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

Amyloid-ß (Aß)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although Aß exerts neuropathogenic activity through tau, the mechanistic link between Aß and tau pathology remains unknown. Here, we showed that the FcγRIIb-SHIP2 axis is critical in Aß1-42-induced tau pathology. Fcgr2b knockout or antagonistic FcγRIIb antibody inhibited Aß1-42-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 Aß1-42, and recruited SHIP2 to form a protein complex. Consequently, treatment with Aß1-42 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 Aß neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2 metabolism, providing insight into therapeutic potential against AD.