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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 Aβ 1-42, not monomeric Aβ 1-42 or oligomeric Aβ 1-40 , was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. Aβ 1-42 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 Aβ 1-42 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. SIGNIFICANCE STATEMENT Accumulating evidences suggest that intraneuronal Aβ is found in the early step of AD brain and is implicated in the pathogenesis of AD. However, the critical mediator involved in these processes is uncertain. Here, we describe that the FcγRIIb2 variant is responsible for both neuronal uptake and intraneuronal distribution of pathogenic Aβ linked to memory deficits in AD mice, showing a pathologic significance of the internalized Aβ. Further, Aβ internalization is attenuated by TOM1, a novel FcγRIIb2-binding protein. Together, we provide a molecular mechanism responsible for neuronal uptake of pathogenic Aβ found in AD.

TOM1 Regulates Neuronal Accumulation of Amyloid-β Oligomers by FcγRIIb2 Variant in Alzheimer's Disease