A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau

Cereb Cortex. 2015 Nov;25(11):4559-71. doi: 10.1093/cercor/bhv096. Epub 2015 May 20.

Abstract

Synaptic spine loss is one of the major preceding consequences of stroke damages, but its underlying molecular mechanisms remain unknown. Here, we report that a direct interaction of DAPK1 with Tau causes spine loss and subsequently neuronal death in a mouse model with stroke. We found that DAPK1 phosphorylates Tau protein at Ser262 (pS(262)) in cortical neurons of stroke mice. Either genetic deletion of DAPK1 kinase domain (KD) in mice (DAPK1-KD(-/-)) or blocking DAPK1-Tau interaction by systematic application of a membrane permeable peptide protects spine damages and improves neurological functions against stroke insults. Thus, disruption of DAPK1-Tau interaction is a promising strategy in clinical management of stroke.

Keywords: DAPK1; dendritic spine; stroke; tau phosphorylation; therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Cell Death
  • Cells, Cultured
  • Cerebral Cortex / pathology
  • Death-Associated Protein Kinases / genetics
  • Death-Associated Protein Kinases / metabolism*
  • Dendritic Spines / drug effects
  • Dendritic Spines / pathology*
  • Dendritic Spines / ultrastructure
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Neurologic Examination
  • Neurons / drug effects
  • Neurons / pathology*
  • Neurons / ultrastructure
  • Peptides / therapeutic use
  • Phosphopyruvate Hydratase / metabolism
  • Phosphorylation
  • Stroke / drug therapy
  • Stroke / pathology*
  • Stroke / physiopathology
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Peptides
  • tau Proteins
  • Dapk1 protein, mouse
  • Death-Associated Protein Kinases
  • Phosphopyruvate Hydratase