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. A deadly game of cellular ‘tag’ might underlie the degenerative spread of damage between brain cells in Alzheimer’s patients. Mark Mattson from the National Institute on Aging in Maryland and colleagues investigated a hallmark of Alzheimer’s disease: the proliferation of tangled amyloid β protein clusters between brain cells. They found that small pouches of the outer membrane of brain cells—called extracellular vesicles-shuttled a particularly damaging form of amyloid β between cells. Extracellular vesicles were isolated from the fluid surrounding the brain in Alzheimer’s patients; when normal brain cells were exposed to these vesicles, cellular function in the exposed brain cells turned aberrant, occasionally leading to cell death. Understanding the propagation of Alzheimer’s disease pathology within the brain might uncover markers for detecting the disease earlier, and perhaps a window to intervene and halt the damage.