Loss of Bin1 Promotes the Propagation of Tau Pathology

Cell Rep. 2016 Oct 18;17(4):931-940. doi: 10.1016/j.celrep.2016.09.063.


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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cells, Cultured
  • Dynamins / metabolism
  • Endocytosis
  • Endosomes / metabolism
  • Intracellular Membranes / metabolism
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Protein Aggregates
  • Protein Isoforms / metabolism
  • Rats, Wistar
  • Tauopathies / metabolism*
  • Tauopathies / pathology
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / metabolism*
  • tau Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Bin1 protein, rat
  • Nerve Tissue Proteins
  • Protein Aggregates
  • Protein Isoforms
  • Tumor Suppressor Proteins
  • tau Proteins
  • Dynamins