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Dunacka J, Świątek G, Wrona D. High Behavioral Reactivity to Novelty as a Susceptibility Factor for Memory and Anxiety Disorders in Streptozotocin-Induced Neuroinflammation as a Rat Model of Alzheimer's Disease. Int J Mol Sci 2024; 25:11562. [PMID: 39519114 PMCID: PMC11546707 DOI: 10.3390/ijms252111562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/18/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Individual differences in responsiveness to environmental factors, including stress reactivity and anxiety levels, which differ between high (HR) and low (LR) responders to novelty, might be risk factors for development of memory and anxiety disorders in sporadic Alzheimer's disease (sAD). In the present study, we investigated whether behavioral characteristics of the HR and LR rats, influence the progression of sAD (neuroinflammation, β-amyloid peptide, behavioral activity related to memory (Morris water maze) and anxiety (elevated plus maze, white and illuminated open field test) in streptozotocin (STZ)-induced neuroinflammation as a model of early pathophysiological alterations in sAD. Early (45 days) in disease progression, there was a more severe impairment of reference memory and higher levels of anxiety in HRs compared with LRs. Behavioral depression in HRs was associated with higher expression of β-amyloid deposits, particularly in the NAcS, and activation of microglia (CD68+ cells) in the hypothalamus, as opposed to less inflammation in the hippocampus, particularly in CA1, compared with LRs in late (90 days) sAD progression. Our findings suggest that rats with higher behavioral activity and increased responsivity to stressors show more rapid progression of disease and anxiety disorders compared with low responders to novelty in the STZ-induced sAD model.
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Affiliation(s)
| | | | - Danuta Wrona
- Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, 59 Wita Stwosza Str., 80-308 Gdansk, Poland; (J.D.); (G.Ś.)
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2
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Abdalla MMI. Insulin resistance as the molecular link between diabetes and Alzheimer's disease. World J Diabetes 2024; 15:1430-1447. [PMID: 39099819 PMCID: PMC11292327 DOI: 10.4239/wjd.v15.i7.1430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/08/2024] [Accepted: 05/06/2024] [Indexed: 07/08/2024] Open
Abstract
Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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3
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Satarker S, Gurram PC, Nassar A, Manandhar S, Vibhavari R, Yarlagadda DL, Mudgal J, Lewis S, Arora D, Nampoothiri M. Evaluating the Role of N-Acetyl-L-Tryptophan in the Aβ 1-42-Induced Neuroinflammation and Cognitive Decline in Alzheimer's Disease. Mol Neurobiol 2024; 61:4421-4440. [PMID: 38091207 PMCID: PMC11236887 DOI: 10.1007/s12035-023-03844-4] [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: 09/27/2023] [Accepted: 11/29/2023] [Indexed: 07/11/2024]
Abstract
Alzheimer's disease (AD), a neurodegenerative condition previously known to affect the older population, is also now seen in younger individuals. AD is often associated with cognitive decline and neuroinflammation elevation primarily due to amyloid β (Aβ) accumulation. Multiple pathological complications in AD call for therapies with a wide range of neuroprotection. Our study aims to evaluate the effect of N-acetyl-L-tryptophan (NAT) in ameliorating the cognitive decline and neuroinflammation induced by Aβ 1-42 oligomers and to determine the therapeutic concentration of NAT in the brain. We administered Aβ 1-42 oligomers in rats via intracerebroventricular (i.c.v.) injection to induce AD-like conditions. The NAT-treated animals lowered the cognitive decline in the Morris water maze characterized by shorter escape latency and increased path efficiency and platform entries. Interestingly, the hippocampus and frontal cortex showed downregulation of tumor necrosis factor, interleukin-6, and substance P levels. NAT treatment also reduced acetylcholinesterase activity and total and phosphorylated nuclear factor kappa B and Tau levels. Lastly, we observed upregulation of cAMP response element-binding protein 1 (CREB1) signaling. Surprisingly, our HPLC method was not sensitive enough to detect the therapeutic levels of NAT in the brain, possibly due to NAT concentrations being below the lowest limit of quantification of our validated method. To summarize, the administration of NAT significantly lowered cognitive decline, neuroinflammatory pathways, and Tau protein and triggered the upregulation of CREB1 signaling, suggesting its neuroprotective role in AD-like conditions.
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Affiliation(s)
- Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Prasada Chowdari Gurram
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Ajmal Nassar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Suman Manandhar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Rja Vibhavari
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Dani Lakshman Yarlagadda
- Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Shaila Lewis
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Devinder Arora
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
- School of Pharmacy and Medical Sciences, Griffith University, QLD, Gold Coast, 4222, Australia
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Pourhadi M, Zali H, Ghasemi R, Faizi M, Mojab F, Soufi Zomorrod M. Restoring Synaptic Function: How Intranasal Delivery of 3D-Cultured hUSSC Exosomes Improve Learning and Memory Deficits in Alzheimer's Disease. Mol Neurobiol 2024; 61:3724-3741. [PMID: 38010560 DOI: 10.1007/s12035-023-03733-w] [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: 04/29/2023] [Accepted: 10/20/2023] [Indexed: 11/29/2023]
Abstract
Memory problems are often the first signs of cognitive impairment related to Alzheimer's disease (AD), and stem cells and stem cell-derived exosomes (EXOs) have been studied for their therapeutic potential to improve the disease signs. While many studies have shown the anti-inflammatory and immunomodulatory effects of stem cells and exosomes on improving memory in different AD models, there is still insufficient data to determine how they modulate neural plasticity to enhance spatial memory and learning ability. Therefore, we conducted a study to investigate the effects of exosomes derived from 3D-cultured human Unrestricted Somatic Stem Cells (hUSSCs) on spatial memory and neuroplasticity markers in a sporadic rat model of AD. Using male Wistar rats induced by intracerebral ventricle injection of streptozotocin, we demonstrated that intranasal administration of hUSSC-derived exosomes could decrease Aβ accumulation and improve learning and memory in the Morris water maze test. We also observed an increase in the expression of pre-synaptic and post-synaptic molecules involved in neuronal plasticity, including NMDAR1, integrin β1, synaptophysin, pPKCα, and GAP-43, in the hippocampus. Our findings suggest that intranasal administration of exosomes can ameliorate spatial learning and memory deficits in rats, at least in part, by increasing the expression of neuroplasticity proteins. These results may encourage researchers to further investigate the molecular pathways involved in memory improvement after stem cell and exosome therapy, with the goal of increasing the efficacy and safety of exosome-based treatments for AD.
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Affiliation(s)
- Masoumeh Pourhadi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Rasoul Ghasemi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mehrdad Faizi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Faraz Mojab
- Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mina Soufi Zomorrod
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Moghazy HM, Abdelhaliem NG, Mohammed SA, Hassan A, Abdelrahman A. Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K/AKT/GSK-3β/TTBK1 pathway and decreasing Tau hyperphosphorylation in high-fat diet- streptozocin rat model. Pflugers Arch 2024; 476:779-795. [PMID: 38536493 PMCID: PMC11033245 DOI: 10.1007/s00424-024-02933-0] [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: 09/16/2023] [Revised: 02/13/2024] [Accepted: 02/22/2024] [Indexed: 04/05/2024]
Abstract
The American Diabetes Association guidelines (2021) confirmed the importance of raising public awareness of diabetes-induced cognitive impairment, highlighting the links between poor glycemic control and cognitive impairment. The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-β deposition, glycogen synthase kinase 3 beta (GSK3β), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K/AKT/GSK-3β/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10 weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200 μg/kg/day sc) or liraglutide (0.6 mg/kg/day sc) for 6 weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K/AKT expression while decreasing GSK-3β/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms.
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Affiliation(s)
- Hoda M Moghazy
- Department of Physiology, Faculty of Medicine, Sohag University, Sohag, 82524, Egypt
| | | | | | - Asmaa Hassan
- Department of Physiology, Faculty of Medicine, Sohag University, Sohag, 82524, Egypt
| | - Amany Abdelrahman
- Department of Physiology, Faculty of Medicine, Sohag University, Sohag, 82524, Egypt.
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Moustafa NA, El-Sayed MA, Abdallah SH, Hazem NM, Aidaros MA, Abdelmoety DA. Effect of Letrozole on hippocampal Let-7 microRNAs and their correlation with working memory and phosphorylated Tau protein in an Alzheimer's disease-like rat model. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2022. [DOI: 10.1186/s41983-022-00504-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Let-7 microRNAs (miRNAs) may contribute to neurodegeneration, including Alzheimer's disease (AD), but, they were not investigated in Streptozotocin (STZ)-induced AD. Letrozole increases the expression of Let-7 in cell lines, with conflicting evidence regarding its effects on memory. This study examined Let-7 miRNAs in STZ-induced AD, their correlation with memory and hyperphosphorylated Tau (p-Tau) and the effects of Letrozole on them.
Methods
Seven groups of adult Sprague Dawley rats were used: Negative control, Letrozole, Letrozole Vehicle, STZ (with AD induced by intracerebroventricular injection of STZ in artificial cerebrospinal fluid (aCSF)), CSF Control, STZ + Letrozole (STZ-L), and CSF + Letrozole Vehicle. Alternation percentage in T-maze was used as a measure of working memory. Let-7a, b and e and p-Tau levels in the hippocampus were estimated using quantitative real-time reverse transcription–polymerase chain reaction (qRT–PCR) and enzyme-linked immunosorbent assay (ELISA), respectively.
Results
Significant decreases in alternation percentage and increase in p-Tau concentration were found in the STZ, Letrozole and STZ-L groups. Expression levels of all studied microRNAs were significantly elevated in the Letrozole and the STZ-L groups, with no difference between the two, suggesting that this elevation might be linked to Letrozole administration. Negative correlations were found between alternation percentage and the levels of all studied microRNAs, while positive ones were found between p-Tau concentration and the levels of studied microRNAs.
Conclusions
This study shows changes in the expression of Let-7a, b and e miRNAs in association with Letrozole administration, and correlations between the expression of the studied Let-7 miRNAs and both the status of working memory and the hippocampal p-Tau levels. These findings might support the theory suggesting that Letrozole aggravates pre-existing lesions. They also add to the possibility of Let-7’s neurotoxicity.
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Effects of Minocycline on Cognitive Impairment, Hippocampal Inflammatory Response, and Hippocampal Alzheimer’s Related Proteins in Aged Rats after Propofol Anesthesia. DISEASE MARKERS 2022; 2022:4709019. [PMID: 35521638 PMCID: PMC9064516 DOI: 10.1155/2022/4709019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/03/2022] [Indexed: 11/26/2022]
Abstract
The aim of this study was to evaluate the effect of minocycline preadministration on cognitive dysfunction, hippocampal inflammatory response, and hippocampal senile dementia-related proteins induced by propofol anesthesia in aged rats. Sixty male SD rats, aged 20 months and weighing 340-410 g, were randomly divided into three groups: normal saline (NC) group, propofol group (prop), and minocycline (M) group. Prop group rats were injected intraperitoneally with 100 mg/kg propofol. The rats in group M were injected intraperitoneally with 50 mg/kg minocycline 30 minutes before injection of 100 mg/kg propofol, and the rest were the same as prop group. The rats in NC group were received intraperitoneal injection of the same amount of normal saline. The results indicated that compared with group C, the expressions of GSK-3β, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta were upregulated, the levels of TNF-α, IL-1β, and IL-6 were increased, the escape incubation period was prolonged, and the exploration time was shortened in prop group, while the expression of GSK-3β, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta in minocycline group was downregulated, the levels of TNF-α, IL-1β, and IL-6 were decreased, the escape incubation period was shortened, and the exploration time was shortened. In conclusion, preadministration of minocycline can improve cognitive impairment induced by propofol anesthesia in aged rats, and its mechanism of action may be related to minocycline inhibiting hippocampal inflammatory reaction and downregulating the expression of GSK-3β, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta proteins in hippocampus.
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Lin DT, Kao NJ, Cross TWL, Lee WJ, Lin SH. nEffects of ketogenic diet on cognitive functions of mice fed high-fat-high-cholesterol diet. J Nutr Biochem 2022; 104:108974. [DOI: 10.1016/j.jnutbio.2022.108974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 12/07/2021] [Accepted: 01/31/2022] [Indexed: 12/28/2022]
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Liu T, Li Y, Yang B, Wang H, Lu C, Chang AK, Huang X, Zhang X, Lu Z, Lu X, Gao B. Suppression of neuronal cholesterol biosynthesis impairs brain functions through insulin-like growth factor I-Akt signaling. Int J Biol Sci 2021; 17:3702-3716. [PMID: 34671194 PMCID: PMC8495388 DOI: 10.7150/ijbs.63512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/18/2021] [Indexed: 12/15/2022] Open
Abstract
Some relationship between abnormal cholesterol content and impairment of insulin/insulin-like growth factor I (IGF-1) signaling has been reported in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanism of this correlation remains unclear. It is known that 3-β hydroxycholesterol Δ 24 reductase (DHCR24) catalyzes the last step of cholesterol biosynthesis. To explore the function of cholesterol in the pathogenesis of AD, we depleted cellular cholesterol by targeting DHCR24 with siRNA (siDHCR24) or U18666A, an inhibitor of DHCR24, and studied the effect of the loss of cholesterol on the IGF-1-Akt signaling pathway in vitro and in vivo. Treatment with U18666A reduced the cellular cholesterol level and blocked the anti-apoptotic function of IGF-1 by impairing the formation of caveolae and the localization of IGF-1 receptor in caveolae of the PC12 cells. Downregulation of the DHCR24 expression induced by siRNA against DHCR24 also yielded similar results. Furthermore, the phosphorylation levels of IGF-1 receptor, insulin receptor substrate (IRS), Akt, and Bad in response to IGF-1 were all found to decrease in the U18666A-treated cells. Rats treated with U18666A via intracerebral injection also exhibited a significant decrease in the cholesterol level and impaired activities of IGF-1-related signaling proteins in the hippocampus region. A significant accumulation of amyloid β and a decrease in the expression of neuron-specific enolase (NSE) was also observed in rats with U18666A. Finally, the Morris water maze experiment revealed that U18666A-treated rats showed a significant cognitive impairment. Our findings provide new evidence strongly supporting that a reduction in cholesterol level can result in neural apoptosis via the impairment of the IGF-1-Akt survival signaling in the brain.
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Affiliation(s)
- Ting Liu
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China.,China Medical University-The Queen's University Belfast Joint College, China Medical University, Shenyang, 110122, China
| | - Yang Li
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Baoyu Yang
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Haozhen Wang
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Chen Lu
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Alan K Chang
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Xiuting Huang
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Xiujin Zhang
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Ziyin Lu
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Xiuli Lu
- The School of Life Science, Liaoning University, Chongshanzhong-lu No.66, Huanggu-qu, Shenyang 110036, China
| | - Bing Gao
- School of Basic Medical Sciences, Shenyang Medical College, Shenyang, 110034, China
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Jin J, Guo J, Cai H, Zhao C, Wang H, Liu Z, Ge ZM. M2-Like Microglia Polarization Attenuates Neuropathic Pain Associated with Alzheimer's Disease. J Alzheimers Dis 2021; 76:1255-1265. [PMID: 32280102 DOI: 10.3233/jad-200099] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Many Alzheimer's disease (AD) patients suffer from persistent neuropathic pain (NP), which is mediated, at least partially, but microglia. Nevertheless, the exact underlying mechanism is unknown. Moreover, a clinically translatable approach through modulating microglia for treating AD-associated NP is not available. Here, in a doxycycline-induced mouse model (rTg4510) for AD, we showed development of NP. We found that the total number of microglia in the CA3 region was not increased, but polarized to pro-inflammatory M1-like phenotype, with concomitant increases in production and secretion of pro-inflammatory cytokines. To examine whether this microglia polarization plays an essential role in the AD-associated NP, we generated an adeno-associated virus (AAV) serotype PHP.B (capable of crossing the blood-brain barrier) carrying shRNA for DNA methyltransferase 1 (DNMT1) under a microglia-specific TMEM119 promoter (AAV-pTMEM119-shDNMT1), which specifically targeted microglia and induced a M2-like polarization in vitro and in vivo in doxycycline-treated rTg4510 mice. Intravenous infusion of AAV-pTMEM119-shDNMT1 induced M2-polarization of microglia and attenuated both AD-associated behavior impairment but also NP in the doxycycline-treated rTg4510 mice. Thus, our data suggest that AD-associated NP may be treated through M2-polarization of microglia.
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Affiliation(s)
- Jing Jin
- Department of Neurology, the Second Hospital of Lanzhou University, Lanzhou, China
| | - Jia Guo
- Department of Neurology, the Second Hospital of Lanzhou University, Lanzhou, China
| | - Hongbin Cai
- Department of Neurology, the Second Hospital of Lanzhou University, Lanzhou, China
| | - Chongchong Zhao
- Department of Neurology, the Second Hospital of Lanzhou University, Lanzhou, China
| | - Huan Wang
- Department of Neurology, the Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhiyan Liu
- Department of Neurology, the Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhao-Ming Ge
- Department of Neurology, the Second Hospital of Lanzhou University, Lanzhou, China
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Elahi M, Motoi Y, Shimonaka S, Ishida Y, Hioki H, Takanashi M, Ishiguro K, Imai Y, Hattori N. High-fat diet-induced activation of SGK1 promotes Alzheimer's disease-associated tau pathology. Hum Mol Genet 2021; 30:1693-1710. [PMID: 33890983 PMCID: PMC8411983 DOI: 10.1093/hmg/ddab115] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/31/2021] [Accepted: 04/18/2021] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer’s disease (AD). However, the molecular links between T2DM and AD remain obscure. Here, we reported that serum-/glucocorticoid-regulated kinase 1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid–mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of AD cases. Our results suggest that SGK1 is a key modifier of tau pathology in AD, linking AD to corticosteroid effects and T2DM.
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Affiliation(s)
- Montasir Elahi
- Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate of Medicine, Tokyo, Japan
- Department of Neurology, Juntendo University Graduate of Medicine, Tokyo, Japan
- Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yumiko Motoi
- Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate of Medicine, Tokyo, Japan
- Department of Neurology, Juntendo University Graduate of Medicine, Tokyo, Japan
| | - Shotaro Shimonaka
- Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate of Medicine, Tokyo, Japan
| | - Yoko Ishida
- Department of Cell Biology and Neuroscience, Juntendo University Graduate of Medicine, Tokyo, Japan
| | - Hiroyuki Hioki
- Department of Cell Biology and Neuroscience, Juntendo University Graduate of Medicine, Tokyo, Japan
| | - Masashi Takanashi
- Department of Neurology, Juntendo University Graduate of Medicine, Tokyo, Japan
| | - Koichi Ishiguro
- Department of Neurology, Juntendo University Graduate of Medicine, Tokyo, Japan
| | - Yuzuru Imai
- Department of Neurology, Juntendo University Graduate of Medicine, Tokyo, Japan
- Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan
- To whom correspondence should be addressed. Tel: +81 368018332; Fax: +81 358000547;
| | - Nobutaka Hattori
- Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate of Medicine, Tokyo, Japan
- Department of Neurology, Juntendo University Graduate of Medicine, Tokyo, Japan
- Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan
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12
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Kadam M, Perveen S, Kushwah N, Prasad D, Panjwani U, Kumar B, Khan N. Elucidating the role of hypoxia/reoxygenation in hippocampus-dependent memory impairment: do SK channels play role? Exp Brain Res 2021; 239:1747-1763. [PMID: 33779792 DOI: 10.1007/s00221-021-06095-8] [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: 09/30/2020] [Accepted: 03/19/2021] [Indexed: 10/21/2022]
Abstract
Professionals and mountaineers often face the problem of reperfusion injury due to re-oxygenation, upon their return to sea-level after sojourn at high altitude. Small conductance calcium-activated potassium channels (SK channels) have a role in regulating hippocampal synaptic plasticity. However, the role of SK channels under hypoxia-reoxygenation (H/R) is unknown. The present study hypothesized that SK channels play a significant role in H/R induced cognitive dysfunction. Sprague-Dawley rats were exposed to simulated HH (25,000 ft) continuously for 7 days followed by reoxygenation periods 3, 6, 24, 48, 72 and 120 h. It was observed that H/R exposure caused impairment in spatial memory as indicated by increased latency (p < 0.001) and pathlength (p < 0.001). The SK1 channel expression increased upon HH exposure (102.89 ± 7.055), which abrogated upon reoxygenation. HH exposure results in an increase in SK2 (CA3, 297.67 ± 6.69) and SK3 (CA1, 246 ± 5.13) channels which continued to increase gradually upon reoxygenation. The number of pyknotic cells (24 ± 2.03) (p < 0.01) and the expression of caspase-3 increased with HH exposure, which continued in the reoxygenation group (177.795 ± 1.264). Similar pattern was observed in lipid peroxidation (p < 0.001), LDH activity (p < 0.001) and ROS production (p < 0.001). A positive correlation of memory, cell death and oxidative stress indicates that H/R exposure increases oxidative stress coupled with SK channel expression, which may play a role in H/R-induced cognitive decline and neurodegeneration.
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Affiliation(s)
- Manisha Kadam
- Neurobiology Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Developmental Organization (DRDO), Lucknow Road, Timarpur, Delhi, 110054, India
| | - Saba Perveen
- Neurobiology Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Developmental Organization (DRDO), Lucknow Road, Timarpur, Delhi, 110054, India
| | - Neetu Kushwah
- Neurobiology Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Developmental Organization (DRDO), Lucknow Road, Timarpur, Delhi, 110054, India
| | - Dipti Prasad
- Neurobiology Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Developmental Organization (DRDO), Lucknow Road, Timarpur, Delhi, 110054, India
| | - Usha Panjwani
- Neurobiology Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Developmental Organization (DRDO), Lucknow Road, Timarpur, Delhi, 110054, India
| | - Bhuvnesh Kumar
- Neurobiology Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Developmental Organization (DRDO), Lucknow Road, Timarpur, Delhi, 110054, India
| | - Nilofar Khan
- Neurobiology Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Developmental Organization (DRDO), Lucknow Road, Timarpur, Delhi, 110054, India.
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Parvin P, Parichehreh Y, Mehdi N, Zahra H. Effects of artemisinin and TSP-1-human endometrial-derived stem cells on a streptozocin-induced model of Alzheimer’s disease and diabetes in Wistar rats. Acta Neurobiol Exp (Wars) 2021. [DOI: 10.21307/ane-2021-013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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14
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Lam S, Bayraktar A, Zhang C, Turkez H, Nielsen J, Boren J, Shoaie S, Uhlen M, Mardinoglu A. A systems biology approach for studying neurodegenerative diseases. Drug Discov Today 2020; 25:1146-1159. [PMID: 32442631 DOI: 10.1016/j.drudis.2020.05.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 04/13/2020] [Accepted: 05/13/2020] [Indexed: 01/06/2023]
Abstract
Neurodegenerative diseases (NDDs), such as Alzheimer's (AD) and Parkinson's (PD), are among the leading causes of lost years of healthy life and exert a great strain on public healthcare systems. Despite being first described more than a century ago, no effective cure exists for AD or PD. Although extensively characterised at the molecular level, traditional neurodegeneration research remains marred by narrow-sense approaches surrounding amyloid β (Aβ), tau, and α-synuclein (α-syn). A systems biology approach enables the integration of multi-omics data and informs discovery of biomarkers, drug targets, and treatment strategies. Here, we present a comprehensive timeline of high-throughput data collection, and associated biotechnological advancements and computational analysis related to AD and PD. We hereby propose that a philosophical change in the definitions of AD and PD is now needed.
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Affiliation(s)
- Simon Lam
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK
| | - Abdulahad Bayraktar
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE-17121, Sweden
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, 25240, Turkey
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, SE-41296, Gothenburg, Sweden
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg, The Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, SE-413 45, Sweden
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE-17121, Sweden
| | - Mathias Uhlen
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE-17121, Sweden
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE-17121, Sweden.
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15
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Huang X, Huang K, Li Z, Bai D, Hao Y, Wu Q, Yi W, Xu N, Pan Y, Zhang L. Electroacupuncture improves cognitive deficits and insulin resistance in an OLETF rat model of Al/D-gal induced aging model via the PI3K/Akt signaling pathway. Brain Res 2020; 1740:146834. [PMID: 32304687 DOI: 10.1016/j.brainres.2020.146834] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/25/2020] [Accepted: 04/13/2020] [Indexed: 02/03/2023]
Abstract
To investigate the effect of electroacupuncture (EA) on cognitive function and insulin resistance (IR) in an Al/D-gal-induced aging model for Alzheimer's disease (AD) using Ostuka Long-Evans Tokushima Fatty (OLETF) rats. The Al/D-gal-OLETF rats for AD were randomly divided into the EA and non-EA groups. Cognitive function was assessed using the Morris water maze (MWM). The morphology of the hippocampal neurons was observed using hematoxylin & eosin (H&E) staining. Aβ and total Tau in the hippocampus and cerebrospinal fluid (CSF) were detected using western blotting (WB) and enzyme-linked immunosorbent assay (ELISA). Fasting blood glucose (FPG) was determined using the glucose oxidase method. Plasma fasting insulin (FINS), serum C-peptide (C-P), and CSF insulin were detected using ELISA. The expression of the genes and proteins in the PI3K signaling pathway was detected using quantitative real-time PCR and WB. After EA intervention, the hippocampal Aβ and total Tau protein levels, body weight, FPG, FINS, and C-P were significantly decreased. The MWM showed that the percentage of time in the target quadrant of the EA group was elevated in the probe test. The protein levels of p-IRS1, p-IRS2, IDE, and p-GSK3β were significantly increased, while p-PI3K-p85α and p-Akt were decreased. In conclusion, EA improves cognitive function and insulin resistance in rat models of AD. The PI3K/Akt signaling pathway is involved in those changes.
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Affiliation(s)
- Xinyu Huang
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Kangbai Huang
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Zhaowei Li
- College of Sport and Healthy, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Dongyan Bai
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Yan Hao
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Qinglong Wu
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Wei Yi
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Nenggui Xu
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Youcan Pan
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Liang Zhang
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
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Abstract
Tau protein which was discovered in 1975 [310] became of great interest when it was identified as the main component of neurofibrillary tangles (NFT), a pathological feature in the brain of patients with Alzheimer's disease (AD) [39, 110, 232]. Tau protein is expressed mainly in the brain as six isoforms generated by alternative splicing [46, 97]. Tau is a microtubule associated proteins (MAPs) and plays a role in microtubules assembly and stability, as well as diverse cellular processes such as cell morphogenesis, cell division, and intracellular trafficking [49]. Additionally, Tau is involved in much larger neuronal functions particularly at the level of synapses and nuclei [11, 133, 280]. Tau is also physiologically released by neurons [233] even if the natural function of extracellular Tau remains to be uncovered (see other chapters of the present book).
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Zhou Y, Deng J, Chu X, Zhao Y, Guo Y. Role of Post-Transcriptional Control of Calpain by miR-124-3p in the Development of Alzheimer's Disease. J Alzheimers Dis 2020; 67:571-581. [PMID: 30584150 DOI: 10.3233/jad-181053] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease prevalent in aged people, clinically characterized by progressive memory loss, behavioral and learning dysfunction, and cognitive deficits. The pathogenesis of AD is hallmarked by formation of amyloid-β peptide aggregates (Aβ) and intraneuronal neurofibrillary tangles (NFTs), which are induced by hyperphosphorylation of amyloid-β protein precursor and tau protein, respectively. The hyperphosphorylation is controlled by cyclin-dependent kinase-5 (CDK5), the aberrant activation of which is mediated by calpain (CAPN)-induced cleavage of p35 into p25. However, the regulation of CAPN in AD remains largely unknown. Here, we studied the post-transcriptional control of CAPN1 by microRNAs (miRNAs) in the setting of AD. We found that miR-124-3p, previously reported as a miRNA that was downregulated in AD, was a CAPN1-targeting miRNA that functionally inhibited the protein translation of CAPN1 in a human neural cell line, HCN-2. In vitro, transfection with miR-124-3p reduced the levels of CAPN1 protein, the cleavage of p35 into p25, and cell apoptosis dose-dependently in HCN-2 cells. Moreover, a significant inverse correlation was detected between the levels of miR-124-3p and CAPN1 in AD specimens. Furthermore, intracranial injection of adeno-associated virus expressing miR-124-3p into APP/PS1-AD mice significantly reduced Aβ deposition and significantly improved the AD-mouse behavior in the social recognition test and plus-maze discriminative avoidance task. Together, our data suggest that post-transcriptional control of calpain by miR-124-3p plays an essential role in the development of AD.
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Affiliation(s)
- Yajun Zhou
- Department of Neurology, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, China
| | - Jiangshan Deng
- Department of Neurology, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, China
| | - Xiuli Chu
- Department of Neurology, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, China
| | - Yuwu Zhao
- Department of Neurology, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, China
| | - Yong Guo
- Department of Critical Care Medicine, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, China
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18
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Moderate protective effect of Kyotorphin against the late consequences of intracerebroventricular streptozotocin model of Alzheimer's disease. Amino Acids 2019; 51:1501-1513. [PMID: 31520285 DOI: 10.1007/s00726-019-02784-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 08/30/2019] [Indexed: 01/08/2023]
Abstract
The established decrease in the level of endogenous kyotorphin (KTP) into the cerebrospinal fluid of patients with an advanced stage of Alzheimer's disease (AD) and the found neuroprotective activity of KTP suggested its participation in the pathophysiology of the disease. We aimed to study the effects of subchronic intracerebroventricular (ICV) treatment (14 days) with KTP on the behavioral, biochemical and histological changes in rats with streptozotocin (STZ-ICV)-induced model of sporadic AD (sAD). Three months after the administration of STZ-ICV, rats developed increased locomotor activity, decreased level of anxiety, impaired spatial and working memory. Histological data from the STZ-ICV group demonstrated decreased number of neurons in the CA1 and CA3 subfields of the hippocampus. The STZ-ICV group was characterized with a decrease of total protein content in the hippocampus and the prefrontal cortex as well as increased levels of the carbonylated proteins in the hippocampus. KTP treatment of STZ-ICV rats normalized anxiety level and regained object recognition memory. KTP abolished the protein loss in prefrontal cortex and decrease the neuronal loss in the CA3 subfield of the hippocampus. STZ-ICV rats, treated with KTP, did not show significant changes in the levels of the carbonylated proteins in specific brain structures or in motor activity and spatial memory compared to the saline-treated STZ-ICV group. Our data show a moderate and selective protective effect of a subchronic ICV administration of the dipeptide KTP on the pathological changes induced by an experimental model of sAD in rats.
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19
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Nakandakari SCBR, Muñoz VR, Kuga GK, Gaspar RC, Sant'Ana MR, Pavan ICB, da Silva LGS, Morelli AP, Simabuco FM, da Silva ASR, de Moura LP, Ropelle ER, Cintra DE, Pauli JR. Short-term high-fat diet modulates several inflammatory, ER stress, and apoptosis markers in the hippocampus of young mice. Brain Behav Immun 2019; 79:284-293. [PMID: 30797044 DOI: 10.1016/j.bbi.2019.02.016] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 02/11/2019] [Accepted: 02/18/2019] [Indexed: 12/22/2022] Open
Abstract
The consumption of saturated fatty acids is one of the leading risk factors for Alzheimer's Disease (AD) development. Indeed, the short-term consumption of a high-fat diet (HFD) is related to increased inflammatory signals in the hippocampus; however, the potential molecular mechanisms linking it to AD pathogenesis are not fully elucidated. In our study, we investigated the effects of short-term HFD feeding (within 3, 7 and 10 days) in AD markers and neuroinflammation in the hippocampus of mice. The short period of HFD increased fasting glucose and HOMA-IR. Also, mice fed HFD increased the protein content of β-Amyloid, pTau, TNFα, IL1β, pJNK, PTP1B, peIF2α, CHOP, Caspase3, Cleaved-Caspase3 and Alzheimer-related genes (Bax, PS1, PEN2, Aph1b). At 10 days, both neuronal (N2a) and microglial (BV2) cells presented higher expression of inflammatory and apoptotic genes when stimulated with palmitate. These findings suggest that a short period of consumption of a diet rich in saturated fat is associated with activation of inflammatory, ER stress and apoptotic signals in the hippocampus of young mice.
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Affiliation(s)
| | - Vitor Rosetto Muñoz
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil
| | - Gabriel Keine Kuga
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil
| | - Rafael Calais Gaspar
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil
| | - Marcella Ramos Sant'Ana
- Laboratory of Nutritional Genomics (LabGeN), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil
| | - Isadora Carolina Betim Pavan
- Multidisciplinary Laboratory of Food and Health (LABMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Luiz Guilherme Salvino da Silva
- Multidisciplinary Laboratory of Food and Health (LABMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Ana Paula Morelli
- Multidisciplinary Laboratory of Food and Health (LABMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Fernando Moreira Simabuco
- Multidisciplinary Laboratory of Food and Health (LABMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Adelino Sanchez Ramos da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, and Postgraduate Program in Physical Education and Sport, School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Leandro Pereira de Moura
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil; OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil; CEPECE - Center of Research in Sport Sciences, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil
| | - Eduardo Rochete Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil; OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil; CEPECE - Center of Research in Sport Sciences, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil
| | - Dennys Esper Cintra
- Laboratory of Nutritional Genomics (LabGeN), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil; CEPECE - Center of Research in Sport Sciences, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil
| | - José Rodrigo Pauli
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil; OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil; CEPECE - Center of Research in Sport Sciences, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP, Brazil.
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20
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Wan W, Cao L, Kalionis B, Murthi P, Xia S, Guan Y. Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling. Front Neurol 2019; 10:607. [PMID: 31275224 PMCID: PMC6593079 DOI: 10.3389/fneur.2019.00607] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 05/22/2019] [Indexed: 12/22/2022] Open
Abstract
Iron deposition in the brain is an early issue in Alzheimer's disease (AD). However, the pathogenesis of iron-induced pathological changes in AD remains elusive. Insulin resistance in brains is an essential feature of AD. Previous studies determined that insulin resistance is involved in the development of pathologies in AD. Tau pathology is one of most important hallmarks in AD and is associated with the impairment of cognition and clinical grades of the disease. In the present study, we observed that ferrous (Fe2+) chloride led to aberrant phosphorylation of tau, and decreased tyrosine phosphorylation levels of insulin receptor β (IRβ), insulin signal substrate 1 (IRS-1) and phosphoinositide 3-kinase p85α (PI3K p85α), in primary cultured neurons. In the in vivo studies using mice with supplemented dietary iron, learning and memory was impaired. As well, hyperphosphorylation of tau and disrupted insulin signaling in the brain was induced in iron-overloaded mice. Furthermore, in our in vitro work we identified the activation of insulin signaling following exogenous supplementation of insulin. This was further attenuated by iron-induced hyperphosphorylation of tau in primary neurons. Together, these data suggest that dysfunctional insulin signaling participates in iron-induced abnormal phosphorylation of tau in AD. Our study highlights the promising role of insulin signaling in pathological lesions induced by iron overloading.
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Affiliation(s)
- Wenbin Wan
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lan Cao
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bill Kalionis
- Department of Maternal-Fetal Medicine, Pregnancy Research Centre, University of Melbourne, Parkville, VIC, Australia.,Department of Obstetrics and Gynecology, Royal Women's Hospital, Parkville, VIC, Australia
| | - Padma Murthi
- Department of Obstetrics and Gynecology, University of Melbourne, Parkville, VIC, Australia
| | - Shijin Xia
- Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai, China
| | - Yangtai Guan
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Crucial players in Alzheimer's disease and diabetes mellitus: Friends or foes? Mech Ageing Dev 2019; 181:7-21. [PMID: 31085195 DOI: 10.1016/j.mad.2019.03.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 03/02/2019] [Accepted: 03/26/2019] [Indexed: 01/21/2023]
Abstract
Alzheimer's disease (AD) and diabetes mellitus, especially type 2 (T2DM), are very common and widespread diseases in contemporary societies, and their incidence is steadily on the increase. T2DM is a multiple metabolic disorder, with several mechanisms including hyperglycaemia, insulin resistance, insulin receptor and insulin growth factor disturbances, glucose toxicity, formation of advanced glycation end products (AGEs) and the activity of their receptors. AD is the most common form of dementia, characterized by the accumulation of extracellular beta amyloid peptide aggregates and intracellular hyper-phosphorylated tau proteins, which are thought to drive and/or accelerate inflammatory and oxidative stress processes leading to neurodegeneration. The aim of this paper is to provide a comprehensive review of the evidence linking T2DM to the onset and development of AD and highlight the unknown or poorly studied "nooks and crannies" of this interesting relationship, hence providing an opportunity to stimulate new ideas for the analysis of comorbidities between AD and DM. Despite, indication of possible biomarkers of early diagnosis of T2DM and AD, this review is also an attempt to answer the question as to whether the crucial factors in the development of both conditions support the link between DM and AD.
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22
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Moreira-Silva D, Carrettiero DC, Oliveira ASA, Rodrigues S, Dos Santos-Lopes J, Canas PM, Cunha RA, Almeida MC, Ferreira TL. Anandamide Effects in a Streptozotocin-Induced Alzheimer's Disease-Like Sporadic Dementia in Rats. Front Neurosci 2018; 12:653. [PMID: 30333717 PMCID: PMC6176656 DOI: 10.3389/fnins.2018.00653] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 08/30/2018] [Indexed: 12/21/2022] Open
Abstract
Alzheimer's disease (AD) is characterized by multiple cognitive deficits including memory and sensorimotor gating impairments as a result of neuronal and synaptic loss. The endocannabinoid system plays an important role in these deficits but little is known about its influence on the molecular mechanism regarding phosphorylated tau (p-tau) protein accumulation - one of the hallmarks of AD -, and on the density of synaptic proteins. Thus, the aim of this study was to investigate the preventive effects of anandamide (N-arachidonoylethanolamine, AEA) on multiple cognitive deficits and on the levels of synaptic proteins (syntaxin 1, synaptophysin and synaptosomal-associated protein, SNAP-25), cannabinoid receptor type 1 (CB1) and molecules related to p-tau degradation machinery (heat shock protein 70, HSP70), and Bcl2-associated athanogene (BAG2) in an AD-like sporadic dementia model in rats using intracerebroventricular (icv) injection of streptozotocin (STZ). Our hypothesis is that AEA could interact with HSP70, modulating the level of p-tau and synaptic proteins, preventing STZ-induced cognitive impairments. Thirty days after receiving bilateral icv injections of AEA or STZ or both, the cognitive performance of adult male Wistar rats was evaluated in the object recognition test, by the escape latency in the elevated plus maze (EPM), by the tone and context fear conditioning as well as in prepulse inhibition tests. Subsequently, the animals were euthanized and their brains were removed for histological analysis or for protein quantification by Western Blotting. The behavioral results showed that STZ impaired recognition, plus maze and tone fear memories but did not affect contextual fear memory and prepulse inhibition. Moreover, AEA prevented recognition and non-associative emotional memory impairments induced by STZ, but did not influence tone fear conditioning. STZ increased the brain ventricular area and this enlargement was prevented by AEA. Additionally, STZ reduced the levels of p-tau (Ser199/202) and increased p-tau (Ser396), although AEA did not affect these alterations. HSP70 was found diminished only by STZ, while BAG2 levels were decreased by STZ and AEA. Synaptophysin, syntaxin and CB1 receptor levels were reduced by STZ, but only syntaxin was recovered by AEA. Altogether, albeit AEA failed to modify some AD-like neurochemical alterations, it partially prevented STZ-induced cognitive impairments, changes in synaptic markers and ventricle enlargement. This study showed, for the first time, that the administration of an endocannabinoid can prevent AD-like effects induced by STZ, boosting further investigations about the modulation of endocannabinoid levels as a therapeutic approach for AD.
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Affiliation(s)
- Daniel Moreira-Silva
- Center for Mathematics, Computing and Cognition, Universidade Federal do ABC, São Bernardo do Campo, Brazil
| | - Daniel C Carrettiero
- Center for Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, Brazil
| | - Adriele S A Oliveira
- Center for Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, Brazil
| | - Samanta Rodrigues
- Center for Mathematics, Computing and Cognition, Universidade Federal do ABC, São Bernardo do Campo, Brazil
| | - Joyce Dos Santos-Lopes
- Center for Mathematics, Computing and Cognition, Universidade Federal do ABC, São Bernardo do Campo, Brazil
| | - Paula M Canas
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Rodrigo A Cunha
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Maria C Almeida
- Center for Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, Brazil
| | - Tatiana L Ferreira
- Center for Mathematics, Computing and Cognition, Universidade Federal do ABC, São Bernardo do Campo, Brazil
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23
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Mohamed HE, Asker ME, Younis NN, Shaheen MA, Eissa RG. Modulation of brain insulin signaling in Alzheimer’s disease: New insight on the protective role of green coffee bean extract. Nutr Neurosci 2018; 23:27-36. [DOI: 10.1080/1028415x.2018.1468535] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Affiliation(s)
- Hoda E. Mohamed
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mervat E. Asker
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Nahla N. Younis
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mohamed A. Shaheen
- Department of Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Rana G. Eissa
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
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24
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Ettcheto M, Petrov D, Pedrós I, Alva N, Carbonell T, Beas-Zarate C, Pallas M, Auladell C, Folch J, Camins A. Evaluation of Neuropathological Effects of a High-Fat Diet in a Presymptomatic Alzheimer's Disease Stage in APP/PS1 Mice. J Alzheimers Dis 2018; 54:233-51. [PMID: 27567882 DOI: 10.3233/jad-160150] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Alzheimer's disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α-secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42, which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice.
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Affiliation(s)
- Miren Ettcheto
- Unitat de Farmacologia i Farmacognòsia, Institut de Neurociencias, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Dmitry Petrov
- Unitat de Farmacologia i Farmacognòsia, Institut de Neurociencias, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ignacio Pedrós
- Unitats de Bioquímica i Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus (Tarragona), Spain.,Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Norma Alva
- Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Teresa Carbonell
- Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Carlos Beas-Zarate
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, CIBO, IMSS, México.,Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, México
| | - Merce Pallas
- Unitat de Farmacologia i Farmacognòsia, Institut de Neurociencias, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Carme Auladell
- Departament de Biologia Cellular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Jaume Folch
- Unitats de Bioquímica i Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus (Tarragona), Spain.,Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Antoni Camins
- Unitat de Farmacologia i Farmacognòsia, Institut de Neurociencias, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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25
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Effects of thymol on amyloid-β-induced impairments in hippocampal synaptic plasticity in rats fed a high-fat diet. Brain Res Bull 2018; 137:338-350. [PMID: 29339105 DOI: 10.1016/j.brainresbull.2018.01.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Revised: 01/01/2018] [Accepted: 01/08/2018] [Indexed: 12/11/2022]
Abstract
Obesity and a high-fat diet (HFD) are known to increase the incidence of Alzheimer's disease (AD). Oxidative stress, a major risk factor for AD, is increased with HFD consumption. Thymol (Thy) has antioxidant properties. Therefore, in the present study, we examined the protective and therapeutic effects of Thy on amyloid-β (Aβ)-induced impairments in the hippocampal synaptic plasticity of HFD-fed rats. In this study, 72 adult male Wistar rats were randomly assigned to 9 groups (n = 8 rats/group): Group 1 (control; standard diet); Group 2: Control + phosphate-buffered saline (PBS) + Oil (Thy vehicle); Group 3 (HFD + PBS); Group 4: (HFD + Aβ); Group 5: Control + PBS + Thy; Group 6: (HFD + Aβ + Oil); Group 7: Control + Aβ + Thy; Group 8: HFD + PBS + Thy; Group 9: (HFD + Aβ + Thy). After stereotaxic surgery, the field potentials were recorded after the implantation of the recording and stimulating electrodes in the dentate gyrus (DG) and perforant pathway, respectively. Following high-frequency stimulation, the long-term potentiation (LTP) of the population spike (PS) amplitude and the slope of the excitatory postsynaptic potentials (EPSPs) were measured in the DG. The HFD rats that received Aβ exhibited a significant decrease in their EPSP slope and PS amplitude as compared to the control group. In contrast, Thy administration in the HFD + Aβ rats reduced the decrease in the EPSP slope and PS amplitude. Thy decreased the Aβ-induced LTP impairments in HFD rats. The HFD significantly increased serum malondialdehyde levels and decreased total antioxidant capacity and total glutathione levels; whereas, Thy supplementation significantly reversed these parameters. Therefore, these results suggest that Thy, a natural antioxidant, can be therapeutic against high risk factors for AD, such as HFD.
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26
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Asadbegi M, Yaghmaei P, Salehi I, Komaki A, Ebrahim-Habibi A. Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet- fed rats. Metab Brain Dis 2017; 32:827-839. [PMID: 28255862 DOI: 10.1007/s11011-017-9960-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 01/24/2017] [Indexed: 01/28/2023]
Abstract
Obesity and consumption of a high fat diet (HFD) are known to increase the risk of Alzheimer's disease (AD). In the present study, we have examined the protective and therapeutic effects of thymol (main monoterpene phenol found in thyme essential oil) on a HFD-fed rat model of AD. Fourty adult male Wistar rats were randomly assigned to 5 groups:(n = 8 rats/group): group 1, control, consumed an ordinary diet, group 2 consumed a HFD for 8 weeks, then received phosphate-buffered saline (PBS) via intrahippocampal (IHP) injection, group 3 consumed HFD for 8 weeks, then received beta-amyloid (Aβ)1-42 via IHP injections to induce AD, group 4 consumed HFD for 8 weeks, then received Aβ1-42, and was treated by thymol (30 mg/kg in sunflower oil) daily for 4 weeks, and group 5 consumed HFD for 8 week, then received Aβ1-42 after what sunflower oil was administered by oral gavage daily for 4 weeks. Biochemical tests showed an impaired lipid profile and higher glucose levels upon consumption of HFD, which was ameliorated by thymol treatment. In behavioral results, spatial memory in group 3 was significantly impaired, but groups treated with thymol showed better spatial memory compared to group 3 (p ≤ 0.01). In histological results, formation of Aβ plaque in hippocampus of group 3 increased significantly compared to group 1 and group 2 (p ≤ 0.05), but group 4 showed decreased Aβ plaques compared to group 3 (p ≤ 0.01). In conclusion, thymol decreased the effects of Aβ on memory and could be considered as neuroprotective.
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Affiliation(s)
- Masoumeh Asadbegi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parichehreh Yaghmaei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
| | - Iraj Salehi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Azadeh Ebrahim-Habibi
- Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, 1411413137, Iran.
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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27
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Zhang Y, Huang LJ, Shi S, Xu SF, Wang XL, Peng Y. L-3-n-butylphthalide Rescues Hippocampal Synaptic Failure and Attenuates Neuropathology in Aged APP/PS1 Mouse Model of Alzheimer's Disease. CNS Neurosci Ther 2016; 22:979-987. [PMID: 27439966 DOI: 10.1111/cns.12594] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 06/22/2016] [Accepted: 06/23/2016] [Indexed: 12/26/2022] Open
Abstract
AIMS Our previous studies showed that L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), improved cognitive ability in animal models of cerebral ischemia, vascular dementia, and Alzheimer's disease (AD). It is well known that cognitive deficit of AD is caused by synaptic dysfunction. In this study, we investigated the effect of L-NBP on hippocampal synaptic function in APP/PS1 AD transgenic mice and related mechanisms. METHODS Eighteen-month-old APP/PS1 transgenic (Tg) mice were administrated 15 mg/kg L-NBP by oral gavage for 3 months. Synaptic morphology and the thickness of postsynaptic density (PSD) in hippocampal neurons were investigated by electron microscope. The dendritic spines, Aβ plaques, and glial activation were detected by staining. The expressions of synapse-related proteins were observed by Western blotting. RESULTS L-NBP treatment significantly increased the number of synapses and apical dendritic thorns and the thickness of PSD, increased the expression levels of synapse-associated proteins including PSD95, synaptophysin (SYN), β-catenin, and GSK-3β, and attenuated Aβ plaques and neuroinflammatory responses in aged APP/PS1 Tg mice. CONCLUSION L-NBP may restore synaptic and spine function in aged APP Tg mice through inhibiting Aβ plaques deposition and neuroinflammatory response. Wnt/β-catenin signaling pathway may be involved in L-NBP-related restoration of synaptic function.
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Affiliation(s)
- Yu Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Long-Jian Huang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Si Shi
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shao-Feng Xu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiao-Liang Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ying Peng
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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28
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Neuroprotective effects of metformin against Aβ-mediated inhibition of long-term potentiation in rats fed a high-fat diet. Brain Res Bull 2016; 121:178-85. [PMID: 26861514 DOI: 10.1016/j.brainresbull.2016.02.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/31/2016] [Accepted: 02/04/2016] [Indexed: 11/24/2022]
Abstract
Metformin (Met) is used to treat neurodegenerative disorders such as Alzheimer's disease (AD). Conversely, high-fat diets (HFD) have been shown to increase AD risk. In this study, we investigated the neuroprotective effects of Met on β-amyloid (Aβ)-induced impairments in hippocampal synaptic plasticity in AD model rats that were fed a HFD. In this study, 32 adult male Wistar rats were randomly assigned to four groups: group I (control group, regular diet); group II (HFD+vehicle); group III (HFD+Aβ); or group IV (Met+HFD+Aβ). Rats fed a HFD were injected with Aβ to induce AD, allowed to recover, and treated with Met for 8 weeks. The rats were then anesthetized with intraperitoneal injections of urethane and placed in a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In vivo electrophysiological recordings were then performed to measure population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope in the hippocampal dentate gyrus. Long-term potentiation (LTP) was induced by high-frequency stimulation of the perforant pathway. Blood samples were then collected to measure plasma levels of triglycerides, low-density lipoproteins, very low-density lipoprotein, and cholesterol. After induction of LTP, PS amplitude and EPSP slope were significantly decreased in Aβ-injected rats fed a HFD compared to vehicle-injected animals or untreated animals that were fed a normal diet. Met treatment of Aβ-injected rats significantly attenuated these decreases, suggesting that Met decreased the effects of Aβ on LTP. These findings suggest that Met treatment is neuroprotective against the detrimental effects of Aβ and HFDs on hippocampal synaptic plasticity.
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29
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Cordner ZA, Tamashiro KLK. Effects of high-fat diet exposure on learning & memory. Physiol Behav 2015; 152:363-71. [PMID: 26066731 PMCID: PMC5729745 DOI: 10.1016/j.physbeh.2015.06.008] [Citation(s) in RCA: 206] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 05/14/2015] [Accepted: 06/05/2015] [Indexed: 01/13/2023]
Abstract
The associations between consumption of a high-fat or 'Western' diet and metabolic disorders such as obesity, diabetes, and cardiovascular disease have long been recognized and a great deal of evidence now suggests that diets high in fat can also have a profound impact on the brain, behavior, and cognition. Here, we will review the techniques most often used to assess learning and memory in rodent models and discuss findings from studies assessing the cognitive effects of high-fat diet consumption. The review will then consider potential underlying mechanisms in the brain and conclude by reviewing emerging literature suggesting that maternal consumption of a high-fat diet may have effects on the learning and memory of offspring.
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Affiliation(s)
- Zachary A Cordner
- Cellular & Molecular Medicine Graduate Program, Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Kellie L K Tamashiro
- Cellular & Molecular Medicine Graduate Program, Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
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30
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Salkovic-Petrisic M, Knezovic A, Osmanovic-Barilar J, Smailovic U, Trkulja V, Riederer P, Amit T, Mandel S, Youdim MB. Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease. Life Sci 2015; 136:108-19. [PMID: 26159898 DOI: 10.1016/j.lfs.2015.06.026] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 05/27/2015] [Accepted: 06/30/2015] [Indexed: 01/04/2023]
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31
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Cai Z, Xiao M, Chang L, Yan LJ. Role of insulin resistance in Alzheimer's disease. Metab Brain Dis 2015; 30:839-51. [PMID: 25399337 DOI: 10.1007/s11011-014-9631-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 11/07/2014] [Indexed: 01/01/2023]
Abstract
A critical role of insulin resistance (IR) in Alzheimer's disease (AD) includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles (NFTs), failure of synaptic transmission and neuronal degeneration. Aβ is sequentially cleavaged from APP by two proteolytic enzymes: β-secretase and γ-secretase. IR could regulate Aβ production via enhancing β- and γ-secretase activity. Meanwhile, IR induces oxidative stress and inflammation in the brain which contributes to Aβ and tau pathology. Aβ accumulation can enhance IR through Aβ-mediated inflammation and oxidative stress. IR is a possible linking between amyloid plaques and NFTs pathology via oxidative stress and neuroinflammation. Additionally, IR could disrupt acetylcholine activity, and accelerate axon degeneration and failures in axonal transport, and lead to cognitive impairment in AD. Preclinical and clinical studies have supported that insulin could be useful in the treatment of AD. Thus, an effective measure to inhibit IR may be a novel drug target in AD.
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Affiliation(s)
- Zhiyou Cai
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan Renmin Hospital, No. 39 Chaoyang Middle Road, Shiyan, 442000, Hubei Province, People's Republic of China,
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