FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's disease
- FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's disease
- 감태인; 송성민; 권영대; 박혜진; ji-Jing Yan; 임이삭; 최지우; 최태용; 김정연; 송동근; Toshiyuki Takai; 김용철; 김기선; 최세영; 최석우; William L. Klein; Junying Yuan; 정용근
- amyloid beta neurotoxicity; Fcgamma receptor IIb; memory impairment; Alzheimer's disease; amloid beta receptor
- Issue Date
- The Journal of clinical investigation
- VOL 123, NO 7, 2791-2802
- Amyloid-β (Aβ) 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 Fcγ receptor II-b (FcγRIIb) mediates Aβ neurotoxicity and neurodegeneration. We found that FcγRIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic Aβ. Neuronal FcγRIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic Aβ-induced cell death in vitro. Fcgr2b deficiency ameliorated Aβ-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted Aβ. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of FcγRIIb in Aβ neurotoxicity, we demonstrated that soluble Aβ oligomers interact with FcγRIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic Aβ neurotoxicity. We conclude that FcγRIIb has an aberrant, but essential, role in Aβ-mediated neuronal dysfunction.
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