Fc?RIIb-SHIP2 axis links A? to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model.

ABSTRACT: Amyloid-? (A?)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although A? exerts neuropathogenic activity through tau, the mechanistic link between A? and tau pathology remains unknown. Here, we showed that the Fc?RIIb-SHIP2 axis is critical in A?_1-42-induced tau pathology. Fcgr2b knockout or antagonistic Fc?RIIb antibody inhibited A?_1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. Fc?RIIb phosphorylation at Tyr273 was found in AD brains, in neuronal cells exposed to A?_1-42, and recruited SHIP2 to form a protein complex. Consequently, treatment with A?_1-42 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 Fc?RIIb-SHIP2 axis links A? neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P₂ metabolism, providing insight into therapeutic potential against AD.

SUBMITTER: Kam TI 

PROVIDER: S-EPMC5106215 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature