Neuronal-Derived EV Biomarkers Track Cognitive Decline in Alzheimer’s Disease

Abstract

The hallmarks of Alzheimer’s disease (AD) pathology are senile plaques containing amyloid-beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. Additional pathologies often co-exist, whereas multiple pathogenic mechanisms are involved in AD, especially synaptic degeneration, which necessitate the need for synaptic integrity-related biomarkers alongside Aβ- and tau-related biomarkers. Plasma neuron-derived Extracellular Vesicles EVs (NDEVs) provide biomarkers related to Aβ and tau and synaptic degeneration. Here, to further establish the latter as a “liquid biopsy” for AD, we examined their relationship with ante-mortem cognition in pathologically-confirmed AD cases. We immunoprecipitated NDEVs by targeting neuronal marker L1CAM from ante-mortem plasma samples from 61 autopsy-confirmed cases of pure AD or AD with additional pathologies and measured Aβ42, p181-Tau, total Tau, synaptophysin, synaptopodin and three canonical EV markers, CD63, CD81 and CD9. Higher NDEV Aβ42 levels were consistently associated with better cognitive status, memory, fluency, working memory and executive function. Higher levels of NDEV synaptic integrity-related biomarkers were associated with better performance on executive function tasks. Our findings motivate the hypothesis that releasing Aβ42-laden NDEVs may be an adaptive mechanism in AD.

Plasma microglial-derived extracellular vesicles are increased in frail patients with Mild Cognitive Impairment and exert a neurotoxic effect

“…The significant decrease in NDVs concentration with progression of cognitive decline supports the hypothesis that NDVs may track cognitive decline in AD, as recently proposed [38]. Reduced levels of NDVs may reflect loss of neurons and/or altered neuronal homeostasis in AD [54,55].…”

“…For the isolation of plasma brain-derived vesicles, specific markers have been used. In particular, for NDVs, the L1CAM marker was chosen according to recent literature that widely accepts its use as marker for neuron-derived EVs [7,32,38]. Considering microglia, there are several markers eligible, and they include surface intracellular and released molecules.…”

Synaptic proteins in neuron-derived extracellular vesicles as biomarkers for Alzheimer’s disease: novel methodology and clinical proof of concept

“…Synaptic dysfunction and loss are early and persistent features of AD that, for some time, precede neuronal cell loss [51] . Several synaptic proteins in the CSF have also been suggested as AD biomarkers [51][52][53] . Complex roles of EVs in synaptic plasticity have been documented [52] , while multiple synaptic proteins have been detected in circulating L1CAM NDEVs [34,35,54] .…”

The Role of Exosomes as Mediators of Neuroinflammation in the Pathogenesis and Treatment of Alzheimer’s Disease

“…Exosomes can carry Aβ, tau, prions, and α-synuclein, and can spread pathogenic proteins across the brain ( Saeedi et al, 2019 ; Aheget et al, 2020 ; Figure 2 ). Furthermore, it has been shown that exosomes are strongly associated with beta-amyloid clearance ( Eren et al, 2022 ). As an inflammatory mediator, exosomes induce neuroinflammation through information exchange between neurons and glial cells.…”