Role of the endolysosomal pathway and exosome release in tau propagation.

1. Neurochem Int. 2021 May;145:104988. doi: 10.1016/j.neuint.2021.104988. Epub 2021 Feb 11. Role of the endolysosomal pathway and exosome release in tau propagation. Yan M(1), Zheng T(2). Author information: (1)Department of Neurology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), 54 Youdian Road, Hangzhou, 310009, China. (2)Department of Neurology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), 54 Youdian Road, Hangzhou, 310009, China. Electronic address: zhengtingting90218@163.com. The progressive deposition of misfolded and aggregated forms of Tau protein in the brain is a pathological hallmark of tauopathies, such as Alzheimer's disease (AD) and frontotemporal degeneration (FTD). The misfolded Tau can be released into the extracellular space and internalized by neighboring cells, acting as seeds to trigger the robust conversion of soluble Tau into insoluble filamentous aggregates in a prion-like manner, ultimately contributing to the progression of the disease. However, molecular mechanisms accountable for the propagation of Tau pathology are poorly defined. We reviewed the Tau processing imbalance in endosomal, lysosomal, and exosomal pathways in AD. Increased exosome release counteracts the endosomal-lysosomal dysfunction of Tau processing but increases the number of aggregates and the propagation of Tau. This review summarizes our current understanding of the underlying tauopathy mechanisms with an emphasis on the emerging role of the endosomal-lysosomal-exosome pathways in this process. The components CHMP6, TSG101, and other components of the ESCRT complex, as well as Rab GTPase such as Rab35 and Rab7A, regulate vesicle cargoes routing from endosome to lysosome and affect Tau traffic, degradation, or secretion. Thus, the significant molecular pathways that should be potential therapeutic targets for treating tauopathies are determined. Copyright © 2021 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.neuint.2021.104988 PMID: 33582164 [Indexed for MEDLINE]