Loss of Bin1 Promotes the Propagation of Tau Pathology

Cell Reports

卷:17

Sara Calafate¹  Diederik Moechars¹  William Flavin²  Patrik Verstreken³ 

[1] Discovery Neuroscience, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium;

[2] Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 90270, USA;

[3] VIB Center for Brain and Disease Research, 3000 Leuven, Belgium;

关键词: Tau;    spreading;    in vitro model;    BIN1;    Alzheimer GWAS;    synapse;    endocytosis;    Rab5;    galectin-3;   

DOI  :  10.1016/j.celrep.2016.09.063

来源: DOAJ

【 摘 要 】

Tau pathology propagates within synaptically connected neuronal circuits, but the underlying mechanisms are unclear. BIN1-amphiphysin2 is the second most prevalent genetic risk factor for late-onset Alzheimer’s disease. In diseased brains, the BIN1-amphiphysin2 neuronal isoform is downregulated. Here, we show that lowering BIN1-amphiphysin2 levels in neurons promotes Tau pathology propagation whereas overexpression of neuronal BIN1-amphiphysin2 inhibits the process in two in vitro models. Increased Tau propagation is caused by increased endocytosis, given our finding that BIN1-amphiphysin2 negatively regulates endocytic flux. Furthermore, blocking endocytosis by inhibiting dynamin also reduces Tau pathology propagation. Using a galectin-3-binding assay, we show that internalized Tau aggregates damage the endosomal membrane, allowing internalized aggregates to leak into the cytoplasm to propagate pathology. Our work indicates that lower BIN1 levels promote the propagation of Tau pathology by efficiently increasing aggregate internalization by endocytosis and endosomal trafficking.

【 授权许可】

Unknown