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Hopkins PCR, Troakes C, King A, Tear G. Transmembrane and coiled-coil 2 associates with Alzheimer's disease pathology in the human brain. Brain Pathol 2025; 35:e13290. [PMID: 39084860 PMCID: PMC11669416 DOI: 10.1111/bpa.13290] [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: 01/09/2024] [Accepted: 07/05/2024] [Indexed: 08/02/2024] Open
Abstract
Transmembrane and coiled-coil 2 (TMCC2) is a human orthologue of the Drosophila gene dementin, mutant alleles of which cause neurodegeneration with features of Alzheimer's disease (AD). TMCC2 and Dementin further have an evolutionarily conserved interaction with the amyloid protein precursor (APP), a protein central to AD pathogenesis. To investigate if human TMCC2 might also participate in mechanisms of neurodegeneration, we examined TMCC2 expression in late onset AD human brain and age-matched controls, familial AD cases bearing a mutation in APP Val717, and Down syndrome AD. Consistent with previous observations of complex formation between TMCC2 and APP in the rat brain, the dual immunocytochemistry of control human temporal cortex showed highly similar distributions of TMCC2 and APP. In late onset AD cases stratified by APOE genotype, TMCC2 immunoreactivity was associated with dense core senile plaques and adjacent neuronal dystrophies, but not with Aβ surrounding the core, diffuse Aβ plaques or tauopathy. In Down syndrome AD, we observed in addition TMCC2-immunoreactive and methoxy-X04-positive pathological features that were morphologically distinct from those seen in the late onset and familial AD cases, suggesting enhanced pathological alteration of TMCC2 in Down syndrome AD. At the protein level, western blots of human brain extracts revealed that human brain-derived TMCC2 exists as at least three isoforms, the relative abundance of which varied between the temporal gyrus and cerebellum and was influenced by APOE and/or dementia status. Our findings thus implicate human TMCC2 in AD via its interactions with APP, its association with dense core plaques, as well as its alteration in Down syndrome AD.
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Affiliation(s)
| | - Claire Troakes
- London Neurodegenerative Diseases Brain BankInstitute of Psychiatry, Psychology and Neuroscience, King's College LondonLondonUK
| | - Andrew King
- London Neurodegenerative Diseases Brain BankInstitute of Psychiatry, Psychology and Neuroscience, King's College LondonLondonUK
| | - Guy Tear
- Centre for Developmental NeurobiologyKing's College LondonLondonUK
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2
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Fu J, Lai X, Huang Y, Bao T, Yang J, Chen S, Chen X, Shang H. Meta-analysis and systematic review of peripheral platelet-associated biomarkers to explore the pathophysiology of alzheimer's disease. BMC Neurol 2023; 23:66. [PMID: 36774494 PMCID: PMC9921402 DOI: 10.1186/s12883-023-03099-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 01/30/2023] [Indexed: 02/13/2023] Open
Abstract
INTRODUCTION Platelets are the primary peripheral reserve of amyloid precursor protein (APP), providing more than 90% of blood amyloid-beta (Aβ). Some oxidative stress markers and neurotransmitter markers were also differentially expressed in the peripheral platelets of AD. Therefore, the present study explored the differences in platelet-associated biomarkers between AD and healthy controls using meta-analysis and systematic review to reveal the value of platelet in the pathogenesis and development of AD. METHODS We searched all the related studies that probed into the platelets in AD based on PubMed, Embase, and web of science databases from the establishment to November 04, 2021. RESULTS Eighty-eight studies were included in the meta-analysis, and the platelets data of 702 AD and 710 controls were analyzed. The results of standardized mean difference (SMD) showed that platelets in AD had lower levels of APP ratio (SMD: -1.89; p < 0.05), ADAM10 (SMD: -1.16; p < 0.05), Na + -K + -ATPase (SMD: -7.23; p < 0.05), but higher levels of HMW/LMW tau (SMD: 0.92; p < 0.05), adenosine A2 receptor (SMD: 4.27; p < 0.05), MAO-B (SMD: 1.73; p < 0.05), NO (SMD: 4.25; p < 0.05) and ONOO- (SMD: 7.33; p < 0.05). In the systematic review, some other platelet markers seem to be meaningful in AD patients. CONCLUSION The results of the present meta-analysis and systematic review demonstrated that the alterations of APP metabolic enzymes, oxidative stress markers, and neurotransmitter factors in platelets were similar to their changes in the central nervous system of AD, suggesting that platelet could be a good source of peripheral biomarkers and may play an important role in the pathophysiological development of AD.
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Affiliation(s)
- Jiajia Fu
- grid.412901.f0000 0004 1770 1022Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Xiaohui Lai
- grid.412901.f0000 0004 1770 1022Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Yan Huang
- grid.412901.f0000 0004 1770 1022Management Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Ting Bao
- grid.412901.f0000 0004 1770 1022Management Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Jing Yang
- grid.412901.f0000 0004 1770 1022Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Sihui Chen
- grid.412901.f0000 0004 1770 1022Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Xueping Chen
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Huifang Shang
- grid.412901.f0000 0004 1770 1022Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan China
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Li TR, Liu FQ. β-Amyloid promotes platelet activation and activated platelets act as bridge between risk factors and Alzheimer's disease. Mech Ageing Dev 2022; 207:111725. [PMID: 35995275 DOI: 10.1016/j.mad.2022.111725] [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: 05/25/2022] [Revised: 08/07/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022]
Abstract
Alzheimer's disease (AD) is an evolving challenge that places an enormous burden on families and society. The presence of obvious brain β-amyloid (Aβ) deposition is a premise to diagnose AD, which induces the subsequent tau hyperphosphorylation and neurodegeneration. Platelets are the primary source of circulating amyloid precursor protein (APP). Upon activation, they can secrete significant amounts of Aβ into the blood, which can be actively transported to the brain across the blood-brain barrier and promote amyloid deposition. In this review, we summarized the changes in the platelet APP metabolic pathway in patients with AD and further comprehensively explored the targets and downstream events of Aβ-activated platelets. In addition, we attempted to clarify whether patients with AD are in a state of general platelet activation, with inconsistent results. Considering the increasingly evident bidirectional relationship between AD and vascular events, we speculate that the AD pathology alone seems to be insufficient to induce the general activation of platelets; however, the intervention of third-party factors, such as atherosclerosis, exposes the extracellular matrix and leads to platelet activation, further promoting AD progression. Therefore, we proposed a framework in which the relationship between platelets and AD is indirect and mediated by vascular factors. Therapies targeting platelets and interventions for vascular risk factors are likely to contribute to the prevention and treatment of AD.
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Affiliation(s)
- Tao-Ran Li
- Department of Neurology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Feng-Qi Liu
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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4
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Wang Q, Shi Y, Qi X, Qi L, Chen X, Shi J, Xie C, Zhang Z. Platelet-Derived Amyloid-β Protein Precursor as a Biomarker of Alzheimer's Disease. J Alzheimers Dis 2022; 88:589-599. [PMID: 35662121 DOI: 10.3233/jad-220122] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Platelet proteins may be associated with Alzheimer's disease (AD) pathology. OBJECTIVE To investigate the relationship between platelet proteins and cerebrospinal fluid (CSF) biomarkers of AD and cognition in individuals with memory decline to identify effective screening methods for detecting the early stages of the disease. METHODS We classified 68 participants with subjective memory decline according to the ATN framework determined by CSF amyloid-β (A), CSF p-tau (T), and t-tau (N). All participants underwent Mini-Mental State Examination (MMSE) and platelet-related protein content testing. RESULTS Eighteen participants had normal AD biomarkers (NCs), 24 subjects had non-AD pathologic changes (non-AD), and 26 subjects fell within the Alzheimer's continuum (AD). The platelet amyloid-β protein precursor (AβPP) ratio in the AD group was significantly lower than in the non-AD and NCs groups, and positively correlated with MMSE scores and CSF amyloid-β42 level, which could affect MMSE scores through CSF amyloid-β42. Levels of platelet phosphorylated-tau 231 and ser396/404 phosphorylated tau were elevated in both AD and non-AD compared to NCs. Additionally, the receiver operating characteristic analysis demonstrated that the platelet AβPP ratio was a sensitive identifier for differentiating the AD from NCs (AUC = 0.846) and non-AD (AUC = 0.768). And ser396/404 phosphorylated tau could distinguish AD from NCs. CONCLUSION Our study was the first to find an association between platelet AβPP ratio and CSF biomarkers of AD, which contribute to the understanding of the peripheral changes in AD. These findings may help to discover potential feasible and effective screening tools for AD.
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Affiliation(s)
- Qing Wang
- Department of Neurology, The Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Yachen Shi
- Department of Neurology, The Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Xinyang Qi
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Lingyu Qi
- Department of Neurology, The Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Xiang Chen
- Department of Neurology, The Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Jingping Shi
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Chunming Xie
- Department of Neurology, The Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China.,The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Zhijun Zhang
- Department of Neurology, The Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China.,The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China.,The Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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Carbone MG, Pagni G, Tagliarini C, Imbimbo BP, Pomara N. Can platelet activation result in increased plasma Aβ levels and contribute to the pathogenesis of Alzheimer's disease? Ageing Res Rev 2021; 71:101420. [PMID: 34371202 DOI: 10.1016/j.arr.2021.101420] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/18/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022]
Abstract
One of the central lesions in the brain of subjects with Alzheimer's disease (AD) is represented by aggregates of β-amyloid (Aβ), a peptide of 40-42 amino acids derived from the amyloid precursor protein (APP). The reasons why Aβ accumulates in the brain of individuals with sporadic forms of AD are unknown. Platelets are the primary source of circulating APP and, upon activation, can secrete significant amounts of Aβ into the blood which can be actively transported to the brain across the blood-brain barrier and promote amyloid deposition. Increased platelet activity can stimulate platelet adhesion to endothelial cells, trigger the recruitment of leukocytes into the vascular wall and cause perivascular inflammation, which can spread inflammation in the brain. Neuroinflammation is fueled by activated microglial cells and reactive astrocytes that release neurotoxic cytokines and chemokines. Platelet activation is also associated with the progression of carotid artery disease resulting in an increased risk of cerebral hypoperfusion which may also contribute to the AD neurodegenerative process. Platelet activation may thus be a pathophysiological mechanism of AD and for the strong link between AD and cerebrovascular diseases. Interfering with platelet activation may represent a promising potential adjunct therapeutic approach for AD.
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Affiliation(s)
- Manuel Glauco Carbone
- Department of Medicine and Surgery, Division of Psychiatry, University of Insubria, Viale Luigi Borri 57, 21100, Varese, Italy; Pisa-School of Experimental and Clinical Psychiatry, University of Pisa, Via Roma 57, 56100, Pisa, Italy.
| | - Giovanni Pagni
- Pisa-School of Experimental and Clinical Psychiatry, University of Pisa, Via Roma 57, 56100, Pisa, Italy.
| | - Claudia Tagliarini
- Pisa-School of Experimental and Clinical Psychiatry, University of Pisa, Via Roma 57, 56100, Pisa, Italy.
| | | | - Nunzio Pomara
- Geriatric Psychiatry Department, Nathan Kline Institute, and Departments of Psychiatry and Pathology, NYU Grossman School of Medicine, 140 Old Orangeburg Road Orangeburg, New York, 10962, United States.
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Wang M, Lv J, Huang X, Wisniewski T, Zhang W. High-fat diet-induced atherosclerosis promotes neurodegeneration in the triple transgenic (3 × Tg) mouse model of Alzheimer's disease associated with chronic platelet activation. ALZHEIMERS RESEARCH & THERAPY 2021; 13:144. [PMID: 34454596 PMCID: PMC8403418 DOI: 10.1186/s13195-021-00890-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/18/2021] [Indexed: 01/14/2023]
Abstract
Background Epidemiological studies link vascular disease risk factors such as atherosclerosis, hypertension, and diabetes mellitus with Alzheimer’s disease (AD). Whether there are direct links between these conditions to β-amyloid (Aβ) aggregation and tau pathology is uncertain. Methods To investigate the possible link between atherosclerosis and AD pathology, we subjected triple transgenic (3 × Tg) AD mice to a high-fat diet (HFD) at 3 months of age, which corresponds to early adulthood in humans. Results After 9 months of treatment, HFD-treated 3 × Tg mice exhibited worse memory deficits accompanied by blood hypercoagulation, thrombocytosis, and chronic platelet activation. Procoagulant platelets from HFD-treated 3 × Tg mice actively induced the conversion of soluble Aβ40 into fibrillar Aβ aggregates, associated with increased expression of integrin αIIbβ3 and clusterin. At 9 months and older, platelet-associated fibrillar Aβ aggregates were observed to obstruct the cerebral blood vessels in HFD-treated 3 × Tg mice. HFD-treated 3 × Tg mice exhibited a greater cerebral amyloid angiopathy (CAA) burden and increased cerebral vascular permeability, as well as more extensive neuroinflammation, tau hyperphosphorylation, and neuron loss. Disaggregation of preexisting platelet micro-clots with humanized GPIIIa49-66 scFv Ab (A11) significantly reduced platelet-associated fibrillar Aβ aggregates in vitro and improved vascular permeability in vivo. Conclusions These findings suggest that a major contribution of atherosclerosis to AD pathology is via its effects on blood coagulation and the formation of platelet-mediated Aβ aggregates that compromise cerebral blood flow and therefore neuronal function. This leads to cognitive decline. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-021-00890-9.
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Affiliation(s)
- Min Wang
- Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China
| | - Junyan Lv
- Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China
| | - Xiaoshan Huang
- Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China
| | - Thomas Wisniewski
- Center for Cognitive Neurology and Departments of Neurology, Pathology and Psychiatry, New York University School of Medicine, Science Building, Rm1017, 435 East 30th Street, New York, NY, 10016, USA.
| | - Wei Zhang
- Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
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Platelet APP Processing: Is It a Tool to Explore the Pathophysiology of Alzheimer's Disease? A Systematic Review. Life (Basel) 2021; 11:life11080750. [PMID: 34440494 PMCID: PMC8401829 DOI: 10.3390/life11080750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/18/2021] [Accepted: 07/20/2021] [Indexed: 11/16/2022] Open
Abstract
The processing of the amyloid precursor protein (APP) is a critical event in the formation of amyloid plaques. Platelets contain most of the enzymatic machinery required for APP processing and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. The goal of the present paper was to analyze studies exploring platelet APP metabolism in Alzheimer's disease patients trying to assess potential reliable peripheral biomarkers, to offer new therapeutic solutions and to understand the pathophysiology of the AD. According to the PRISMA guidelines, we performed a systematic review through the PubMed database up to June 2020 with the search terms: "((((((APP) OR Amyloid Precursor Protein) OR AbetaPP) OR Beta Amyloid) OR Amyloid Beta) OR APP-processing) AND platelet". Thirty-two studies were included in this systematic review. The papers included are analytic observational studies, namely twenty-nine cross sectional studies and three longitudinal studies, specifically prospective cohort study. The studies converge in an almost unitary way in affirming that subjects with AD show changes in APP processing compared to healthy age-matched controls. However, the problem of the specificity and sensitivity of these biomarkers is still at issue and would deserve to be deepened in future studies.
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8
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Key Disease Mechanisms Linked to Alzheimer's Disease in the Entorhinal Cortex. Int J Mol Sci 2021; 22:ijms22083915. [PMID: 33920138 PMCID: PMC8069371 DOI: 10.3390/ijms22083915] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Alzheimer’s disease (AD) is a chronic, neurodegenerative brain disorder affecting millions of Americans that is expected to increase in incidence with the expanding aging population. Symptomatic AD patients show cognitive decline and often develop neuropsychiatric symptoms due to the accumulation of insoluble proteins that produce plaques and tangles seen in the brain at autopsy. Unexpectedly, some clinically normal individuals also show AD pathology in the brain at autopsy (asymptomatic AD, AsymAD). In this study, SWItchMiner software was used to identify key switch genes in the brain’s entorhinal cortex that lead to the development of AD or disease resilience. Seventy-two switch genes were identified that are differentially expressed in AD patients compared to healthy controls. These genes are involved in inflammation, platelet activation, and phospholipase D and estrogen signaling. Peroxisome proliferator-activated receptor γ (PPARG), zinc-finger transcription factor (YY1), sterol regulatory element-binding transcription factor 2 (SREBF2), and early growth response 1 (EGR1) were identified as transcription factors that potentially regulate switch genes in AD. Comparing AD patients to AsymAD individuals revealed 51 switch genes; PPARG as a potential regulator of these genes, and platelet activation and phospholipase D as critical signaling pathways. Chemical–protein interaction analysis revealed that valproic acid is a therapeutic agent that could prevent AD from progressing.
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9
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Beyond Haemostasis and Thrombosis: Platelets in Depression and Its Co-Morbidities. Int J Mol Sci 2020; 21:ijms21228817. [PMID: 33233416 PMCID: PMC7700239 DOI: 10.3390/ijms21228817] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 12/11/2022] Open
Abstract
Alongside their function in primary haemostasis and thrombo-inflammation, platelets are increasingly considered a bridge between mental, immunological and coagulation-related disorders. This review focuses on the link between platelets and the pathophysiology of major depressive disorder (MDD) and its most frequent comorbidities. Platelet- and neuron-shared proteins involved in MDD are functionally described. Platelet-related studies performed in the context of MDD, cardiovascular disease, and major neurodegenerative, neuropsychiatric and neurodevelopmental disorders are transversally presented from an epidemiological, genetic and functional point of view. To provide a complete scenario, we report the analysis of original data on the epidemiological link between platelets and depression symptoms suggesting moderating and interactive effects of sex on this association. Epidemiological and genetic studies discussed suggest that blood platelets might also be relevant biomarkers of MDD prediction and occurrence in the context of MDD comorbidities. Finally, this review has the ambition to formulate some directives and perspectives for future research on this topic.
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10
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Inyushin M, Zayas-Santiago A, Rojas L, Kucheryavykh L. On the Role of Platelet-Generated Amyloid Beta Peptides in Certain Amyloidosis Health Complications. Front Immunol 2020; 11:571083. [PMID: 33123145 PMCID: PMC7567018 DOI: 10.3389/fimmu.2020.571083] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/15/2020] [Indexed: 12/15/2022] Open
Abstract
As do many other immunity-related blood cells, platelets release antimicrobial peptides that kill bacteria, fungi, and even certain viruses. Here we review the literature suggesting that there is a similarity between the antimicrobials released by other blood cells and the amyloid-related Aβ peptide released by platelets. Analyzing the literature, we also propose that platelet-generated Aβ amyloidosis may be more common than currently recognized. This systemic Aβ from a platelet source may participate in various forms of amyloidosis in pathologies ranging from brain cancer, glaucoma, skin Aβ accumulation, and preeclampsia to Alzheimer’s disease and late-stage Parkinson’s disease. We also discuss the advantages and disadvantages of specific animal models for studying platelet-related Aβ. This field is undergoing rapid change, as it evaluates competing ideas in the light of new experimental observations. We summarized both in order to clarify the role of platelet-generated Aβ peptides in amyloidosis-related health disorders, which may be helpful to researchers interested in this growing area of investigation.
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Affiliation(s)
- Mikhail Inyushin
- Department of Physiology, Universidad Central del Caribe, Bayamon, Puerto Rico
| | - Astrid Zayas-Santiago
- Department of Pathology & Laboratory Medicine, Universidad Central del Caribe, Bayamon, Puerto Rico
| | - Legier Rojas
- Department of Physiology, Universidad Central del Caribe, Bayamon, Puerto Rico
| | - Lilia Kucheryavykh
- Department of Biochemistry, Universidad Central del Caribe, Bayamon, Puerto Rico
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Casoli T, Giuli C, Balietti M, Fabbietti P, Conti F. Effect of a Cognitive Training Program on the Platelet APP Ratio in Patients with Alzheimer's Disease. Int J Mol Sci 2020; 21:ijms21145110. [PMID: 32698329 PMCID: PMC7403991 DOI: 10.3390/ijms21145110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/14/2020] [Accepted: 07/17/2020] [Indexed: 12/11/2022] Open
Abstract
In patients with Alzheimer’s disease (AD), synaptic plasticity seems to be involved in cognitive improvement induced by cognitive training. The platelet amyloid precursor protein (APP) ratio (APPr), i.e., the ratio between two APP isoforms, may be a useful peripheral biomarker to investigate synaptic plasticity pathways. This study evaluates the changes in neuropsychological/cognitive performance and APPr induced by cognitive training in AD patients participating in the “My Mind Project”. Neuropsychological/cognitive variables and APPr were evaluated in the trained group (n = 28) before a two-month experimental protocol, immediately after its termination at follow-up 1 (FU1), after 6 months at follow-up 2 (FU2), and after 24 months at follow-up 3 (FU3). The control group (n = 31) received general psychoeducational training for two months. Some memory and attention parameters were significantly improved in trained vs. control patients at FU1 and FU2 compared to baseline (Δ values). At FU3, APPr and Mini Mental State Examination (MMSE) scores decreased in trained patients. Δ APPr correlated significantly with the Δ scores of (i) MMSE at FU1, (ii) the prose memory test at FU2, and (iii) Instrumental Activities of Daily Living (IADL), the semantic word fluency test, Clinical Dementia Rating (CDR), and the attentive matrices test at FU3. Our data demonstrate that the platelet APPr correlates with key clinical variables, thereby proving that it may be a reliable biomarker of brain function in AD patients.
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Affiliation(s)
- Tiziana Casoli
- Center for Neurobiology of Aging, IRCCS INRCA, 60121 Ancona, Italy; (M.B.); (F.C.)
- Correspondence: ; Tel.: +39-071-800-4203
| | - Cinzia Giuli
- Geriatrics Operative Unit, IRCCS INRCA, 63023 Fermo, Italy;
| | - Marta Balietti
- Center for Neurobiology of Aging, IRCCS INRCA, 60121 Ancona, Italy; (M.B.); (F.C.)
| | - Paolo Fabbietti
- Unit of Geriatric Pharmacoepidemiology, IRCCS INRCA, 87100 Cosenza, Italy;
| | - Fiorenzo Conti
- Center for Neurobiology of Aging, IRCCS INRCA, 60121 Ancona, Italy; (M.B.); (F.C.)
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Università Politecnica delle Marche, 60126 Ancona, Italy
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12
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Vinothkumar G, Krishnakumar S, Riya, Venkataraman P. Correlation between abnormal GSK3β, β Amyloid, total Tau, p-Tau 181 levels and neuropsychological assessment total scores in CKD patients with cognitive dysfunction: Impact of rHuEPO therapy. J Clin Neurosci 2019; 69:38-42. [DOI: 10.1016/j.jocn.2019.08.073] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 08/06/2019] [Accepted: 08/08/2019] [Indexed: 11/16/2022]
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13
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Inyushin M, Zayas-Santiago A, Rojas L, Kucheryavykh Y, Kucheryavykh L. Platelet-generated amyloid beta peptides in Alzheimer's disease and glaucoma. Histol Histopathol 2019; 34:843-856. [PMID: 30945258 PMCID: PMC6667289 DOI: 10.14670/hh-18-111] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Amyloid beta (Aβ) peptides have been implicated in both Alzheimer's disease (AD) and glaucoma and have been shown to be the key etiological factor in these dangerous health complications. On the other hand, it is well known that Aβ peptide can be generated from its precursor protein and massively released from the blood to nearby tissue upon the activation of platelets due to their involvement in innate immunity and inflammation processes. Here we review evidence about the development of AD and glaucoma neuronal damage showing their dependence on platelet count and activation. The correlation between the effect on platelet count and the effectiveness of anti-AD and anti-glaucoma therapies suggest that platelets may be an important player in these diseases.
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Affiliation(s)
- Mikhail Inyushin
- School of Medicine, Universidad Central del Caribe (UCC), PR, USA.
| | | | - Legier Rojas
- School of Medicine, Universidad Central del Caribe (UCC), PR, USA
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Guzman-Martinez L, Maccioni RB, Farías GA, Fuentes P, Navarrete LP. Biomarkers for Alzheimer’s Disease. Curr Alzheimer Res 2019; 16:518-528. [DOI: 10.2174/1567205016666190517121140] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 04/08/2019] [Accepted: 04/25/2019] [Indexed: 12/15/2022]
Abstract
Alzheimer´s disease (AD) and related forms of dementia are increasingly affecting the aging population throughout the world, at an alarming rate. The World Alzheimer´s Report indicates a prevalence of 46.8 million people affected by AD worldwide. As population ages, this number is projected to triple by 2050 unless effective interventions are developed and implemented. Urgent efforts are required for an early detection of this disease. The ultimate goal is the identification of viable targets for the development of molecular markers and validation of their use for early diagnosis of AD that may improve treatment and the disease outcome in patients. The diagnosis of AD has been difficult to resolve since approaches for early and accurate detection and follow-up of AD patients at the clinical level have been reported only recently. Some proposed AD biomarkers include the detection of pathophysiological processes in the brain in vivo with new imaging techniques and novel PET ligands, and the determination of pathogenic proteins in cerebrospinal fluid showing anomalous levels of hyperphosphorylated tau and low Aβ peptide. These biomarkers have been increasingly accepted by AD diagnostic criteria and are important tools for the design of clinical trials, but difficulties in accessibility to costly and invasive procedures have not been completely addressed in clinical settings. New biomarkers are currently being developed to allow determinations of multiple pathological processes including neuroinflammation, synaptic dysfunction, metabolic impairment, protein aggregation and neurodegeneration. Highly specific and sensitive blood biomarkers, using less-invasive procedures to detect AD, are derived from the discoveries of peripheric tau oligomers and amyloid variants in human plasma and platelets. We have also developed a blood tau biomarker that correlates with a cognitive decline and also with neuroimaging determinations of brain atrophy.
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Balietti M, Giuli C, Conti F. Peripheral Blood Brain-Derived Neurotrophic Factor as a Biomarker of Alzheimer's Disease: Are There Methodological Biases? Mol Neurobiol 2018; 55:6661-6672. [PMID: 29330839 PMCID: PMC6061178 DOI: 10.1007/s12035-017-0866-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 12/26/2017] [Indexed: 12/13/2022]
Abstract
Mounting evidence that alterations in brain-derived neurotrophic factor (BDNF) levels and signaling may be involved in the etiopathogenesis of Alzheimer's disease (AD) has suggested that its blood levels could be used as a biomarker of the disease. However, higher, lower, or unchanged circulating BDNF levels have all been described in AD patients compared to healthy controls. Although the reasons for such different findings are unclear, methodological issues are likely to be involved. The heterogeneity of participant recruitment criteria and the lack of control of variables that influence circulating BDNF levels regardless of dementia (depressive symptoms, medications, lifestyle, lack of overlap between serum and plasma, and experimental aspects) are likely to bias result and prevent study comparability. The present work reviews a broad panel of factors, whose close control could help reduce the inconsistency of study findings, and offers practical advice on their management. Research directed at elucidating the weight of each of these variables and at standardizing analytical methodologies is urgently needed.
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Affiliation(s)
- Marta Balietti
- Center for Neurobiology of Aging, INRCA, Via Birarelli 8, 60121, Ancona, Italy.
| | - Cinzia Giuli
- Geriatrics Operative Unit, INRCA, Fermo, 63023, Italy
| | - Fiorenzo Conti
- Center for Neurobiology of Aging, INRCA, Via Birarelli 8, 60121, Ancona, Italy
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Università Politecnica delle Marche, Ancona, 60126, Italy
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Peripheral Biomarkers for Early Detection of Alzheimer's and Parkinson's Diseases. Mol Neurobiol 2018; 56:2256-2277. [PMID: 30008073 DOI: 10.1007/s12035-018-1151-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 05/24/2018] [Indexed: 01/18/2023]
Abstract
Neurological disorders are found to be influencing the peripheral tissues outside CNS. Recent developments in biomarkers for CNS have emerged with various diagnostic and therapeutic shortcomings. The role of central biomarkers including CSF-based and molecular imaging-based probes are still unclear for early diagnosis of major neurological diseases. Current trends show that early detection of neurodegenerative diseases with non-invasive methods is a major focus of researchers, and the development of biomarkers aiming peripheral tissues is in demand. Alzheimer's and Parkinson's diseases are known for the progressive loss in neural structures or functions, including the neural death. Various dysfunctions of metabolic and biochemical pathways are associated with early occurrence of neuro-disorders in peripheral tissues including skin, blood cells, and eyes. This article reviews the peripheral biomarkers explored for early detection of Alzheimer's and Parkinson's diseases including blood cells, skin fibroblast, proteomics, saliva, olfactory, stomach and colon, heart and peripheral nervous system, and others. Graphical Abstract.
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17
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Emergence of breath testing as a new non-invasive diagnostic modality for neurodegenerative diseases. Brain Res 2018; 1691:75-86. [PMID: 29684335 DOI: 10.1016/j.brainres.2018.04.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 04/13/2018] [Accepted: 04/17/2018] [Indexed: 12/11/2022]
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Amyloid Beta Peptide Is Released during Thrombosis in the Skin. Int J Mol Sci 2018; 19:ijms19061705. [PMID: 29890636 PMCID: PMC6032379 DOI: 10.3390/ijms19061705] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 06/04/2018] [Accepted: 06/06/2018] [Indexed: 12/12/2022] Open
Abstract
While it is known that amyloid beta (Aβ) deposits are found in different tissues of both Alzheimer’s disease (AD) patients and healthy individuals, there remain questions about the physiological role of these deposits, the origin of the Aβ peptide, and the mechanisms of its localization to the tissues. Using immunostaining with specific antibodies, as well as enzyme-linked immunosorbent assay, this study demonstrated Aβ40 peptide accumulation in the skin during local experimental photothrombosis in mice. Specifically, Aβ peptide accumulation was concentrated near the dermal blood vessels in thrombotic skin. It was also studied whether the released peptide affects microorganisms. Application of Aβ40 (4 µM) to the external membrane of yeast cells significantly increased membrane conductance with no visible effect on mouse host cells. The results suggest that Aβ release in the skin is related to skin injury and thrombosis, and occurs along with clotting whenever skin is damaged. These results support the proposition that Aβ release during thrombosis serves as part of a natural defense against infection.
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Shi Y, Gu L, Alsharif AA, Zhang Z. The Distinction of Amyloid-β Protein Precursor (AβPP) Ratio in Platelet Between Alzheimer's Disease Patients and Controls: A Systematic Review and Meta-Analysis. J Alzheimers Dis 2018; 59:1037-1044. [PMID: 28731441 DOI: 10.3233/jad-170253] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
To systematically assess the clinical significance of platelet amyloid-β protein precursor (AβPP) ratio between Alzheimer's disease (AD) patients and controls. 14 articles were selected in this analysis by search of databases including PubMed and Web of Science up to December 2016. Random effects models were used to calculate the standardized mean difference (SMD). Subgroup analyses were used to detect the cause of heterogeneity. The result showed a significant drop in platelet AβPP ratio in AD patients compared to controls [SMD: -1.871; 95% CI: (-2.33, -1.41); p < 0.001; I2 = 88.0% ]. Subgroup analysis revealed races or the quality of studies may be the cause of high heterogeneity. This meta-analysis concluded that there is a close association between platelet AβPP ratio and AD. It is necessary to design a sizable sample study to further support that platelet AβPP ratio can be a biomarker of AD.
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Affiliation(s)
- Yachen Shi
- Department of Neurology, Affiliated ZhongDaHospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Lihua Gu
- Department of Neurology, Affiliated ZhongDaHospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Abdul Azeez Alsharif
- Department of Neurology, Affiliated ZhongDaHospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Zhijun Zhang
- Department of Neurology, Affiliated ZhongDaHospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
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20
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Platelet Proteomic Analysis Revealed Differential Pattern of Cytoskeletal- and Immune-Related Proteins at Early Stages of Alzheimer’s Disease. Mol Neurobiol 2018; 55:8815-8825. [DOI: 10.1007/s12035-018-1039-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 03/23/2018] [Indexed: 12/15/2022]
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A β Peptide Originated from Platelets Promises New Strategy in Anti-Alzheimer's Drug Development. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3948360. [PMID: 29018812 PMCID: PMC5605787 DOI: 10.1155/2017/3948360] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 07/10/2017] [Indexed: 12/20/2022]
Abstract
The amyloid beta (Aβ) peptide and its deposits in the brain are known to be implicated in the neurodegeneration that occurs during Alzheimer's disease (AD). Recently, alternative theories views concerning both the source of this peptide and its functions have been developed. It has been shown that, as in all other known types of amyloidosis, the production of Aβ originates in blood cells or cells related to blood plasma, from which it can then spread from the blood to inside the brain, with the greatest concentration around brain blood vessels. In this review, we summarize research progress in this new area and outline some future perspectives. While it is still unclear whether the main source of Aβ deposits in AD is the blood, the possibility of blocking the chain of reactions that lead to constant Aβ release from the blood to the brain may be exploited in an attempt to reduce the amyloid burden in AD. Solving the problem of Aβ accumulation in this way may provide an alternative strategy for developing anti-AD drugs.
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Kucheryavykh LY, Dávila-Rodríguez J, Rivera-Aponte DE, Zueva LV, Washington AV, Sanabria P, Inyushin MY. Platelets are responsible for the accumulation of β-amyloid in blood clots inside and around blood vessels in mouse brain after thrombosis. Brain Res Bull 2016; 128:98-105. [PMID: 27908798 DOI: 10.1016/j.brainresbull.2016.11.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 11/21/2016] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Platelets contain beta-amyloid precursor protein (APP) as well as Aβ peptide (Aβ) that can be released upon activation. During thrombosis, platelets are concentrated in clots and activated. METHODS We used in vivo fluorescent analysis and electron microscopy in mice to determine to what degree platelets are concentrated in clots. We used immunostaining to visualize Aβ after photothrombosis in mouse brains. RESULTS Both in vivo results and electron microscopy revealed that platelets were 300-500 times more concentrated in clots than in non-clotted blood. After thrombosis in control mice, but not in thrombocytopenic animals, Aβ immunofluorescence was present inside blood vessels in the visual cortex and around capillaries in the entorhinal cortex. CONCLUSION The increased concentration of platelets allows enhanced release of Aβ during thrombosis, suggesting an additional source of Aβ in the brains of Alzheimer's patients that may arise if frequent micro-thrombosis events occur in their brains.
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Affiliation(s)
- Lilia Y Kucheryavykh
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamon, PR 00960-6032, (P.O. Box 60327), USA.
| | - Josué Dávila-Rodríguez
- School of Medicine, Universidad Central del Caribe, Bayamon, PR 00960-6032, (P.O. Box 60327), USA.
| | - David E Rivera-Aponte
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamon, PR 00960-6032, (P.O. Box 60327), USA.
| | - Lidia V Zueva
- Department of Physics, University of Puerto Rico Rio Piedras, San Juan, PR 00936, USA.
| | - A Valance Washington
- Department of Anatomy, School of Medicine, Universidad Central del Caribe, Bayamon, PR 00960-6032, (P.O. Box 60327), USA; The Department of Biology, University of Puerto Rico Rio Piedras, San Juan, PR 00936, USA.
| | - Priscilla Sanabria
- Department of Physiology, School of Medicine, Universidad Central del Caribe, Bayamon, PR 00960-6032, (P.O. Box 60327), USA.
| | - Mikhail Y Inyushin
- Department of Physiology, School of Medicine, Universidad Central del Caribe, Bayamon, PR 00960-6032, (P.O. Box 60327), USA.
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Ruan Q, D'Onofrio G, Sancarlo D, Greco A, Yu Z. Potential fluid biomarkers for pathological brain changes in Alzheimer's disease: Implication for the screening of cognitive frailty. Mol Med Rep 2016; 14:3184-98. [PMID: 27511317 PMCID: PMC5042792 DOI: 10.3892/mmr.2016.5618] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 07/18/2016] [Indexed: 11/27/2022] Open
Abstract
Cognitive frailty (CF) overlaps with early neuropathological alterations associated with aging-related major neurocognitive disorders, including Alzheimer's disease (AD). Fluid biomarkers for these pathological brain alterations allow for early diagnosis in the preclinical stages of AD, and for objective prognostic assessments in clinical intervention trials. These biomarkers may also be helpful in the screening of CF. The present study reviewed the literature and identified systematic reviews of cohort studies and other authoritative reports. The selection criteria for potentially suitable fluid biomarkers included: i) Frequent use in studies of fluid-derived markers and ii) evidence of novel measurement techniques for fluid-derived markers. The present study focused on studies that assessed these biomarkers in AD, mild cognitive impairment and non-AD demented subjects. At present, widely used fluid biomarkers include cerebrospinal fluid (CSF), total tau, phosphorylated tau and amyloid-β levels. With the development of novel measurement techniques and improvements in understanding regarding the mechanisms underlying aging-related major neurocognitive disorders, numerous novel biomarkers associated with various aspects of AD neuropathology are being explored. These include specific measurements of Aβ oligomer or monomer forms, tau proteins in the peripheral plasma and CSF, and novel markers of synaptic dysfunction, neuronal damage and apoptosis, neuronal activity alteration, neuroinflammation, blood brain barrier dysfunction, oxidative stress, metabolites, mitochondrial function and aberrant lipid metabolism. The proposed panels of fluid biomarkers may be useful in the early diagnosis of AD, prediction of the progression of AD from preclinical stages to the dementia stage, and the differentiation of AD from non-AD dementia. In combination with physical frailty, the present study surmised that these biomarkers may also be used as biomarkers for CF, thus contribute to discovering causes and informing interventions for cognitive impairment in individuals with CF.
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Affiliation(s)
- Qingwei Ruan
- Shanghai Institute of Geriatrics and Gerontology, Shanghai Key Laboratory of Clinical Geriatrics, Department of Geriatrics, Huadong Hospital, and Research Center of Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai 200040, P.R. China
| | - Grazia D'Onofrio
- Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, I‑71013 Foggia, Italy
| | - Daniele Sancarlo
- Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, I‑71013 Foggia, Italy
| | - Antonio Greco
- Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, I‑71013 Foggia, Italy
| | - Zhuowei Yu
- Shanghai Institute of Geriatrics and Gerontology, Shanghai Key Laboratory of Clinical Geriatrics, Department of Geriatrics, Huadong Hospital, and Research Center of Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai 200040, P.R. China
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Dziedzic T, Pera J, Klimkowicz-Mrowiec A, Mroczko B, Slowik A. Biochemical and Radiological Markers of Alzheimer's Disease Progression. J Alzheimers Dis 2016; 50:623-44. [PMID: 26757184 DOI: 10.3233/ifs-150578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative, inevitably progressive disease with a rate of cognitive, functional, and behavioral decline that varies highly from patient to patient. Although several clinical predictors of AD progression have been identified, to our mind in clinical practice there is a lack of a reliable biomarker that enables one to stratify the risk of deterioration. Identification of biomarkers that allow the monitoring of AD progression could change the way physicians and caregivers make treatment decisions. This review summarizes the results of studies on potential biochemical and radiological markers related to AD progression.
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Affiliation(s)
- Tomasz Dziedzic
- Department of Neurology, Jagiellonian University, Krakow, Poland
| | - Joanna Pera
- Department of Neurology, Jagiellonian University, Krakow, Poland
| | | | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Białystok, Poland.,Department of Biochemical Diagnostics, University Hospital, Białystok, Poland
| | - Agnieszka Slowik
- Department of Neurology, Jagiellonian University, Krakow, Poland
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25
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Plagg B, Marksteiner J, Kniewallner KM, Humpel C. Platelet dysfunction in hypercholesterolemia mice, two Alzheimer's disease mouse models and in human patients with Alzheimer's disease. Biogerontology 2015; 16:543-58. [PMID: 25947203 PMCID: PMC4487346 DOI: 10.1007/s10522-015-9580-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 04/28/2015] [Indexed: 12/22/2022]
Abstract
Alzheimer’s disease (AD) is a severe neurodegenerative disorder characterized mainly by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss. Blood platelets contain the neurotransmitter serotonin and amyloid-precursor protein (APP), and may thus be useful as a peripheral biomarker for AD. The aim of the present study was to functionally characterize platelets by FACS, to examine alterations in APP expression and secretion, and to measure serotonin levels in hypercholesterolemia mice with AD-like pathology and in two AD mouse models, the triple transgenic AD model (3xTg) and the APP overexpressing AD model with the Swedish–Dutch–Iowa mutations (APP_SweDI). These data are supplemented with epidermal growth factor (EGF) levels and compared with changes observed in platelets of patients with AD. We observed decreased platelet APP isoforms in 3xTg mice and patients with AD when analysed by means of Western blot. In patients, a significant increase of APP levels was observed when assessed by ELISA. Secreted APPβ proved to be altered amongst all three animal models of AD at different time points and in human patients with AD. Serotonin levels were only reduced in 7 and 14 month old 3xTg mice. Moreover, we found significantly lower EGF levels in human AD patients and could thereby reproduce previous findings. Taken together, our data confirm that platelets are dysfunctional in AD, however, results from AD animal models do not coincide in all aspects, and markedly differ when compared to AD patients. We support previous data that APP, as well as EGF, could become putative biomarkers for diagnosing AD in human platelets.
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Affiliation(s)
- Barbara Plagg
- Laboratory of Psychiatry and Experimental Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria
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Chatterjee P, Gupta VB, Fagan AM, Jasielec MS, Xiong C, Sohrabi HR, Dhaliwal S, Taddei K, Bourgeat P, Brown BM, Benzinger T, Bateman RJ, Morris JC, Martins RN. Decreased platelet APP isoform ratios in autosomal dominant Alzheimer's disease: baseline data from a DIAN cohort subset. Curr Alzheimer Res 2015; 12:157-64. [PMID: 25654503 PMCID: PMC4383703 DOI: 10.2174/1567205012666150204125732] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 09/05/2014] [Accepted: 10/29/2014] [Indexed: 01/17/2023]
Abstract
INTRODUCTION This study examines platelet amyloid precursor protein (APP) isoform ratios of 120KDa to 110KDa (APPr) between mutation carriers (MC) carrying a mutation for autosomal dominant Alzheimer's disease (ADAD) and non-carriers (NC). Two previous studies reported no significant difference in APPr between ADAD MC and NC, which may have been due to the small sample size in both studies. The current study examines APPr in MC versus NC in a larger sample. In addition, it investigated whether APPr correlate with neuroimaging data, neuropsychological data and cerebrospinal fluid biomarkers in a cohort subset derived from the Dominantly Inherited Alzheimer Network (DIAN) study. METHODS APPr were quantified by western blotting. Fifteen MC (symptomatic and asymptomatic) were compared against twelve NC using univariate general linear model. All participants underwent neuroimaging and neuropsychological testing which were correlated with APPr using Pearson's correlation coefficient (r). RESULTS APPr were lower in MC compared to NC (p=0.003) while Mini-Mental State Examination (MMSE) scores were not significantly different (p>0.1). Furthermore, APPr inversely correlated with amyloid imaging in the Caudate Nucleus (r=-0.505; p<0.05) and Precuneus (r=-0.510; p<0.05). CONCLUSION APPr are lower in ADAD MC compared to NC, and inversely correlated with brain amyloid load prior to significant differences in cognitive health. However, the use of APPr as a biomarker needs to be explored further.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Ralph N Martins
- School of Medical Science, Edith Cowan University, 270 Joondalup Dr., Joondalup, WA 6027, Australia.
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Milovanovic M, Eriksson K, Winblad B, Nilsson S, Lindahl TL, Post C, Järemo P. Alzheimer and platelets: Low-density platelet populations reveal increased serotonin content in Alzheimer type dementia. Clin Biochem 2014; 47:51-3. [DOI: 10.1016/j.clinbiochem.2014.07.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 07/05/2014] [Accepted: 07/08/2014] [Indexed: 10/25/2022]
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Veitinger M, Varga B, Guterres SB, Zellner M. Platelets, a reliable source for peripheral Alzheimer's disease biomarkers? Acta Neuropathol Commun 2014; 2:65. [PMID: 24934666 PMCID: PMC4229876 DOI: 10.1186/2051-5960-2-65] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 06/01/2014] [Indexed: 12/20/2022] Open
Abstract
Peripheral biomarkers play an indispensable role in quick and reliable diagnoses of any kind of disease. With the population ageing, the number of people suffering from age-related diseases is expected to rise dramatically over the coming decades. In particular, all types of cognitive deficits, such as Alzheimer's disease, will increase. Alzheimer's disease is characterised mainly by coexistence of amyloid plaques and neurofibrillary tangles in brain. Reliable identification of such molecular characteristics antemortem, however, is problematic due to restricted availability of appropriate sample material and definitive diagnosis is only possible postmortem. Currently, the best molecular biomarkers available for antemortem diagnosis originate from cerebrospinal fluid. Though, this is not convenient for routine diagnosis because of the required invasive lumbar puncture. As a consequence, there is a growing demand for additional peripheral biomarkers in a more readily accessible sample material. Blood platelets, due to shared biochemical properties with neurons, can constitute an attractive alternative as discussed here. This review summarises potential platelet Alzheimer's disease biomarkers, their role, implication, and alteration in the disease. For easy comparison of their performance, the Hedge effect size was calculated whenever data were available.
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Affiliation(s)
- Michael Veitinger
- />Institute of Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, EU, Austria
| | - Balazs Varga
- />Institute of Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, EU, Austria
| | - Sheila B Guterres
- />Institute of Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, EU, Austria
- />Institute of Chemistry at São Carlos, University of São Paulo, São Paulo, Brazil
| | - Maria Zellner
- />Institute of Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, EU, Austria
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Manzine PR, Barham EJ, Vale FAC, Selistre-de-Araújo HS, Pavarini SCI, Cominetti MR. Platelet a disintegrin and metallopeptidase 10 expression correlates with clock drawing test scores in Alzheimer's disease. Int J Geriatr Psychiatry 2014; 29:414-20. [PMID: 23970375 DOI: 10.1002/gps.4020] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 07/30/2013] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Earlier studies have demonstrated that a disintegrin and metallopeptidase 10 (ADAM10) levels are reduced in Alzheimer's disease (AD) patients compared with healthy subjects. The objective of this study was to evaluate whether platelet ADAM10 levels correlates with the clock drawing test (CDT) scores, which is a simple and a reliable measure of visuospatial ability and executive function in AD patients. METHODS Thirty elderly patients with probable AD and 25 healthy patients forming the control group, matched by age, gender, and educational level, were evaluated. Platelet proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, and ADAM10 was identified by western blotting. The Spearman's correlation coefficient between ADAM10 and CDT was obtained for each group. The areas under the curves were used to compare the receiver operating characteristic curves. RESULTS The CDT scores and platelet ADAM10 expression were significantly different between patients with AD and controls and also along the disease's progression. In AD patients, there was a positive correlation between ADAM10 expression and CDT scores. Among non-AD subjects, no correlation was found. The combination of ADAM10 and CDT was significantly better to confirm the AD diagnosis than the AUCs of ADAM10 and CDT separately. CONCLUSIONS The association of blood-based biomarkers, such as ADAM10, and cognitive tests may be helpful for a more reliable AD diagnosis.
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Gowert NS, Donner L, Chatterjee M, Eisele YS, Towhid ST, Münzer P, Walker B, Ogorek I, Borst O, Grandoch M, Schaller M, Fischer JW, Gawaz M, Weggen S, Lang F, Jucker M, Elvers M. Blood platelets in the progression of Alzheimer's disease. PLoS One 2014; 9:e90523. [PMID: 24587388 PMCID: PMC3938776 DOI: 10.1371/journal.pone.0090523] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 01/31/2014] [Indexed: 11/18/2022] Open
Abstract
Alzheimer's disease (AD) is characterized by neurotoxic amyloid-ß plaque formation in brain parenchyma and cerebral blood vessels known as cerebral amyloid angiopathy (CAA). Besides CAA, AD is strongly related to vascular diseases such as stroke and atherosclerosis. Cerebrovascular dysfunction occurs in AD patients leading to alterations in blood flow that might play an important role in AD pathology with neuronal loss and memory deficits. Platelets are the major players in hemostasis and thrombosis, but are also involved in neuroinflammatory diseases like AD. For many years, platelets were accepted as peripheral model to study the pathophysiology of AD because platelets display the enzymatic activities to generate amyloid-ß (Aß) peptides. In addition, platelets are considered to be a biomarker for early diagnosis of AD. Effects of Aß peptides on platelets and the impact of platelets in the progression of AD remained, however, ill-defined. The present study explored the cellular mechanisms triggered by Aß in platelets. Treatment of platelets with Aß led to platelet activation and enhanced generation of reactive oxygen species (ROS) and membrane scrambling, suggesting enhanced platelet apoptosis. More important, platelets modulate soluble Aß into fibrillar structures that were absorbed by apoptotic but not vital platelets. This together with enhanced platelet adhesion under flow ex vivo and in vivo and platelet accumulation at amyloid deposits of cerebral vessels of AD transgenic mice suggested that platelets are major contributors of CAA inducing platelet thrombus formation at vascular amyloid plaques leading to vessel occlusion critical for cerebrovascular events like stroke.
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Affiliation(s)
- Nina S. Gowert
- Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany
| | - Lili Donner
- Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany
| | - Madhumita Chatterjee
- Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls-Universität, Tübingen, Germany
| | - Yvonne S. Eisele
- Department of Cellular Neurology, Hertie-Institut for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany
- DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
| | - Seyda T. Towhid
- Department of Physiology, Eberhard-Karls University, Tübingen, Germany
| | - Patrick Münzer
- Department of Physiology, Eberhard-Karls University, Tübingen, Germany
| | - Britta Walker
- Department of Physiology, Eberhard-Karls University, Tübingen, Germany
| | - Isabella Ogorek
- Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany
| | - Oliver Borst
- Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls-Universität, Tübingen, Germany
- Department of Physiology, Eberhard-Karls University, Tübingen, Germany
| | - Maria Grandoch
- Institut für Pharmakologie u. Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Martin Schaller
- Department of Dermatology, Eberhard-Karls University, Tübingen, Germany
| | - Jens W. Fischer
- Institut für Pharmakologie u. Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Meinrad Gawaz
- Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls-Universität, Tübingen, Germany
| | - Sascha Weggen
- Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany
| | - Florian Lang
- Department of Physiology, Eberhard-Karls University, Tübingen, Germany
| | - Mathias Jucker
- Department of Cellular Neurology, Hertie-Institut for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany
| | - Margitta Elvers
- Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany
- Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls-Universität, Tübingen, Germany
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Liu JP, Feng L, Zhang MH, Ma DY, Wang SY, Gu J, Fu Q, Qu R, Ma SP. Neuroprotective effect of Liuwei Dihuang decoction on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat. JOURNAL OF ETHNOPHARMACOLOGY 2013; 150:371-81. [PMID: 24041458 DOI: 10.1016/j.jep.2013.09.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 09/02/2013] [Accepted: 09/05/2013] [Indexed: 05/22/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liuwei Dihuang decoction (LWDHD) is a well-known prescription of traditional Chinese medicine (TCM) and consists of six crude drugs including Rehmannia glutinosa Libosch. (family: Scrophulariaceae), Cornus officinalis Sieb. (family: Cornaceae), Dioscorea oppositifolia L. (family: Dioscoreaceae), Paoenia ostii (family: Paeoniaceae), Alisma orientale (G. Samuelsson) Juz (family: Alismataceae) and Poria cocos (Schw.) Wolf (family: Polyporaceae). It has been used for the treatment of "Kidney-Yin" deficiency syndrome in clinic in China for a long time. Recent studies found that LWDHD had a potential benefit for the treatment of diabetic complications. The aim of the present study is to investigate the neuroprotective effect of LWDHD on memory and cognition deficits in streptozotocin (STZ)-induced diabetic encephalopathy (DE) rats. MATERIALS AND METHODS Adult male Sprague Dawley (SD) rats were fed with high-glucose-fat diet for 50 days and then received an intraperitoneal injection of STZ (40 mg/kg) to induce DE model. Morris water maze test was used to evaluate the memory and cognition capability of DE rats. Choline acetyltransferase (ChAT), acetylcholinesterase (AChE), Na(+)-K(+)-ATP enzyme, iNOS and GSH kits were used to determine their activities or content in hippocampus. TUNEL staining, immunohistochemistry and Congo red staining were conducted to evaluate the apoptosis, caspase-3 protein expression, insulin-like growth factors 1 (IGF-1) and brain derived neurophic factor (BDNF) expressions, as well as Aβ deposition. RESULTS The treatment with LWDHD (1 and 2g/kg, p.o., once daily, 30 days) could significantly reduce the escape latency time and path length, and obviously enhance the spent time in the target quadrant and platform crossings in Morris water maze test compared with model group (P<0.05, P<0.01). LWDHD could also significantly decrease the level of fasting blood glucose, increase Na(+)-K(+)-ATP enzyme and ChAT activities, enhance remarkedly GSH level while decrease significantly AChE and iNOS activities in hippocampus (P<0.05, P<0.01). Furthermore, TUNEL staining, Congo red staining and immunohistochemistry showed that LWDHD significantly improved the expressions of IGF-1 and BDNF, attenuated the neural apoptosis, overexpression of caspase-3 and Aβ deposition in the hippocampus and cerebral cortex of STZ-induced DE rats (P<0.01). CONCLUSION Our findings suggested that LWDHD had a neuroprotective effect on DE rats. LWDHD may be of benefit in the treatment of DE.
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Affiliation(s)
- Ji-ping Liu
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Jiangsu, Nanjing 210009, PR China; Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China
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32
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The platelet amyloid precursor protein ratio as a diagnostic marker for Alzheimer’s disease in Thai patients. J Clin Neurosci 2013; 20:644-8. [DOI: 10.1016/j.jocn.2012.06.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Revised: 05/29/2012] [Accepted: 06/01/2012] [Indexed: 11/18/2022]
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Henry MS, Passmore AP, Todd S, McGuinness B, Craig D, Johnston JA. The development of effective biomarkers for Alzheimer's disease: a review. Int J Geriatr Psychiatry 2013; 28:331-40. [PMID: 22674539 DOI: 10.1002/gps.3829] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 04/11/2012] [Indexed: 12/29/2022]
Abstract
OBJECTIVE There is a widely recognised need to develop effective Alzheimer's disease (AD) biomarkers to aid the development of disease-modifying treatments, to facilitate early diagnosis and to improve clinical care. This overview aims to summarise the utility of key neuroimaging and cerebrospinal fluid (CSF) biomarkers for AD, before focusing on the latest efforts to identify informative blood biomarkers. DESIGN A literature search was performed using PubMed up to September 2011 for reviews and primary research studies of neuroimaging (magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and amyloid imaging), CSF and blood-based (plasma, serum and platelet) biomarkers in AD and mild cognitive impairment. Citations within individual articles were examined to identify additional studies relevant to this review. RESULTS Evidence of AD biomarker potential was available for imaging techniques reflecting amyloid burden and neurodegeneration. Several CSF measures are promising, including 42 amino acid β-amyloid peptide (Aβ42 ); total tau (T-tau) protein, reflecting axonal damage; and phosphorylated tau (P-tau), reflecting neurofibrillary tangle pathology. Studies of plasma Aβ have produced inferior diagnostic discrimination. Alternative plasma and platelet measures are described, which represent potential avenues for future research. CONCLUSIONS Several imaging and CSF markers demonstrate utility in predicting AD progression and determining aetiology. These require standardisation before forming core elements of diagnostic criteria. The enormous potential available for identifying a minimally-invasive, easily-accessible blood measure as an effective AD biomarker currently remains unfulfilled.
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Affiliation(s)
- Mark S Henry
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
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Talib LL, Joaquim HP, Forlenza OV. Platelet biomarkers in Alzheimer’s disease. World J Psychiatry 2012; 2:95-101. [PMID: 24175175 PMCID: PMC3782189 DOI: 10.5498/wjp.v2.i6.95] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 10/23/2012] [Accepted: 11/17/2012] [Indexed: 02/05/2023] Open
Abstract
The search for diagnostic and prognostic markers in Alzheimer’s disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.
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Affiliation(s)
- Leda L Talib
- Leda L Talib, Helena PG Joaquim, Orestes V Forlenza, Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, 05403-010 São Paulo, SP, Brazil
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Evin G, Li QX. Platelets and Alzheimer’s disease: Potential of APP as a biomarker. World J Psychiatry 2012; 2:102-13. [PMID: 24175176 PMCID: PMC3782192 DOI: 10.5498/wjp.v2.i6.102] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 07/13/2012] [Accepted: 07/23/2012] [Indexed: 02/05/2023] Open
Abstract
Platelets are the first peripheral source of amyloid precursor protein (APP). They possess the proteolytic machinery to produce Aβ and fragments similar to those produced in neurons, and thus offer an ex-vivo model to study APP processing and changes associated with Alzheimer’s disease (AD). Platelet process APP mostly through the α-secretase pathway to release soluble APP (sAPP). They produce small amounts of Aβ, predominantly Aβ40 over Aβ42. sAPP and Aβ are stored in α-granules and are released upon platelet activation by thrombin and collagen, and agents inducing platelet degranulation. A small proportion of full-length APP is present at the platelet surface and this increases by 3-fold upon platelet activation. Immunoblotting of platelet lysates detects APP as isoforms of 130 kDa and 106-110 kDa. The ratio of these of APP isoforms is significantly lower in patients with AD and mild cognitive impairment (MCI) than in healthy controls. This ratio follows a decrease that parallels cognitive decline and can predict conversion from MCI to AD. Alterations in the levels of α-secretase ADAM10 and in the enzymatic activities of α- and β-secretase observed in platelets of patients with AD are consistent with increased processing through the amyloidogenic pathway. β-APP cleaving enzyme activity is increased by 24% in platelet membranes of patients with MCI and by 17% in those with AD. Reports of changes in platelet APP expression with MCI and AD have been promising so far and merit further investigation as the search for blood biomarkers in AD, in particular at the prodromal stage, remains a priority and a challenge.
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Affiliation(s)
- Geneviève Evin
- Geneviève Evin, Qiao-Xin Li, Department of Pathology and Mental Health Research Institute, The University of Melbourne, Parkville 3010, Australia
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Catricala S, Torti M, Ricevuti G. Alzheimer disease and platelets: how's that relevant. IMMUNITY & AGEING 2012; 9:20. [PMID: 22985434 PMCID: PMC3545835 DOI: 10.1186/1742-4933-9-20] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Accepted: 08/01/2012] [Indexed: 02/06/2023]
Abstract
Alzheimer Disease (AD) is the most common neurodegenerative disorder worldwide, and account for 60% to 70% of all cases of progressive cognitive impairment in elderly patients. At the microscopic level distinctive features of AD are neurons and synapses degeneration, together with extensive amounts of senile plaques and neurofibrillars tangles. The degenerative process probably starts 20-30 years before the clinical onset of the disease. Senile plaques are composed of a central core of amyloid β peptide, Aβ, derived from the metabolism of the larger amyloid precursor protein, APP, which is expressed not only in the brain, but even in non neuronal tissues. More than 30 years ago, some studies reported that human platelets express APP and all the enzymatic activities necessary to process this protein through the same pathways described in the brain. Since then a large number of evidence has been accumulated to suggest that platelets may be a good peripheral model to study the metabolism of APP, and the pathophysiology of the onset of AD. In this review, we will summarize the current knowledge on the involvement of platelets in Alzheimer Disease. Although platelets are generally accepted as a suitable model for AD, the current scientific interest on this model is very high, because many concepts still remain debated and controversial. At the same time, however, these still unsolved divergences mirror a difficulty to establish constant parameters to better defined the role of platelets in AD.
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Affiliation(s)
- Silvia Catricala
- Department of Internal Medicine and Therapeutics, Section of Geriatrics, University of Pavia, ASP-IDR S,Margherita, Via Emilia 12, Pavia, 27100, Italy.
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Järemo P, Milovanovic M, Buller C, Nilsson S, Winblad B. Low-density platelet populations demonstrate lowin vivoactivity in sporadic Alzheimer disease. Platelets 2011; 23:116-20. [DOI: 10.3109/09537104.2011.593654] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Mohamad López H. Transfer of the amyloid β and/or of β-amyloid precursor protein of the fetus with trisomy 21 to the maternal blood stream and its possible contribution to the pathogenesis of the maternal Alzheimer's Disease. Med Hypotheses 2011; 77:1058-61. [PMID: 21944886 DOI: 10.1016/j.mehy.2011.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Revised: 08/08/2011] [Accepted: 09/02/2011] [Indexed: 10/17/2022]
Abstract
Down Syndrome (DS) is the most frequent genetic pathology. It affects 1 out of every 800 newborn babies. Approximately between a 90% and a 95% of all the cases of DS are attributed to a trisomy in chromosome 21. One of the genes contained in this chromosome is the gene of β-amyloid precursor protein (βAPP). The metabolism of this protein yields, among others, the amyloid beta peptides made up of 40 amino acids (Aβ40) and 42 amino acids (Aβ42). The evidence that is derived from several sources--genetic, among them--suggests that the Aβ participates in the pathogenesis of Alzheimer's Disease (AD). It is worth pointing at the fact that the transfer of cells, extracellular chromosomal material and some proteins from the fetus to the mother and vice versa has been widely described. The transfer rate from the fetus to the mother is higher when the mother is carrying a baby with trisomy 21. This has led to the hypothesis that sets forth that during the gestation of a baby with DS there is a greater fetomaternal transfer of cells and of products of the genes of chromosome 21--among them, βAPP and its metabolites Aβ40 and Aβ42. It is possible to speculate on the possible contribution of the fetal components--among them, Aβ--to the higher risk of suffering AD, which has been reported in a subpopulation of women who have given birth to children with DS. On the other hand, the detection of the βAPP--mainly intracellular--and of the β amyloid peptides in maternal blood and urine during the early stages of gestation could be taken as a potential non invasive biochemical prenatal marker of DS.
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Affiliation(s)
- Himara Mohamad López
- Cátedra de Bioquímica, Escuela de Medicina Luis Razzetti, Facultad de Medicina, Universidad Central de Venezuela, Luis Razzetti School of Medicine, Faculty of Medicine, Central University of Venezuela, Caracas, Venezuela.
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Blood-based protein biomarkers for diagnosis and classification of neurodegenerative diseases: current progress and clinical potential. Mol Diagn Ther 2011; 15:83-102. [PMID: 21623645 DOI: 10.1007/bf03256398] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Biomarker research is a rapidly advancing field in medicine. Recent advances in genomic, genetic, epigenetic, neuroscientific, proteomic, and metabolomic knowledge and technologies have opened the way to thriving research. In the most general sense, a biomarker refers to any useful characteristic that can be measured and used as an indicator of a normal biologic process, a pathogenic process, or a pharmacologic response to a therapeutic agent. Despite the extensive resources concentrated on this area, there are very few biomarkers currently available that qualify and are satisfactorily validated for mental disorders, and there is still a major lack of biomarkers for typifying neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. This article provides an overview of this field of research and focuses on recent advances in biomarker research in Alzheimer's disease and Parkinson's disease.
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Stellos K, Panagiota V, Kögel A, Leyhe T, Gawaz M, Laske C. Predictive value of platelet activation for the rate of cognitive decline in Alzheimer's disease patients. J Cereb Blood Flow Metab 2010; 30:1817-20. [PMID: 20717123 PMCID: PMC3023934 DOI: 10.1038/jcbfm.2010.140] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Vascular risk factors contribute to the progression of dementia in Alzheimer's disease (AD) and influence platelet activation. However, the degree of platelet activation as a possible underlying mechanism of this progression has not been studied till now. Significantly higher baseline expression of both platelet activation biomarkers, activated glycoprotein IIb-IIIa complex and P-selectin, was observed in patients with AD with fast cognitive decline compared with AD patients with slow cognitive decline during a 1-year follow-up period. These results suggest that platelet activation could be a putative prognostic biomarker for the rate of cognitive decline and a potential new treatment target in AD patients.
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Affiliation(s)
- Konstantinos Stellos
- Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls Universität Tübingen, Otfried-Mueller-Straße 10, Tübingen, Germany.
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Schneider P, Hampel H, Buerger K. Biological marker candidates of Alzheimer's disease in blood, plasma, and serum. CNS Neurosci Ther 2009; 15:358-74. [PMID: 19840034 DOI: 10.1111/j.1755-5949.2009.00104.x] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
At the earliest clinical stages of Alzheimer's disease (AD), when first symptoms are mild, making a reliable and accurate diagnosis is difficult. AD related brain pathology and underlying molecular mechanisms precede symptoms. Biological markers can serve as supportive early screening and diagnostic tools as well as indicators of presymptomatic biochemical change. Moreover, biomarkers cover a variety of roles and functions such as disease prediction, indicating disease acuity and progression, and may ensure biological mapping of treatment outcome. Early screening, detection, and diagnosis of AD would permit earlier disease modifying intervention at potentially reversible stages. To date, most established biological markers from both cerebrospinal fluid neurochemistry and structural and functional neuroimaging have not reached widespread clinical application. Crucial remaining problems, such as easy acceptance and application of a test, cost-effectiveness, and noninvasiveness, need to be resolved. The development and validation of precise, reliable, and robust tests and biomarkers in blood, plasma, or serum has therefore been for a long time the ultimate focus of many research groups worldwide. Blood-based testing will most likely be the prerequisite to future sensitive screening of large populations at risk of AD and the baseline in a diagnostic flow approach to AD. The status and emerging perspectives on hypothesis and exploratory-based candidate biomarkers derived from blood, plasma, and serum are reviewed and discussed.
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Affiliation(s)
- Philine Schneider
- Department of Psychiatry, Ludwig-Maximilian University, Alzheimer Memorial Center, Munich, Germany.
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42
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Smith CCT, Prichard BNC, Cooper MB. Platelet α- and β-secretase activities: A preliminary study in normal human subjects. Platelets 2009; 20:29-34. [DOI: 10.1080/09537100802334434] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Gispen-de Wied CC, Kritsidima M, Elferink AJA. The validity of biomarkers as surrogate endpoints in Alzheimer's disease by means of the Quantitative Surrogate Validation Level of Evidence Scheme (QSVLES). J Nutr Health Aging 2009; 13:376-87. [PMID: 19300886 DOI: 10.1007/s12603-009-0049-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To evaluate the validity of biomarkers that are currently being proposed as potential surrogate endpoints in AD clinical trials with the aid of the "Quantitative Surrogate Validation Level of Evidence Schema" (QSVLES) proposed by Lassere et.al. (1). PROCEDURE A Pubmed literature search was conducted to identify AD biomarkers with SEP potential, and the QSVLES was applied to determine the extent of the SEP validity. RESULTS MRI, PET and MRS measures attained a total validity score of 4, NAA/Cre a total score of 5, and cerebral blood flow (SPECT), Abeta , Tau and APP a total score of 2. None of these biomarkers could fall into the rank of Levels 1 or 2, reserved for SEPs, according to the QSVLES criteria. This was mainly attributed to the lack of sufficient evidence that was derived from high ranking studies (RCT, prospective observational studies). CONCLUSION Though residing on SEPs as sole determinants of the benefit/risk ratio of AD medications seems to be pretty far, there could be certain cases where the use of SEPs may be beneficial, making efficient therapies available faster when there is a major public health interest involved. However, the potential risks of relying on invalid SEPs should not be underestimated and therefore the research on SEP validation and the development of specific validation guidance should be encouraged. The QSVLES, though not devoid of criticism, may be proposed as a starting point.
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Abstract
Alzheimer disease is the most common cause of dementia, yet its clinical diagnosis remains uncertain until an eventual postmortem histopathology examination. Currently, therapy for patients with Alzheimer disease only treats the symptoms; however, it is anticipated that new disease-modifying drugs will soon become available.Diagnostic tools for detecting Alzheimer disease at an incipient stage that can reliably differentiate the disease from other forms of dementia are of key importance for optimal treatment. Biomarkers have the potential to aid in a correct diagnosis, and great progress has been made in the discovery and development of potentially useful biomarkers in recent years. This includes single protein biomarkers in the cerebrospinal fluid, as well as multi-component biomarkers, and biomarkers based on gene expression. Novel biomarkers that use blood and urine, the more easily available clinical samples, are also being discovered and developed. The plethora of potential biomarkers currently being investigated may soon provide biomarkers that fulfill different functions, not only for diagnostic purposes but also for drug development and to follow disease progression.
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Prodan CI, Ross ED, Vincent AS, Dale GL. Rate of progression in Alzheimer's disease correlates with coated-platelet levels--a longitudinal study. Transl Res 2008; 152:99-102. [PMID: 18774538 DOI: 10.1016/j.trsl.2008.07.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2008] [Revised: 07/08/2008] [Accepted: 07/10/2008] [Indexed: 10/21/2022]
Abstract
Coated-platelets represent a subset of platelets produced by activation with both collagen and thrombin that retain full-length amyloid precursor protein on their surface. In our initial cross-sectional study, coated-platelet levels correlated inversely with disease severity in Alzheimer's disease (AD). Higher levels were observed in the early stage compared with the advanced stage of the disease. In this longitudinal study, we investigated for the first time the relationship between initial coated-platelet levels and disease progression in individuals with AD. Coated-platelet levels were assayed in 25 patients with AD who where then clinically monitored for 2 years. A significant linear correlation (r = 0.47, P = 0.017) was detected between the initial coated-platelet levels and disease progression measured in the Mini-Mental State Examination score. The most severe decline was noted in individuals with the highest initial coated-platelet production. These findings support our previous observations from cross-sectional studies and suggest the need for additional study of coated-platelets as a link to the sequence of events leading to the development of AD.
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Affiliation(s)
- Calin I Prodan
- Neurology Service, Veterans Administration Medical Center, Oklahoma City, OK 73104, USA.
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46
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Liu WW, Todd S, Craig D, Passmore AP, Coulson DTR, Murphy S, Irvine GB, Johnston JA. Elevated platelet beta-secretase activity in mild cognitive impairment. Dement Geriatr Cogn Disord 2008; 24:464-8. [PMID: 17986817 DOI: 10.1159/000110739] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2007] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS We have recently reported that platelet activity of the rate-limiting enzyme for beta-amyloid peptide production is elevated in established Alzheimer's disease. Laboratory investigation of the very early stages of dementia provides an opportunity to investigate pathological mechanisms before advanced disease hinders interpretation. Mild cognitive impairment (MCI) exists prior to obvious dementia, and is associated with increased risk of conversion to overt disease. METHODS We developed and used a fluorimetric assay to quantify platelet membrane beta-secretase activity in 52 patients with MCI and 75 controls. RESULTS Platelet membrane beta-secretase activity was 24% higher in individuals with MCI compared to controls (p = 0.001, unpaired t test with Welch correction). CONCLUSION Elevated platelet beta-secretase activity in subjects with MCI is an area for further study in relation to the etiology and diagnosis of MCI.
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Affiliation(s)
- W W Liu
- Division of Psychiatry and Neuroscience, School of Medicine and Dentistry, Queen's University Belfast, Belfast, UK
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Jarvik L, LaRue A, Blacker D, Gatz M, Kawas C, McArdle JJ, Morris JC, Mortimer JA, Ringman JM, Ercoli L, Freimer N, Gokhman I, Manly JJ, Plassman BL, Rasgon N, Roberts JS, Sunderland T, Swan GE, Wolf PA, Zonderman AB. Children of persons with Alzheimer disease: what does the future hold? Alzheimer Dis Assoc Disord 2008; 22:6-20. [PMID: 18317242 PMCID: PMC3377487 DOI: 10.1097/wad.0b013e31816653ac] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent's fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.
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Affiliation(s)
- Lissy Jarvik
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA.
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Schipper HM. The role of biologic markers in the diagnosis of Alzheimer's disease. Alzheimers Dement 2007; 3:325-32. [PMID: 19595953 DOI: 10.1016/j.jalz.2007.07.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2007] [Accepted: 07/12/2007] [Indexed: 11/28/2022]
Affiliation(s)
- Hyman M Schipper
- Centre for Neurotranslational Research and Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
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Zainaghi IA, Forlenza OV, Gattaz WF. Abnormal APP processing in platelets of patients with Alzheimer's disease: correlations with membrane fluidity and cognitive decline. Psychopharmacology (Berl) 2007; 192:547-53. [PMID: 17356877 DOI: 10.1007/s00213-007-0748-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2006] [Accepted: 02/13/2007] [Indexed: 12/15/2022]
Abstract
RATIONALE Previous studies have implicated platelet amyloid precursor protein (APP) as a candidate biomarker for Alzheimer's disease (AD). Platelets contain more than 95% of the circulating APP and enclose the enzymatic machinery for the APP metabolism yielding both soluble APP and amyloid-beta peptides. OBJECTIVES The objective of this study is to compare the ratio of 130- to 110-kDa fragments of APP in platelets from patients with AD, mild cognitive impairment (MCI), and elderly controls. MATERIALS AND METHODS After subjects were grouped according to diagnosis, APP ratio in platelets was evaluated by means of Western blot analysis. RESULTS The APP ratio was significantly lower in AD patients (1.01 +/- 0.21) as compared to controls (1.24 +/- 0.21, p = 0.001) and MCI patients (1.18 +/- 0.21, p = 0.027), but no significant differences were found between MCI and controls (p = 0.904). In addition, we found positive correlations between the APP ratio and 1,6-diphenyl-1,3,5-hexatriene anisotropy (r = 0.3, p = 0.01), as well as with certain parameters of cognitive decline, namely, the mini-mental state examination score (r = 0.33, p = 0.003), the total Cambridge cognitive test (CAMCOG) score (r = 0.37, p = 0.001), and the score on the memory subscale of the CAMCOG (r = 0.38, p = 0.001). CONCLUSIONS The pattern of platelet APP fragments was altered in patients with AD but not in patients with MCI. The alteration of APP fragments was correlated with membrane fluidity and the cognitive decline.
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Affiliation(s)
- Isis A Zainaghi
- Laboratory of Neuroscience LIM 27, Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
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Prodan CI, Ross ED, Vincent AS, Dale GL. Coated-platelets correlate with disease progression in Alzheimer disease. J Neurol 2007; 254:548-9. [PMID: 17380246 DOI: 10.1007/s00415-006-0323-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2006] [Revised: 06/13/2006] [Accepted: 06/19/2006] [Indexed: 10/23/2022]
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