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 June 10, 2013
Citation Information: J Clin Invest. 2013;123(7):2791-2802. https://doi.org/10.1172/JCI66827.
View: Text | PDF
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

×

Figure 6

Interaction of FcγRIIb with Aβ1-42 is linked to i.c.v.

Options: View larger image (or click on image) Download as PowerPoint
Interaction of FcγRIIb with Aβ1-42 is linked to i.c.v. Aβ1-42-induced ...
Aβ1-42-induced memory impairment. (A–C) Suppression of i.c.v. Aβ1-42-induced cognitive defects in Fcgr2b-deficient mice. Mice were i.c.v. injected with nontoxic Aβ40-1 or Aβ1-42 (410 pm). One day later, Y-maze (A; **P < 0.005, 1-way ANOVA), passive avoidance (B; n = 10 for each group; *P < 0.05, 1-way ANOVA), and novel object recognition (C; n = 10 for each group) tests were performed as described in the methods. Bars represent the mean ± SEM. (D and E) Suppression of i.c.v. Aβ1-42-induced memory impairment by the peptides inhibiting the interaction between Aβ1-42 and FcγRIIb. WT mice (2-month-old) were i.c.v. injected with Aβ40-1 or Aβ1-42 (410 pm) alone or together with Aβ1-9 (#1), Aβ1-9 mutant (#7), or FcγRIIb107-114 (#9) peptide (molar ratio of 1:3). One day later, the mice were analyzed using Y-maze (D) and passive avoidance (E) tests (n = 8–10). Bars represent the mean ± SEM. **P < 0.005; ***P < 0.001; 1-way ANOVA.