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

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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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.

Original languageEnglish
Pages (from-to)2791-2802
Number of pages12
JournalJournal of Clinical Investigation
Volume123
Issue number7
DOIs
Publication statusPublished - 2013 Jul 1

ASJC Scopus subject areas

  • Medicine(all)

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    Kam, T. I., Song, S., Gwon, Y., Park, H., Yan, J. J., Im, I., Choi, J. W., Choi, T. Y., Kim, J., Song, D. K., Takai, T., Kim, Y. C., Kim, K. S., Choi, S. Y., Choi, S., Klein, W. L., Yuan, J., & Jung, Y. K. (2013). FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's disease. Journal of Clinical Investigation, 123(7), 2791-2802. https://doi.org/10.1172/JCI66827