iowa City, IA USA
| | - Anna DeModena
- grid.266100.30000 0001 2107 4242University of California San Diego, San Diego, CA USA
| | - Scott Feeder
- grid.66875.3a0000 0004 0459 167XMayo Clinic, Rochester, MN USA
| | - Carrie Fisher
- grid.411377.70000 0001 0790 959XIndiana University, Bloomington, IN USA
| | - Nicole Frazier
- grid.214458.e0000000086837370University of Michigan, Ann Arbor, MI USA
| | - Mark Frye
- grid.66875.3a0000 0004 0459 167XMayo Clinic, Rochester, MN USA
| | - Keming Gao
- grid.67105.350000 0001 2164 3847Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106 USA
| | - Julie Garnham
- grid.55602.340000 0004 1936 8200Department of Psychiatry, Dalhousie University Halifax, Halifax, NS B3H 2E2 Canada
| | - Elliot S. Gershon
- grid.170205.10000 0004 1936 7822University of Chicago, Chicago, IL 60637 USA
| | - Kara Glazer
- grid.21107.350000 0001 2171 9311Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD USA
| | - Fernando S. Goes
- grid.21107.350000 0001 2171 9311Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD USA
| | - Toyomi Goto
- grid.67105.350000 0001 2164 3847Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106 USA
| | | | - Petter Jakobsen
- grid.7914.b0000 0004 1936 7443NORMENT, Division of Psychiatry, Haukeland University Hospital and Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Masoud Kamali
- grid.214458.e0000000086837370University of Michigan, Ann Arbor, MI USA
| | - Marisa Kelly
- grid.214458.e0000000086837370University of Michigan, Ann Arbor, MI USA
| | - Susan Leckband
- grid.266100.30000 0001 2107 4242University of California San Diego, San Diego, CA USA
| | - Else Marie Løberg
- grid.7914.b0000 0004 1936 7443NORMENT, Division of Psychiatry, Haukeland University Hospital and Department of Clinical Medicine, University of Bergen, Bergen, Norway ,grid.7914.b0000 0004 1936 7443Department of Addiction Medicine, Haukeland University Hospital, University of Bergen, Bergen, Norway ,grid.7914.b0000 0004 1936 7443Department of Clinical Psychology, University of Bergen, Bergen, Norway
| | - Falk W. Lohoff
- grid.420085.b0000 0004 0481 4802National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD USA
| | - Adam X. Maihofer
- grid.266100.30000 0001 2107 4242University of California San Diego, San Diego, CA USA
| | - Michael J. McCarthy
- grid.266100.30000 0001 2107 4242University of California San Diego, San Diego, CA USA
| | - Melvin McInnis
- grid.214458.e0000000086837370University of Michigan, Ann Arbor, MI USA
| | - Gunnar Morken
- grid.412835.90000 0004 0627 2891Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway
| | | | - John Nurnberger
- grid.411377.70000 0001 0790 959XIndiana University, Bloomington, IN USA
| | - Ketil J. Oedegaard
- grid.7914.b0000 0004 1936 7443NORMENT, Division of Psychiatry, Haukeland University Hospital and Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Abigail Ortiz
- grid.17063.330000 0001 2157 2938Centre for Addiction and Mental Health, University of Toronto, Toronto, ON Canada
| | - Megan Ritchey
- grid.21107.350000 0001 2171 9311Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD USA
| | - Kelly Ryan
- grid.214458.e0000000086837370University of Michigan, Ann Arbor, MI USA
| | - Martha Schinagle
- grid.67105.350000 0001 2164 3847Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106 USA
| | - Candice Schwebel
- grid.25879.310000 0004 1936 8972Center for Neurobiology and Behavior, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA
| | - Martha Shaw
- grid.214572.70000 0004 1936 8294University of Iowa, Iowa City, IA USA
| | - Paul Shilling
- grid.266100.30000 0001 2107 4242University of California San Diego, San Diego, CA USA
| | - Claire Slaney
- grid.55602.340000 0004 1936 8200Department of Psychiatry, Dalhousie University Halifax, Halifax, NS B3H 2E2 Canada
| | - Emma Stapp
- grid.21107.350000 0001 2171 9311Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD USA
| | - Bruce Tarwater
- grid.214572.70000 0004 1936 8294University of Iowa, Iowa City, IA USA
| | - Peter Zandi
- grid.21107.350000 0001 2171 9311Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD USA
| | - John R. Kelsoe
- grid.266100.30000 0001 2107 4242University of California San Diego, San Diego, CA USA
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36
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Safar MM, Shahin NN, Mohamed AF, Abdelkader NF. Suppression of BACE1 and amyloidogenic/RAGE axis by sitagliptin ameliorates PTZ kindling-induced cognitive deficits in rats. Chem Biol Interact 2020; 328:109144. [PMID: 32653415 DOI: 10.1016/j.cbi.2020.109144] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 12/22/2022]
Abstract
The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and β-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3β (GSK-3β). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both β-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3β/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.
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Affiliation(s)
- Marwa M Safar
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Nancy N Shahin
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Ahmed F Mohamed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Noha F Abdelkader
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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37
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Fagiani F, Lanni C, Racchi M, Govoni S. Targeting dementias through cancer kinases inhibition. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2020; 6:e12044. [PMID: 32671184 PMCID: PMC7341824 DOI: 10.1002/trc2.12044] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022]
Abstract
The failures in Alzheimer's disease (AD) therapy strongly suggest the importance of reconsidering the research strategies analyzing other mechanisms that may take place in AD as well as, in general, in other neurodegenerative dementias. Taking into account that in AD a variety of defects result in neurotransmitter activity and signaling efficiency imbalance, neuronal cell degeneration and defects in damage/repair systems, aberrant and abortive cell cycle, glial dysfunction, and neuroinflammation, a target may be represented by the intracellular signaling machinery provided by the kinome. In particular, based on the observations of a relationship between cancer and AD, we focused on cancer kinases for targeting neurodegeneration, highlighting the importance of targeting the intracellular pathways at the intersection between cell metabolism control/duplication, the inhibition of which may stop a progression in neurodegeneration.
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Affiliation(s)
- Francesca Fagiani
- Department of Drug Sciences (Pharmacology Section)University of PaviaPaviaItaly
- Scuola Universitaria Superiore IUSS PaviaPaviaItaly
| | - Cristina Lanni
- Department of Drug Sciences (Pharmacology Section)University of PaviaPaviaItaly
| | - Marco Racchi
- Department of Drug Sciences (Pharmacology Section)University of PaviaPaviaItaly
| | - Stefano Govoni
- Department of Drug Sciences (Pharmacology Section)University of PaviaPaviaItaly
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38
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Unravelling the Role of Glycogen Synthase Kinase-3 in Alzheimer's Disease-Related Epileptic Seizures. Int J Mol Sci 2020; 21:ijms21103676. [PMID: 32456185 PMCID: PMC7279454 DOI: 10.3390/ijms21103676] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 12/21/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common form of dementia. An increasing body of evidence describes an elevated incidence of epilepsy in patients with AD, and many transgenic animal models of AD also exhibit seizures and susceptibility to epilepsy. However, the biological mechanisms that underlie the occurrence of seizure or increased susceptibility to seizures in AD is unknown. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates various cellular signaling pathways, and plays a crucial role in the pathogenesis of AD. It has been suggested that GSK-3 might be a key factor that drives epileptogenesis in AD by interacting with the pathological hallmarks of AD, amyloid precursor protein (APP) and tau. Furthermore, seizures may also contribute to the progression of AD through GSK-3. In this way, GSK-3 might be involved in initiating a vicious cycle between AD and seizures. This review aims to summarise the possible role of GSK-3 in the link between AD and seizures. Understanding the role of GSK-3 in AD-associated seizures and epilepsy may help researchers develop new therapeutic approach that can manage seizure and epilepsy in AD patients as well as decelerate the progression of AD.
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39
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McCamphill PK, Stoppel LJ, Senter RK, Lewis MC, Heynen AJ, Stoppel DC, Sridhar V, Collins KA, Shi X, Pan JQ, Madison J, Cottrell JR, Huber KM, Scolnick EM, Holson EB, Wagner FF, Bear MF. Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome. Sci Transl Med 2020; 12:eaam8572. [PMID: 32434848 PMCID: PMC8095719 DOI: 10.1126/scitranslmed.aam8572] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 07/15/2019] [Accepted: 01/11/2020] [Indexed: 01/06/2023]
Abstract
Fragile X syndrome is caused by FMR1 gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the Fmr1-/y mouse model of fragile X syndrome indicate that aberrant cerebral protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) signaling contributes to disease pathogenesis, but clinical trials using mGluR5 inhibitors were not successful. Animal studies suggested that treatment with lithium might be an alternative approach. Targets of lithium include paralogs of glycogen synthase kinase 3 (GSK3), and nonselective small-molecule inhibitors of these enzymes improved disease phenotypes in a fragile X syndrome mouse model. However, the potential therapeutic use of GSK3 inhibitors has been hampered by toxicity arising from inhibition of both α and β paralogs. Recently, we developed GSK3 inhibitors with sufficient paralog selectivity to avoid a known toxic consequence of dual inhibition, that is, increased β-catenin stabilization. We show here that inhibition of GSK3α, but not GSK3β, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in Fmr1-/y mice. Although inhibiting either paralog prevented induction of NMDA receptor-dependent long-term depression (LTD) in the hippocampus, only inhibition of GSK3α impaired mGluR5-dependent and protein synthesis-dependent LTD. Inhibition of GSK3α additionally corrected deficits in learning and memory in Fmr1-/y mice; unlike mGluR5 inhibitors, there was no evidence of tachyphylaxis or enhanced psychotomimetic-induced hyperlocomotion. GSK3α selective inhibitors may have potential as a therapeutic approach for treating fragile X syndrome.
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Affiliation(s)
- Patrick K McCamphill
- Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Laura J Stoppel
- Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Rebecca K Senter
- Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Michael C Lewis
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Arnold J Heynen
- Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - David C Stoppel
- Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Vinay Sridhar
- University of Texas Southwestern Medical Center, Department of Neuroscience, Dallas, TX 75390, USA
| | - Katie A Collins
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Xi Shi
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jen Q Pan
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jon Madison
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jeffrey R Cottrell
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Kimberly M Huber
- University of Texas Southwestern Medical Center, Department of Neuroscience, Dallas, TX 75390, USA
| | - Edward M Scolnick
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Edward B Holson
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Florence F Wagner
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Mark F Bear
- Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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40
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Mechanisms of Electroacupuncture on Alzheimer’s Disease: A Review of Animal Studies. Chin J Integr Med 2020; 26:473-480. [DOI: 10.1007/s11655-020-3092-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2019] [Indexed: 12/22/2022]
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41
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Haghaei H, Soltani S, Aref Hosseini S, Rashidi MR, Karima S. Boswellic Acids as Promising Leads in Drug Development against Alzheimer’s Disease. PHARMACEUTICAL SCIENCES 2020. [DOI: 10.34172/ps.2020.25] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Biological activity of Boswellia extract (BE) has been attributed to its main active ingredients; i.e. Boswellic acids (BAs). BE/BAs possess a promising therapeutic potential in neurodegenerative disorders; including Alzheimer's disease (AD). The multifactorial nature of AD pathophysiology necessitates the development of the disease-modifying agents (DMA). Recent multi-targeting approaches for the DMAs development have brought more attention to the plant-derived compounds regarding their better human compatibility because of their biologic origin. This review addresses the current knowledge on the anti-AD activity of BE/BAs based on the available in silico, in vitro, in vivo studies and clinical trials. The contribution of BE/BAs in inflammatory pathways, Tau and β-amyloid proteins, microtubule functions, oxidative stress, cholinesterase and diabetes/insulin pathways involved in AD have been discussed. BAs efficacy in different AD-related pathways has been confirmed in vitro and in vivo. They can be considered as valuable scaffold/lead compounds for multi-targeted DMAs in anti-AD drug discovery and development.
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Affiliation(s)
- Hossein Haghaei
- Nutrition and food Sciences Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somaieh Soltani
- Drug Applied Research Center and Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Reza Rashidi
- Drug Applied Research Center and Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Pharmaceutical Nanotechnology and Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Karima
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
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42
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Huichalaf CH, Al-Ramahi I, Park KW, Grunke SD, Lu N, de Haro M, El-Zein K, Gallego-Flores T, Perez AM, Jung SY, Botas J, Zoghbi HY, Jankowsky JL. Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease. Hum Mol Genet 2020; 28:2014-2029. [PMID: 30753434 DOI: 10.1093/hmg/ddz034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 01/07/2019] [Accepted: 02/01/2019] [Indexed: 12/12/2022] Open
Abstract
An early hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ), inspiring numerous therapeutic strategies targeting this peptide. An alternative approach is to destabilize the amyloid beta precursor protein (APP) from which Aβ is derived. We interrogated innate pathways governing APP stability using a siRNA screen for modifiers whose own reduction diminished APP in human cell lines and transgenic Drosophila. As proof of principle, we validated PKCβ-a known modifier identified by the screen-in an APP transgenic mouse model. PKCβ was genetically targeted using a novel adeno-associated virus shuttle vector to deliver microRNA-adapted shRNA via intracranial injection. In vivo reduction of PKCβ initially diminished APP and delayed plaque formation. Despite persistent PKCβ suppression, the effect on APP and amyloid diminished over time. Our study advances this approach for mining druggable modifiers of disease-associated proteins, while cautioning that prolonged in vivo validation may be needed to reveal emergent limitations on efficacy.
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Affiliation(s)
| | - Ismael Al-Ramahi
- Department of Molecular and Human Genetics.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | | | | | - Nan Lu
- Department of Molecular and Human Genetics.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Maria de Haro
- Department of Molecular and Human Genetics.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Karla El-Zein
- Department of Molecular and Human Genetics.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Tatiana Gallego-Flores
- Department of Molecular and Human Genetics.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Alma M Perez
- Department of Molecular and Human Genetics.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | | | - Juan Botas
- Department of Molecular and Human Genetics.,Department of Molecular and Cellular Biology.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Huda Y Zoghbi
- Department of Neuroscience.,Department of Molecular and Human Genetics.,Department of Pediatrics.,Department of Neurology.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.,Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, USA
| | - Joanna L Jankowsky
- Department of Neuroscience.,Department of Molecular and Cellular Biology.,Department of Neurology.,Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
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43
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Xiang J, Cao K, Dong YT, Xu Y, Li Y, Song H, Zeng XX, Ran LY, Hong W, Guan ZZ. Lithium chloride reduced the level of oxidative stress in brains and serums of APP/PS1 double transgenic mice via the regulation of GSK3β/Nrf2/HO-1 pathway. Int J Neurosci 2019; 130:564-573. [DOI: 10.1080/00207454.2019.1688808] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Jie Xiang
- Department of Pathology at Guizhou Medical University and Pathological Department at the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Kun Cao
- Department of Pathology at Guizhou Medical University and Pathological Department at the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Yang-Ting Dong
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Medical Molecular Biology, Guiyang, Guizhou, People’s Republic of China
| | - Yi Xu
- Department of Pathology at Guizhou Medical University and Pathological Department at the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Yi Li
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Medical Molecular Biology, Guiyang, Guizhou, People’s Republic of China
| | - Hui Song
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Medical Molecular Biology, Guiyang, Guizhou, People’s Republic of China
| | - Xiao-Xiao Zeng
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Medical Molecular Biology, Guiyang, Guizhou, People’s Republic of China
| | - Long-Yan Ran
- Department of Pathology at Guizhou Medical University and Pathological Department at the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Wei Hong
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Medical Molecular Biology, Guiyang, Guizhou, People’s Republic of China
| | - Zhi-Zhong Guan
- Department of Pathology at Guizhou Medical University and Pathological Department at the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Key Laboratory of Medical Molecular Biology, Guiyang, Guizhou, People’s Republic of China
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The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodents. Sci Rep 2019; 9:18045. [PMID: 31792284 PMCID: PMC6888874 DOI: 10.1038/s41598-019-54557-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 11/15/2019] [Indexed: 12/20/2022] Open
Abstract
Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer’s disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25–35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25–35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
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Cao Q, Meng T, Man J, Peng D, Chen H, Xiang Q, Su Z, Zhang Q, Huang Y. aFGF Promotes Neurite Growth by Regulating GSK3β-CRMP2 Signaling Pathway in Cortical Neurons Damaged by Amyloid-β. J Alzheimers Dis 2019; 72:97-109. [DOI: 10.3233/jad-190458] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Qin Cao
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Tian Meng
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jianhui Man
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Dong Peng
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Hongxia Chen
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
- Cell Biology Department and National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China
| | - Qi Xiang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
- Cell Biology Department and National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China
| | - Zhijian Su
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
- Cell Biology Department and National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China
| | - Qihao Zhang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
- Cell Biology Department and National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China
| | - Yadong Huang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
- Cell Biology Department and National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China
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Hoffman JL, Faccidomo S, Kim M, Taylor SM, Agoglia AE, May AM, Smith EN, Wong LC, Hodge CW. Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2019; 148:169-230. [PMID: 31733664 PMCID: PMC6939615 DOI: 10.1016/bs.irn.2019.10.017] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.
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Affiliation(s)
- Jessica L Hoffman
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Sara Faccidomo
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Michelle Kim
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Seth M Taylor
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Abigail E Agoglia
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ashley M May
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Evan N Smith
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - L C Wong
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Clyde W Hodge
- Department of Psychiatry, Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
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Pacholko AG, Wotton CA, Bekar LK. Poor Diet, Stress, and Inactivity Converge to Form a "Perfect Storm" That Drives Alzheimer's Disease Pathogenesis. NEURODEGENER DIS 2019; 19:60-77. [PMID: 31600762 DOI: 10.1159/000503451] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/17/2019] [Indexed: 11/19/2022] Open
Abstract
North American incidence of Alzheimer's disease (AD) is expected to more than double over the coming generation. Although genetic factors surrounding the production and clearance of amyloid-β and phosphorylated tau proteins are known to be responsible for a subset of early-onset AD cases, they do not explain the pathogenesis of the far more prevalent sporadic late-onset variant of the disease. It is thus likely that lifestyle and environmental factors contribute to neurodegenerative processes implicated in the pathogenesis of AD. Herein, we review evidence that (1) excess sucrose consumption induces AD-associated liver pathologies and brain insulin resistance, (2) chronic stress overdrives activity of locus coeruleus neurons, leading to loss of function (a common event in neurodegeneration), (3) high-sugar diets and stress promote the loss of neuroprotective sex hormones in men and women, and (4) Western dietary trends set the stage for a lithium-deficient state. We propose that these factors may intersect as part of a "perfect storm" to contribute to the widespread prevalence of neurodegeneration and AD. In addition, we put forth the argument that exercise and supplementation with trace lithium can counteract many of the deleterious consequences associated with excessive caloric intake and perpetual stress. We conclude that lifestyle and environmental factors likely contribute to AD pathogenesis and that simple lifestyle and dietary changes can help counteract their effects.
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Affiliation(s)
- Anthony G Pacholko
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Caitlin A Wotton
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Lane K Bekar
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada,
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Barrett T, Marchalant Y, Park KH. p35 Hemizygous Deletion in 5xFAD Mice Increases Aβ Plaque Load in Males but Not in Females. Neuroscience 2019; 417:45-56. [DOI: 10.1016/j.neuroscience.2019.08.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 07/25/2019] [Accepted: 08/08/2019] [Indexed: 12/29/2022]
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Norwitz NG, Mota AS, Norwitz SG, Clarke K. Multi-Loop Model of Alzheimer Disease: An Integrated Perspective on the Wnt/GSK3β, α-Synuclein, and Type 3 Diabetes Hypotheses. Front Aging Neurosci 2019; 11:184. [PMID: 31417394 PMCID: PMC6685392 DOI: 10.3389/fnagi.2019.00184] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 07/05/2019] [Indexed: 12/12/2022] Open
Abstract
As the prevalence of Alzheimer disease (AD) continues to rise unabated, new models have been put forth to improve our understanding of this devastating condition. Although individual models may have their merits, integrated models may prove more valuable. Indeed, the reliable failures of monotherapies for AD, and the ensuing surrender of major drug companies, suggests that an integrated perspective may be necessary if we are to invent multifaceted treatments that could ultimately prove more successful. In this review article, we discuss the Wnt/Glycogen Synthase Kinase 3β (GSK3β), α-synuclein, and type 3 diabetes hypotheses of AD, and their deep interconnection, in order to foster the integrative thinking that may be required to reach a solution for the coming neurological epidemic.
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Affiliation(s)
- Nicholas G Norwitz
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Adrian Soto Mota
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Sam G Norwitz
- Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
| | - Kieran Clarke
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
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Ali AA, Ahmed HI, Khaleel SA, Abu-Elfotuh K. Vinpocetine mitigates aluminum-induced cognitive impairment in socially isolated rats. Physiol Behav 2019; 208:112571. [PMID: 31175888 DOI: 10.1016/j.physbeh.2019.112571] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 05/11/2019] [Accepted: 06/04/2019] [Indexed: 12/18/2022]
Abstract
Several reports have highlighted the role of vinpocetine in Alzheimer's disease (AD). However, the role of vinpocetine in AD under social isolation conditions has not yet been elucidated. Henceforth, this study aimed to investigate the potential neuroprotective effect of vinpocetine in aluminum-induced AD model associated with social isolation. Social isolation increased the escape latency in Morris water maze (MWM) test, elevated the immobility score and decreased swimming score in forced swimming test (FST) in aluminum treated rats. However, vinpocetine enhanced acquisition in MWM test and exerted anti-depressive effect in FST. The histopathological examination showed marked deterioration in the cerebral cortex and hippocampus of AD isolated rats, while vinpocetine revealed overt improvement. In addition, the levels of amyloid-β protein (Aβ), phosphorylated-tau (Ser396), malondialdehyde (MDA), interleukin 1-beta (IL-1β), tumor necrosis alpha (TNFα), p- Glycogen synthase kinase-3β (p-GSK3β) (Tyr216), and β-secretase (BACE1) gene expression were increased in socially isolated aluminum treated rats, yet, vinpocetine treatment reversed these deteriorating effects. Hence, this study provides profound insights into the role of vinpocetine in AD particularly in the conditions of social isolation. The effects of vinpocetine might be attributed not only to its antioxidant and anti-inflammatory properties, but also to its suppressing effect on GSK3β activity and its downstream BACE1.
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Affiliation(s)
- Azza A Ali
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Hebatalla I Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt; Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University for sustainable development, Cairo, Egypt
| | - Sahar A Khaleel
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt; Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
| | - Karema Abu-Elfotuh
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
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