FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's disease.
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.
Global Research Laboratory, School of Biological Sciences/Bio-Max Institute, Seoul National University, Seoul, Republic of Korea.
Tae-In
TI
Kam
Sungmin
S
Song
Youngdae
Y
Gwon
Hyejin
H
Park
Ji-Jing
JJ
Yan
Isak
I
Im
Ji-Woo
JW
Choi
Tae-Yong
TY
Choi
Jeongyeon
J
Kim
Dong-Keun
DK
Song
Toshiyuki
T
Takai
Yong-Chul
YC
Kim
Key-Sun
KS
Kim
Se-Young
SY
Choi
Sukwoo
S
Choi
William L
WL
Klein
Junying
J
Yuan
Yong-Keun
YK
Jung
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology*; D061251:Primary Cell Culture; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology; D015533:Transcriptional Activation
D000682:Amyloid; D016229:Amyloid beta-Peptides; C499173:FCGR2B protein, human; D010446:Peptide Fragments; D017452:Receptors, IgG; C075222:amyloid beta-protein (1-42)