Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss

J Neurosci. 2019 Mar 6;39(10):1910-1929. doi: 10.1523/JNEUROSCI.2983-18.2018. Epub 2019 Jan 9.

Abstract

The intracellular tyrosine kinase Pyk2 (PTK2B) is related to focal adhesion kinase and localizes to postsynaptic sites in brain. Pyk2 genetic variation contributes to late onset Alzheimer's disease (AD) risk. We recently observed that Pyk2 is required for synapse loss and for learning deficits in a transgenic mouse model of AD. Here, we explore the cellular and biochemical basis for the action of Pyk2 tyrosine kinase in amyloid-β oligomer (Aβo)-induced dendritic spine loss. Overexpression of Pyk2 reduces dendritic spine density of hippocampal neurons by a kinase-dependent mechanism. Biochemical isolation of Pyk2-interacting proteins from brain identifies Graf1c, a RhoA GTPase-activating protein inhibited by Pyk2. Aβo-induced reductions in dendritic spine motility and chronic spine loss require both Pyk2 kinase and RhoA activation. Thus, Pyk2 functions at postsynaptic sites to modulate F-actin control by RhoA and regulate synapse maintenance of relevance to AD risk.SIGNIFICANCE STATEMENT Genetic variation at the Pyk2 locus is a risk for Alzheimer's disease. We have observed that Pyk2 is required for AD transgenic synapse loss and memory dysfunction. However, the cellular and biochemical basis for Pyk2 function related to AD is not defined. Here, we show that brain Pyk2 interacts with the RhoGAP protein Graf1 to alter dendritic spine stability via RhoA GTPase. Amyloid-β oligomer-induced dendritic spine loss requires the Pyk2/Graf1 pathway.

Keywords: Alzheimer; Graf1; PTK2B; Rho; actin; synapse loss.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Dendritic Spines / metabolism*
  • Female
  • Focal Adhesion Kinase 2 / genetics
  • Focal Adhesion Kinase 2 / metabolism*
  • GTPase-Activating Proteins / metabolism*
  • HEK293 Cells
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction
  • Synapses / metabolism*
  • Synapses / pathology*
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Amyloid beta-Peptides
  • GRAF1 protein, mouse
  • GTPase-Activating Proteins
  • Focal Adhesion Kinase 2
  • Ptk2b protein, mouse
  • RhoA protein, mouse
  • rhoA GTP-Binding Protein