title: Loss of Bin1 Promotes the Propagation of Tau Pathology.
abstract: 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.
authors.affiliation: Discovery Neuroscience, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium; VIB Center for Brain and Disease Research, 3000 Leuven, Belgium; KU Leuven Department for Human Genetics, 3000 Leuven, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Calafate
authors.affiliation: Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 90270, USA.
authors.forename: William
authors.initials: W
authors.lastname: Flavin
authors.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium; KU Leuven Department for Human Genetics, 3000 Leuven, Belgium. Electronic address: patrik.verstreken@cme.vib-kuleuven.be.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.affiliation: Discovery Neuroscience, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium. Electronic address: dmoechar@its.jnj.com.
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D066329:Protein Aggregates; D020033:Protein Isoforms / Q000378:metabolism; D017208:Rats, Wistar; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530914:Bin1 protein, rat; D009419:Nerve Tissue Proteins; D066329:Protein Aggregates; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D016875:tau Proteins; D034281:Dynamins
keywords: Alzheimer GWAS; BIN1; Rab5; Tau; endocytosis; galectin-3; in vitro model; spreading; synapse