Editors' ChoiceNEURODEGENERATIVE DISEASE

IgG Receptors in Alzheimer’s Disease

Science Signaling  30 Jul 2013:
Vol. 6, Issue 286, pp. ec173
DOI: 10.1126/scisignal.2004547

The pathological features of Alzheimer’s disease (AD) are associated with the toxic accumulation of β-amyloid (Aβ) in the brain. Using cells, AD-model mice, and human AD brain tissue, Kam et al. found that the IgG Fcγ receptor IIb (FcγRIIb) mediated Aβ toxicity in neurons. Compared with controls, the abundance of FcγRIIb was increased in the brains of adult AD-model mice and in the hippocampus of human AD brain tissue, where it colocalized in situ (and coprecipitated in homogenates) with endogenous Aβ. In human SH-SY5Y neuroblastoma cells and wild-type, but not Fcgr2b-knockout, mouse cortical neurons, Aβ increased the mRNA and protein abundance of FcγRIIb and activated the c-Jun N-terminal kinase (JNK) and its target the transcription factor c-Jun (known to transcriptionally activate FCGR2B). In vitro, both cell-derived and synthetic Aβ oligomers bound to immobilized FcγRIIb ectodomain (ED), and treating SH-SY5Y cells or mouse cortical neurons with FcγRIIb-ED inhibited Aβ-induced JNK activation and Fcgr2b expression, indicating that FcγRIIb functions as a receptor for Aβ. Additionally, pharmacological inhibition revealed that JNK was essential for Aβ-induced expression of Fcgr2b and an Fcgr2b promoter-linked reporter in SH-SY5Y cells, indicating that FcγRIIb activates JNK to trigger a positive transcriptional feedback that increases the abundance of the receptor. In wild-type, but not Fcgr2b-knockout, cortical neurons, oligomeric Aβ also increased the abundance of endoplasmic reticulum (ER) stress response proteins, which were also increased, along with Aβ-induced cell death, by overexpression of FcγRIIb in HT22 human hippocampal cells. Salubrinal, an ER stress inhibitor, prevented Aβ-induced cell death in wild-type and FcγRIIb-overexpressing HT22 cells. Hippocampal slices and primary cortical and hippocampal neurons from Fcgr2b-knockout mice were resistant to Aβ-induced neurotoxicity [manifested by cell death and decreased long-term potentiation (LTP), synapse stability, and spine density]. Fcgr2b knockout by cross-breeding restored synaptic function and memory retention in AD-model mice. Treatment with synthetic peptides targeting the Aβ-FcγRIIb interaction at specific amino acids in either protein (predicted by a docking simulation) inhibited Aβ-induced neurotoxicity in primary mouse cortical and hippocampal neurons and Aβ-induced memory impairment in AD-model mice. Together, the data suggest that targeting the Aβ-FcγRIIb interaction may treat Aβ pathology in Alzheimer’s disease.

T.-I. Kam, S. Song, Y. Gwon, H. Park, J.-J. Yan, I. Im, J.-W. Choi, T.-Y. Choi, J. Kim, D.-K. Song, T. Takai, Y.-C. Kim, K.-S. Kim, S.-Y. Choi, S. Choi, W. L. Klein, J. Yuan, Y.-K. Jung, FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer’s disease. J. Clin. Invest. 123, 2791–2802 (2013). [PubMed]

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