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 1

Increased expression of FcγRIIb in the neurons of AD brains.

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Increased expression of FcγRIIb in the neurons of AD brains. (A) Increas...
(A) Increased expression of FcγRIIb in AD patients. Hippocampal homogenates from normal, MCI (Braak III), and AD patients with Braak stage V/VI were analyzed by Western blotting. PHF1 antibody detecting phospho-tau was used as a marker for AD. (B) Levels of FcγRIIb (left) and NeuN (right) were quantified by densitometric measurement. Values are the mean ± SEM. *P < 0.05; **P < 0.005; ***P < 0.001; 2-tailed t test. (C) Immunohistochemical detection of FcγRIIb in the NeuN-positive hippocampal neurons of AD patients. Tissue samples from normal and AD patients (n = 3) were immunostained using anti-FcγRIIb and anti-NeuN antibodies and examined under a confocal microscope. Scale bars: 20 μm. (D) Immunohistochemical detection of FcγRIIb and Aβ in the hippocampus of AD patients. Tissue samples were immunostained using anti-FcγRIIb and anti-Aβ antibodies and then examined under a confocal microscope. Scale bars: 10 μm. (E) Immunoblot analysis showing FcγRIIb induction by Aβ1-42 in neuronal cells. Primary cortical neurons and SH-SY5Y cells were incubated with 5 μM Aβ1-42 for 36 hours, and cell extracts were analyzed with Western blotting using anti-FcγRIIb antibody (left, 2.4G2; right, EP888Y). The signals on the blots were quantified by densitometric analysis (bottom). (F) Increase in Fcgr2b mRNA by Aβ1-42 in primary cortical neurons. Neurons cultured from WT and Fcgr2b KO mice were incubated with 5 μM Aβ1-42 for 36 hours, after which total RNA was isolated for RT-PCR analysis with synthetic primers (top). Levels of mRNA in WT neurons were quantified by densitometric measurement (bottom). Values are the mean ± SD (n = 3). *P < 0.05; 2-tailed t test.