FcgRIIb SHIP2 axis links Ab to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model
Amyloid b (Ab) containing extracellular plaques and hyperphosphorylated tau loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD) Although Ab exerts neuropathogenic activity through tau, the mechanistic link between Ab and tau pathology remains unknown. Here, we showed that the FcgRIIb SHIP2 axis is critical in Ab1 42 induced tau pathology. Fcgr2b knockout or antagonistic FcgRIIb antibody inhibited Ab1 42 induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. FcgRIIb phosphorylation at Tyr273 was found in AD brains, in neuronal cells exposed to Ab1 42, and recruited SHIP2 to form a protein complex. Consequently, treatment with Ab1 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 FcgRIIb SHIP2 axis links Ab neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2 metabolism, providing insight into therapeutic potential against AD. DOI: http:/dx.doi.org/10.7554/eLife.18691.001
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