FcγRIIb-SHIP2 axis links Aβ to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model

Elife. 2016 Nov 11:5:e18691. doi: 10.7554/eLife.18691.

Abstract

Amyloid-β (Aβ)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although Aβ exerts neuropathogenic activity through tau, the mechanistic link between Aβ and tau pathology remains unknown. Here, we showed that the FcγRIIb-SHIP2 axis is critical in Aβ1-42-induced tau pathology. Fcgr2b knockout or antagonistic FcγRIIb antibody inhibited Aβ1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. FcγRIIb phosphorylation at Tyr273 was found in AD brains, in neuronal cells exposed to Aβ1-42, and recruited SHIP2 to form a protein complex. Consequently, treatment with Aβ1-42 increased PtdIns(3,4)P2 levels from PtdIns(3,4,5)P3 to mediate tau hyperphosphorylation. Further, we found that targeting SHIP2 expression by lentiviral siRNA in 3xTg-AD mice or pharmacological inhibition of SHIP2 potently rescued tau hyperphosphorylation and memory impairments. Thus, we concluded that the FcγRIIb-SHIP2 axis links Aβ neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2 metabolism, providing insight into therapeutic potential against AD.

Keywords: Alzheimer; E. coli; SHIP2; amyloid; cell biology; fc gamma receptor; human; mouse; neuroscience; phosphoinositide; tau.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Disease Models, Animal
  • Gene Knockout Techniques
  • Mice
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / metabolism*
  • Phosphatidylinositols / metabolism*
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism*
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Fcgr2b protein, mouse
  • Mapt protein, mouse
  • Phosphatidylinositols
  • Receptors, IgG
  • tau Proteins
  • Inppl1 protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.