Emerging evidences suggest that intraneuronal Aβ correlates with the onset of Alzheimer’s disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for Aβ uptake in AD pathology needs to be clarified. Here, we report that FcγRIIb2, a variant of Fcγ-receptor IIb (FcγRIIb), functions in neuronal uptake of pathogenic Aβ. Cellular accumulation of oligomeric Aβ1–42, not monomeric Aβ1–42 or oligomeric Aβ1–40, was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. Aβ1–42 internalization was FcγRIIb2 di-leucine motif-dependent and attenuated by TOM1, a FcγRIIb2-binding protein that repressed the receptor recycling. TOM1 expression was downregulated in the hippocampus of male 3xTg-AD mice and AD patients, and regulated by miR-126-3p in neuronal cells after exposure to Aβ1–42. In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented Aβ uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of Aβ in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of Aβ-uptake-defective Fcgr2b mutant. Our findings suggest that FcγRIIb2 is essential for neuropathic uptake of Aβ in AD.
Bibliographical noteFunding Information:
This work was supported by the BK21 program and Global PhD program to Y.G. and S.-H.K., the CRI Grant (NRF-2016R1A2A1A005005304) funded by the Ministry of Education, Science and Technology, and the Samsung ScienceandTechnologyFoundationunderProjectNumberSSTFBA1401-16.WethankDr.F.M.LaFerla(Universityof California, Irvine, CA) for providing 3xTg-AD mice, Dr. P. Davies (Albert Einstein College of Medicine, NY) for PHF1 antibody, Dr. D.J. Selkoe (Harvard Medical School, MA) for CHO and 7PA2 cells, Dr. E.H. Joe (Ajou University, Korea) for the technical assistance of primary astrocyte culture. The authors declare no competing financial interests. *Y.G. and T.-I.K. contributed equally to this work.
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