Fc?RIIb mediates amyloid-? neurotoxicity and memory impairment in Alzheimer's disease.

ABSTRACT: Amyloid-? (A?) 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? receptor II-b (Fc?RIIb) mediates A? neurotoxicity and neurodegeneration. We found that Fc?RIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic A?. Neuronal Fc?RIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic A?-induced cell death in vitro. Fcgr2b deficiency ameliorated A?-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted A?. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of Fc?RIIb in A? neurotoxicity, we demonstrated that soluble A? oligomers interact with Fc?RIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic A? neurotoxicity. We conclude that Fc?RIIb has an aberrant, but essential, role in A?-mediated neuronal dysfunction.

SUBMITTER: Kam TI 

PROVIDER: S-EPMC3696552 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature