FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's disease

Amyloid-beta (A beta) induces neuronal loss and cognitive deficits and is believed to be a prominent cause of Alzheimer's disease (AD); however, the cellular pathology of the disease is not fully understood. Here, we report that IgG Fc gamma receptor II-b (Fc gamma RIIb) mediates A beta neurotoxicity and neurodegeneration. We found that Fc gamma RIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic A beta. Neuronal Fc gamma RIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic A beta-induced cell death in vitro. Fcgr2b deficiency ameliorated A beta-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted A beta. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of Fc gamma RIIb in A beta neurotoxicity, we demonstrated that soluble A beta oligomers interact with Fc gamma RIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic A beta neurotoxicity. We conclude that Fc gamma RIIb has an aberrant, but essential, role in A beta-mediated neuronal dysfunction.