Tae-In Kam1, Sungmin Song1, Youngdae Gwon1, Hyejin Park1, Ji-Jing Yan2, Isak Im3, Ji-Woo Choi4, Tae-Yong Choi5, Jeongyeon Kim6, Dong-Keun Song2, Toshiyuki Takai7, Yong-Chul Kim3, Key-Sun Kim4, Se-Young Choi5, Sukwoo Choi6, William L. Klein8, Junying Yuan9 and Yong-Keun Jung1,*
1Global Research Laboratory, School of Biological Sciences/Bio-Max Institute, Seoul National University, Seoul, Republic of Korea.
2Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chunchon, Republic of Korea.
3Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
4Center for Neural Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
5Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul, Republic of Korea.
6School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
7Department of Experimental Immunology, Tohoku University, Sendai, Japan.
8Department of Neurobiology and Physiology, Northwestern University, Chicago, Illinois, USA.
9Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
*Address correspondence to: Yong-Keun Jung, School of Biological Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-747, Republic of Korea.
Authorship note: Tae-In Kam and Sungmin Song contributed equally to this work.
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.