eLife 5, e18691 (2016)

Alzheimer's disease (AD) is characterized by amyloid-b (Ab) plaques in the brain and neurofibrillary tangles of hyperphosphorylated tau, a microtubule-binding protein. The neurotoxicity of Ab in vitro requires tau, but the mechanism linking tau and Ab and its relevance to neurodegeneration and memory loss in AD are unclear. Using neuronal cell cultures and mouse models of AD, Kam et al. showed that tau hyperphosphorylation and memory impairments induced by Ab oligomers are dependent on Fc gamma receptor IIb (FcgRIIb) a receptor that mediates Ab neurotoxicity. Moreover, the effects of Ab treatment—on tau and on neuronal toxicity—required phosphorylation of FcgRIIb at Tyr273 and its recruitment of the inositol phosphatase SHIP2. Metabolism of phosphoinositides—phosphorylated derivatives of phosphatidylinositol—has been reported to be dysregulated in AD. When the authors exposed neuronal cells to Ab, they found altered levels of PIP2 and PIP3, dependent on expression of FcgRIIb and SHIP2. Direct treatment of cells with PIP2 increased activation of GSK3b, a tau kinase, as well as tau hyperphosphorylation. Using a SHIP2 inhibitor, the authors showed that interrupting this pathway can reduce memory impairment in a mouse model of AD, suggesting a new candidate target for the treatment of AD.