Kam, Tae-In Song, Sungmin Gwon, Youngdae Park, Hyejin Yan, Ji-Jing Im, Isak Choi, Ji-Woo Choi, Tae-Yong Kim, Jeongyeon Song, Dong-Keun Takai, Toshiyuki Kim, Yong-Chul Kim, Key-Sun Choi, Se-Young Choi, Sukwoo Klein, William L. Yuan, Junying Jung, Yong-Keun 2024-01-20T12:03:08Z 2024-01-20T12:03:08Z 2021-09-04 2013-07 0021-9738 https://pubs.kist.re.kr/handle/201004/127930 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. English AMER SOC CLINICAL INVESTIGATION INC Fc gamma RIIb mediates amyloid-beta neurotoxicity and memory impairment in Alzheimer's disease Article 10.1172/JCI66827 1 JOURNAL OF CLINICAL INVESTIGATION, v.123, no.7, pp.2791 - 2802 JOURNAL OF CLINICAL INVESTIGATION 123 7 2791 2802 N scie scopus 000321316700011 2-s2.0-84879616001 Medicine, Research & Experimental Research & Experimental Medicine Article CELLULAR PRION PROTEIN LONG-TERM POTENTIATION A-BETA COGNITIVE DEFICITS MOUSE MODEL INHIBITORY RECEPTORS SYNAPTIC PLASTICITY OLIGOMERS PEPTIDE E2-25K/HIP-2 amyloid beta neurotoxicity Fcgamma receptor IIb memory impairment Alzheimer&apos s disease amloid beta receptor