Platelets are responsible for the accumulation of β-amyloid in blood clots inside and around blood vessels in mouse brain after thrombosis

Kucheryavykh, Lilia; Dávila-Rodríguez, Josué; Rivera-Aponte, David E.; Zueva, Lidia; Washington, A. Valance; Sanabria, Priscilla; Inyushin, Mikhail

doi:10.1016/j.brainresbull.2016.11.008

Cited by 54 publications

(71 citation statements)

References 70 publications

(85 reference statements)

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“…It is future science group www.futuremedicine.com known that during thrombosis, platelets are concentrated in clots and activated, and that activated platelets release Aβ. Enhanced release of Aβ during thrombosis suggests an additional source of Aβ in the brains of AD patients with frequent micro-thrombosis events occurring in their brains [45]. This possibility is consistent with findings in mice models and with highly conserved pattern of Aβ peptides that are known to be released by platelets in the CSF [43,45].…”

Section: Platelet Levels Of Lipids and Serotoninsupporting

confidence: 81%

“…Aβ was shown to activate platelets and trigger platelet aggregation by stimulating intracellular signaling pathways that are involved in phospholipase C phosphorylation, protein kinase C (PKC) activation and increased intracellular [Ca 2+ ], resulting in increased Aβ secretion. These findings raise the possibility that Aβ activation may initiate a mutual cycle of platelet activation and Aβ release, which may play a role in Aβ upregulation in the periphery and in the CSF, further leading to the development of cerebral amyloid angiopathy [43][44][45].In summary, platelets have been studied as both a cellular model to investigate Aβ-induced responses, and a peripheral cell type that actively contribute to AD pathogenesis. Main molecules and platelet functions that can be applied as potential AD biomarkers are shown in Figure 1B.…”

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confidence: 99%

“…Enhanced release of Aβ during thrombosis suggests an additional source of Aβ in the brains of AD patients with frequent micro-thrombosis events occurring in their brains [45]. This possibility is consistent with findings in mice models and with highly conserved pattern of Aβ peptides that are known to be released by platelets in the CSF [43,45]. Some authors suggested an inverse pathway, in other words that circulating Aβ derives from the CNS, crosses the blood-CSF barrier, and can be absorbed by platelets and other blood cells.…”

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confidence: 99%

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Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients. Alzheimer's disease (AD) is the most prevalent age-related dementia worldwide and one of the major unmet, increasing medical and economic problems of the modern world. As of 2015, there were an estimated 46.8 million people with dementia worldwide. This number will increase to an estimated 74.7 million in 2030 [1].Among the neuropathological hallmarks of AD are: the progressive loss of brain neurons, synaptic degeneration and the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) in such regions of the brain as the hippocampus, cortex and amygdala. Amyloid plaques consist mainly of 40-and 42-amino-acid Aβ peptides (Aβ40 and Aβ42). Peptides are proteolytic cleavage products of the Aβ protein precursor (APP) but with no fully elucidated biological function. NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5]. Increasing proof demonstrates that the therapeutic methods' effectiveness is strictly contingent on the early diagnosis of AD, before the occurrence of massive neuron loss and dementia. This highlights the key importance of biochemical biomarkers for early AD diagnostics. AD diagnostics & demand for novel, improved biomarkersThe broadly accepted recommendations for AD diagnosis...

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Section: Platelet Levels Of Lipids and Serotoninsupporting

confidence: 81%

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confidence: 99%

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confidence: 99%

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Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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“…It is also important to consider that plasma amyloid peptides are not only of central nervous system (CNS) origin but have also been found to be produced by platelets, vascular walls, and skeletal muscles (Askanas, Engel, & Nogalska, 2015;Kuo et al, 2000;Li et al, 1998;Nostrand, 2016). Particularly platelets are regarded as an important source of blood amyloid peptides (Chen, Inestrosa, Ross, & Fernandez, 1995;Kucheryavykh et al, 2017). This can influence plasma Aβ levels and obscure the relationship between plasma Aβ levels and Aβ brain pathology.…”

Section: Discussionmentioning

confidence: 99%

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta‐analyses

Alhajraf

Ness

Hye

et al. 2019

Developmental Neurobiology

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Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta‐analyses of studies comparing plasma amyloid beta (Aβ) levels between DS individuals and controls, and between DS individuals with and without dementia. PubMed, Embase, and Google Scholar were searched for studies investigating the relationship between Aβ plasma concentrations and dementia in DS and 10 studies collectively comprising >1,600 adults, including >1,400 individuals with DS, were included. RevMan 5.3 was used to perform meta‐analyses. Meta‐analyses showed higher plasma Aβ40 (SMD = 1.79, 95% CI [1.14, 2.44], Z = 5.40, p < .00001) and plasma Aβ42 levels (SMD = 1.41, 95% CI [1.15, 1.68], Z = 10.46, p < .00001) in DS individuals than controls, and revealed that DS individuals with dementia had higher plasma Aβ40 levels (SMD = 0.23, 95% CI [0.05, 0.41], Z = 2.54, p = .01) and lower Aβ42/Aβ40 ratios (SMD = −0.33, 95% CI [−0.63, −0.03], Z = 2.15, p = .03) than DS individuals without dementia. Our results indicate that plasma Aβ40 levels may constitute a promising biomarker for predicting dementia status in individuals with DS. Further investigations using new ultra‐sensitive assays are required to obtain more reliable results and to investigate to what extent these results may be generalizable beyond the DS population.

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“…Since platelets present neuron-like metabolic pathways, previous studies have shown that in AD, APP acts as a platelet-membrane receptor contributing mostly to soluble β-amyloid after platelet activation [43]. Mitochondrial dysfunction, higher content in phosphorylated TDP43, and morphological and structural platelet changes in AD and PD have also been reported [44,45]. Whether miRNA deregulation in platelets promotes neurodegeneration or merely re ects its effects remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease: A cross-sectional study.

Gámez-Valero

Campdelacreu

Vilas

et al. 2020

Preprint

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Background Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia after Alzheimer’s disease (AD) and presents pathological and clinical overlap with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets have been previously related to neurodegeneration. They contain microRNAs (miRNAs), and their analysis may provide disease biomarkers. Methods Small RNAs from platelets of DLB patients and controls were analyzed by Next Generation Sequencing (NGS), and miRNAs deregulated in DLB were selected. Expression of these miRNAs was then determined and validated by LNA-based qRT-PCR in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Their predictive diagnostic potential was calculated by ROC curve analysis. miRTarbase and miRGate were used for target prediction. Results We profiled the whole platelet miRNA transcriptome from 7 DLB patients and 7 controls using NGS. Twenty-two selected miRNAs were further validated in independent studies (2017–2019) including DLB (n = 59), AD (n = 28), and PD (n = 24) patients, and control individuals (n = 51). Our results demonstrated downregulated expression levels for hsa-let-7d-5p (fold change 0.14; p = 0.006), hsa-miR-132-5p (0.12; p = 0.0015), hsa-miR-142-3p (0.07; p = 0.00047), hsa-miR-146a-5p (0.07; p = 0.00035), hsa-miR-150-5p (0.10; p = 0.0098), hsa-miR-25-3p (0.13; p = 0.0019) and hsa-miR-26b-5p (0.09; p = 0.0014) in DLB compared to AD. ROC curve for this seven-miRNA biosignature yielded an area under the curve (AUC) of 1. Both hsa-miR-142-3p and hsa-miR-150-5p, were down-regulated in DLB compared to controls (AUC = 0.85). Comparing AD and controls, miRNAs hsa-miR-132-5p, hsa-miR-146a-5p, hsa-miR-25-3p, and hsa-miR-6747-3p were up-regulated in AD (AUC = 0.94); and hsa-miR-128-3p and hsa-miR-139-5p were down-regulated in PD compared to controls (AUC = 0.81). Predictive target analysis identified three disease-specific pathway clusters as a result of platelet-miRNA deregulation. In DLB, pathways related to gene expression and small RNA metabolism; in AD, pathways related to stress response and RNA stress granules; and in PD pathways related to protein phosphorylation, metabolism and degradation were identified. Conclusion A platelet-associated bio-signature composed of 7 miRNAs is highly specific and sensitive for distinguishing DLB from AD.

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Platelets are responsible for the accumulation of β-amyloid in blood clots inside and around blood vessels in mouse brain after thrombosis

Cited by 54 publications

References 70 publications

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta‐analyses

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease: A cross-sectional study.

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