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

Amyloid-beta (A beta)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although A beta exerts neuropathogenic activity through tau, the mechanistic link between A beta and tau pathology remains unknown. Here, we showed that the Fc gamma RIIb-SHIP2 axis is critical in A beta(1-42)-induced tau pathology. Fc gamma RIIb knockout or antagonistic Fc?RIIb antibody inhibited A beta(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 beta(1-42), and recruited SHIP2 to form a protein complex. Consequently, treatment with A beta(1-42) increased PtdIns(3,4)P-2 levels from PtdIns(3,4,5)P-3 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 gamma RIIb-SHIP2 axis links A beta neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P-2 metabolism, providing insight into therapeutic potential against AD.