Loss of BIN1 protein in Alzheimer’s disease promotes synaptic accumulation of phosphorylated tau and disrupts tau release: Tau-directed effects of BIN1 loss in AD

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
122 Downloads (Pure)

Abstract

Polymorphisms associated with BIN1 confer the second greatest risk for developing late onset Alzheimer’s disease. The biological consequences of this genetic variation are not fully understood, however BIN1 is a binding partner for tau. Tau is normally a highly soluble cytoplasmic protein, but in Alzheimer’s disease tau is abnormally phosphorylated and accumulates at synapses to exert synaptotoxicity. The purpose of this study was to determine if alterations to BIN1 and tau in Alzheimer’s disease promote the damaging redistribution of tau to synapses, as a mechanism by which BIN1 polymorphisms may increase risk of developing Alzheimer’s disease. We show that BIN1 is lost from the cytoplasmic fraction of Alzheimer’s disease cortex, and this is accompanied by the progressive mislocalization of phosphorylated tau to synapses. We confirmed proline 216 in tau as critical for tau interaction with the BIN1-SH3 domain and show that phosphorylation of tau disrupts this binding, suggesting that tau phosphorylation in Alzheimer’s disease disrupts tau-BIN1 associations. Moreover, we show that BIN1 knockdown in rat primary neurons to mimic BIN1 loss in Alzheimer’s disease brain, causes the damaging accumulation of phosphorylated tau at synapses and alterations in dendritic spine morphology. We also observed reduced release of tau from neurons upon BIN1 silencing, suggesting that BIN1 loss disrupts the function of extracellular tau. Together, these data indicate that polymorphisms associated with BIN1 that reduce BIN1 protein levels in the brain likely act synergistically with increased tau phosphorylation to increase risk of Alzheimer’s disease by disrupting cytoplasmic tau-BIN1 interactions, promoting the damaging mis-sorting of phosphorylated tau to synapses to alter synapse structure, and by reducing the release of physiological forms of tau to disrupt tau function.
Original languageEnglish
JournalBrain Communications
Volume2(1):fcaa011
Early online date8 Mar 2020
DOIs
Publication statusPublished - 14 Mar 2020

Keywords

  • tau
  • synapse
  • Alzheimer's disease
  • BIN1

Fingerprint

Dive into the research topics of 'Loss of BIN1 protein in Alzheimer’s disease promotes synaptic accumulation of phosphorylated tau and disrupts tau release: Tau-directed effects of BIN1 loss in AD'. Together they form a unique fingerprint.

Cite this