Spineless


Alzheimer's disease is associated with the accumulation of amyloid-beta (Abeta) in the brain and has been linked to memory loss and neuronal degeneration.  Tae-In Kam and colleagues report that IgG receptor FCgammaRIIb mediates Abeta neurotoxicity and neurodegeneration. FcgammaRIIb was significantly up regulated in the hippocampus of AD brains and Abeta exposure activated stress and death pathways and inhibited long-term potentiation (an enhancement in communication between two neurons) in a FCgammaRIIb-dependent manner. Moreover, Fcgr2b depletion ameliorated memory impairments in a mouse model of AD, demonstrating that FCgammaRIIb is essential for Abeta-induced neurotoxicity. In the accompanying image, cultured hippocampal neurons express a fluorescent protein, allowing for the visualization of dendritic spines by microscopy. Kam and colleagues compared the effects of Abeta treatment in wildtype neurons (two left panels, right panel treated with Abeta) and neurons lacking FCgammaRIIb (two right panels, right panel treated with Abeta). In the absence of FCgammaRIIb, Abeta did not alter spine density.

Published June 10, 2013, by Jillian Hurst

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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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