Blood extracellular vesicles carrying synaptic function‐ and brain‐related proteins as potential biomarkers for Alzheimer's disease

Abstract

Introduction:Objective and accessible markers for Alzheimer's disease (AD) and other dementias are critically needed. Methods:We identified NMDAR2A, a protein related to synaptic function, as a novel marker of central nervous system (CNS)-derived plasma extracellular vesicles (EVs) and developed a flow cytometry-based technology for detecting such plasma EVs readily. The assay was initially tested in our local cross-sectional study to distinguish AD patients from healthy controls (HCs) or from Parkinson's disease (PD) patients, followed by a validation study using an independent cohort collected from multiple medical centers (the Alzheimer's Disease Neuroimaging Initiative). Cerebrospinal fluid AD molecular signature was used to confirm diagnoses of all AD participants.

Traumatic brain injury and post‐traumatic stress disorder are not associated with Alzheimer's disease pathology measured with biomarkers

“…42 Synaptic dysfunction is implicated as an early pathological event in AD and may be the final common biological mechanism most proximal to neurodegeneration that links protein pathologies to disease symptoms. 42 Future studies may therefore examine changes of markers of synaptic function such as synaptosomal-associated protein 25kDa, neurogranin, postsynaptic density protein 95, 43 N-methyl D-aspartate receptor 2A 44 or neuroimaging markers such as synaptic vesicle glycoprotein 2A PET imaging, 45 as changes in this protein have been observed with TBI in mice. 46 In contrast, MCI is a clinical rather than biological construct, and is considered the earliest clinical stage of AD and other dementias 11 although some patients do not progress to dementia.…”

“…This suggests that these participants may have non‐amnestic MCI (naMCI) characterized by deficits in other cognitive domains 11 . TBI was reported to impair processing speed and executive function, 50,51 but not memory 50‐53 consistent with naMCI, although mTBI was additionally associated with impaired working memory and visual learning 54 . Veterans with PTSD had primarily impaired processing speed, executive function, and learning, 55 also consistent naMCI, which has a number of neurological sequelae distinct from AD including frontotemporal dementia, dementia with Lewy bodies, and vascular dementia, 11 and which may also be due to psychiatric problems.…”

Extracellular vesicles and their cells of origin: Open issues in autoimmune diseases

“…EVs from individuals diagnosed with AD possess a specific protein content and miRNAs profiles which could be applied for early detection of the disease. In a recent experiment, NMDAR2A was identified as a CNS-specific EV surface marker, and it was shown in a multicenter study, including both discovery and validation cohorts, that the number of plasma EVs with NMDAR2A and L1CAM expression is lower in patients with AD in comparison to the healthy controls ( 129 ). On the other hand, as EVs are responsible for the “spread of tau pathology”, their secretion inhibition could be proposed as a novel targeted therapeutic strategy for patients with Alzheimer’s disease ( 126 , 130 , 131 ).…”

Dumbbell Aptamer Sensor Based on Dual Biomarkers for Early Detection of Alzheimer’s Disease

“…8 Compared with cerebrospinal fluid (CSF), neuroderived exosomes can carry brain-derived cargo (such as lipids, protein, nucleic acid, etc.) across the blood-brain barrier (BBB) to the peripheral blood and can be detected in the blood, 9,10 indicating that substances in exosomes are ideal biomarkers for noninvasive diagnosis of AD and thought to be comparable to the diagnostic efficacy of CSF. 11 The study has investigated that AβO42 is a key factor in the progression of AD.…”

“…Compared with cerebrospinal fluid (CSF), neuroderived exosomes can carry brain-derived cargo (such as lipids, protein, nucleic acid, etc.) across the blood-brain barrier (BBB) to the peripheral blood and can be detected in the blood, , indicating that substances in exosomes are ideal biomarkers for noninvasive diagnosis of AD and thought to be comparable to the diagnostic efficacy of CSF . The study has investigated that AβO42 is a key factor in the progression of AD. , Additionally, the level of AβO42 in neurogenic exosomes increased significantly with the development of AD, which was characteristic of the asymptomatic period of AD, predicting the status of the first 10 years of clinical onset. , A single biomarker is often insufficient to achieve a definitive diagnosis of AD.…”