Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ 1-42 synaptotoxicity

J Cell Biol. 2017 Oct 2;216(10):3161-3178. doi: 10.1083/jcb.201701045. Epub 2017 Sep 6.

Abstract

Oligomeric Amyloid β1-42 (Aβ) plays a crucial synaptotoxic role in Alzheimer's disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Axons / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cytochrome-B(5) Reductase / genetics
  • Cytochrome-B(5) Reductase / metabolism*
  • Dendritic Spines / metabolism*
  • Formins
  • Mice
  • Mice, Knockout
  • Microtubules / genetics
  • Microtubules / metabolism*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Processing, Post-Translational / genetics
  • Protein Transport / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / genetics
  • Synapses / metabolism*
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Carrier Proteins
  • Diap1 protein, mouse
  • Formins
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Cyb5R3 protein, rat
  • Cytochrome-B(5) Reductase