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.

阿尔茨海默病 (AD) 是一种与年龄相关的神经退行性疾病，其中易于聚集的神经毒性 β-淀粉样蛋白肽 (Aβ) 在大脑中积聚。细胞外囊泡 (EV)，包括外泌体，是一种 50-150 nm 的小膜囊泡，最近与自聚集蛋白的朊病毒样传播有关。在这里，我们报告从 AD 患者脑脊液和血浆、两种 AD 小鼠模型的血浆以及从表达家族性 AD 早老素 1 突变的神经细胞培养基中分离出的 EV，会破坏神经元 Ca ²⁺稳态的稳定，损害线粒体功能，并使细胞变得敏感。神经元兴奋性毒性。 EV 中 Aβ 含量相对较低，但 Aβ42/Aβ40 比率较高；大部分 Aβ 位于 ​​EV 的表面。溶酶体功能受损会导致 EV 生成增加，且 Aβ42 水平升高。 EV 可能介导致病性 Aβ 种类的跨细胞传播，从而损害神经元 Ca ²⁺处理和线粒体功能，从而可能使神经元容易受到兴奋性毒性的影响。