Extracellular vesicle-associated Aβ mediates trans-neuronal bioenergetic and Ca2+-handling deficits in Alzheimer’s disease models

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca2+ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation of EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species that impair neuronal Ca2+ handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity.

Release of astroglial vimentin by extracellular vesicles: Modulation of binding and internalization of C3 transferase in astrocytes and neurons

“…showing astrocytes to secrete exosomes enriched with the proapoptotic factor PAR-4 in a murine model system for Alzheimer's disease (Wang et al, 2012). Also in line with a role in Alzheimer's disease EVs have been shown to release pathogenic Aβ species thereby impairing neuronal Ca 2+ handling and causing mitochondrial dysfunction (Eitan et al, 2016). Supporting evidence for an exosomal release of vimentin stems from CT-26 cells, a macrophage-derived cell line, in which transfected vimentin was detected in the exosomal fraction obtained from culture supernatant .…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…EVs are small vesicles (50–150 nm diameter) released from multivesicular bodies upon their fusion with the plasma membrane or from budding of the plasma membrane (Budnik et al, 2016). EVs may propagate Aβ pathology between, within, and across neuronal networks as AD progresses (Eitan et al, 2016; Zhang et al, 2017). Even moderate deficits in DNA repair, neurotrophic factor signaling, and mitochondrial function can render neurons vulnerable to death when they are concomitantly exposed to Aβ (Sykora et al, 2015; Camandola and Mattson, 2017).…”

Alzheimer’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers

“…Exosomes can carry different cargos such as proteins, RNA and miRNA and can also contain monomeric Aß, tau and α-synuclein [12, 17, 46, 59] and can propagate tau pathology [4]. Thus, exosomes could potentially also carry aggregated proteins such as oAß.…”