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.

Amyloid beta: structure, biology and structure-based therapeutic development

“…Two immune globin receptors, FccRIIb and PirB, originally believed to function exclusively in the immune system, were recently shown to play neuropathic roles as Aβ receptors in Alzheimer's disease brains [97,127,128] . These two proteins show similarity in their structures and in the high binding affinity for Aβ oligomers.…”

The Alzheimer Disease Protective Mutation A2T Modulates Kinetic and Thermodynamic Properties of Amyloid-β (Aβ) Aggregation

“…Moreover, the flexible N-terminal part of the A␤ fragment itself may be important for interaction with some "toxic A␤ receptors," e.g. FcybII (30), and thus, N-terminal mutations in A␤ may affect receptor-driven synaptotoxic cascades. Furthermore, the changes in full-length A␤ production caused by the A2T and A2V mutations might also affect more indirectly the toxic or aggregation behaviors of the resulting A␤ mixes.…”

Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s disease

“…Please see main text for details aspartate receptor (NMDAR), a7-nicotinic acetylcholine receptor (a7 nAChR), cellular prion protein (PrP c ), ephrin type B receptor 2, immunoglobulin G Fc gamma receptor IIb (FccRIIb), and paired immunoglobulin-like receptor B (PirB) (Fig. 1) [22][23][24][25][26][27][28].…”