FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer’s disease
Tae-In Kam, … , Junying Yuan, Yong-Keun Jung
Tae-In Kam, … , Junying Yuan, Yong-Keun Jung
Published July 1, 2013; First published June 10, 2013
Citation Information: J Clin Invest. 2013;123(7):2791-2802. https://doi.org/10.1172/JCI66827.
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Research Article Neuroscience

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

Abstract

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.

Authors

Tae-In Kam, Sungmin Song, Youngdae Gwon, Hyejin Park, Ji-Jing Yan, Isak Im, Ji-Woo Choi, Tae-Yong Choi, Jeongyeon Kim, Dong-Keun Song, Toshiyuki Takai, Yong-Chul Kim, Key-Sun Kim, Se-Young Choi, Sukwoo Choi, William L. Klein, Junying Yuan, Yong-Keun Jung

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Figure 2

FcγRIIb is required for Aβ neurotoxicity.

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FcγRIIb is required for Aβ neurotoxicity. (A) Characterization of Aβ1-42...
(A) Characterization of Aβ1-42 oligomers. The prepared Aβ1-42 oligomers were identified by SDS-PAGE (left) and atomic force microscopy (right). Scale bars: 0.5 μm. (B) Fcgr2b KO neurons are resistant to Aβ toxicity. Primary hippocampal neurons (5 DIV) were incubated with Aβ1-42 oligomers for 2 days, after which the relative neuronal viability was determined by MTT assay. Data are the mean ± SD (n = 6). ***P < 0.001, 1-way ANOVA. (C) FcγRIIb I232T mutant potently inhibits Aβ toxicity. HT22 cells transfected and incubated with or without Aβ1-42. Bars depict the incidence of cell death. Values are the mean ± SD (n = 3). *P < 0.05; ***P < 0.001, unpaired t test (top). Expression of constructs was identified by Western blotting (bottom). (D) FcγRIIb sensitizes Aβ-induced cell death. HT22 cells transfected with the indicated constructs were incubated for 48 hours with or without CHO-CM, 7PA2-CM, or 1 μM of synthetic Aβ1-42. Values are the mean ± SD (n = 3). *P < 0.05; **P < 0.005, unpaired t test. NS, not significant. (E and F) Inhibition of Aβ1-42-induced FcγRIIb expression and neuronal death by the addition of purified hFcγRIIb-ED protein. SH-SY5Y cells (E) and primary cortical neurons (F) were incubated for 48 hours with Aβ1-42 with or without 50 μg/ml of hFcγRIIb-ED protein. Cell extracts were subjected to Western blot analysis (E); cell viability was determined using Calcein-AM (F). Values are the mean ± SD (n = 4).