Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic and Ca2+-Handling Deficits in Alzheimer's Disease Models.

Dong Liu,Krisztina Marosi,Saket M Nigam,Dimitrios Kapogiannis,Kenneth W Witwer,James Comotto,Maja Mustapic,Erez Eitan,Chinmoyee Maharana,Emmette R Hutchison,Gregory A Jicha,Mark P Mattson,Vasiliki Machairaki,Caitlin Suire

doi:10.1038/npjamd.2016.19

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.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that accounts for 60–70% of cases of dementia in the aging population
Aβ40 and Aβ42 were significantly lower in the Extracellular vesicles (EVs) fraction than in the examined EVs released from cultured human neurons derived from induced pluripotent stem cells generated from fibroblasts taken from a patient with AD caused by a presenilin 1 (PS1) mutation and control neurons generated from fibroblasts from a neurologically normal human subject.[33]
To determine whether EV-associated amyloid β (Aβ) from AD patient cerebrospinal fluid (CSF) was contained within EVs and/or on their surface, EVs were incubated with 1 mg/ml trypsin for 1 h prior to two rounds of 120,000g centrifugation to purify EVs

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that accounts for 60–70% of cases of dementia in the aging population. Pathogenic forms of Aβ and Tau can impair synaptic function and trigger a series of events leading to neuronal death.[1] the causes of Aβ and Tau aggregation and cytotoxicity in the common sporadic late-onset cases of AD are unclear, 1–5% of AD patients exhibit early-onset disease resulting from mutations in the amyloid precursor protein (APP) or presenilin 1 (PS1; an enzyme that cleaves APP to generate Aβ).[1,2] Studies of the consequences of expressing AD PS1 and APP mutations in cultured cells and transgenic mice have provided insight into the molecular and cellular alterations underlying the pathogenesis of AD.[3] In particular, aggregating Aβ and Tau can impair mitochondrial function and perturb neuronal Ca2+ handling, thereby rendering synapses and neurons vulnerable to degeneration.[4,5,6,7,8]

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