Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, USA.
Cell Biology and Skirball Institute of Biomolecular Medicine, NYU Langone School of Medicine, New York, NY, 10016, USA.
Acta Neuropathol Commun. 2017 Aug 29;5(1):65. doi: 10.1186/s40478-017-0466-0.
A dysfunctional endosomal pathway and abnormally enlarged early endosomes in neurons are an early characteristic of Down syndrome (DS) and Alzheimer's disease (AD). We have hypothesized that endosomal material can be released by endosomal multivesicular bodies (MVBs) into the extracellular space via exosomes to relieve neurons of accumulated endosomal contents when endosomal pathway function is compromised. Supporting this, we found that exosome secretion is enhanced in the brains of DS patients and a mouse model of the disease, and by DS fibroblasts. Furthermore, increased levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Importantly, CD63 knockdown diminished exosome release and worsened endosomal pathology in DS fibroblasts. Taken together, these data suggest that increased CD63 expression enhances exosome release as an endogenous mechanism mitigating endosomal abnormalities in DS. Thus, the upregulation of exosome release represents a potential therapeutic goal for neurodegenerative disorders with endosomal pathology.
神经元中功能失调的内体途径和异常增大的早期内体是唐氏综合征（DS）和阿尔茨海默病（AD）的早期特征。我们假设，当内体途径功能受损时，内体物质可以通过内体多泡体（MVB）释放到细胞外空间，通过外泌体将积累的内体内容物从神经元中释放出来。支持这一观点的是，我们发现 DS 患者和疾病小鼠模型以及 DS 成纤维细胞的外泌体分泌增强。此外，在 DS 大脑中观察到四跨膜蛋白 CD63 的水平升高，CD63 是外泌体生物发生的调节因子。重要的是，CD63 敲低减少了 DS 成纤维细胞中外泌体的释放，并加重了内体病理学。总之，这些数据表明，CD63 表达的增加增强了外泌体的释放，这是一种缓解 DS 中内体异常的内源性机制。因此，外泌体释放的上调代表了具有内体病理学的神经退行性疾病的潜在治疗目标。
