Emerging evidences suggest that intraneuronal A beta correlates with the onset of Alzheimer's disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for A beta uptake in AD pathology needs to be clarified. Here, we report that Fc gamma RIIb2, a variant of Fc gamma-receptor IIb (Fc gamma RIIb), functions in neuronal uptake of pathogenic A beta. Cellular accumulation of oligomeric A beta(1-42), not monomeric A beta(1-42) or oligomeric A beta(1-40), was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. A beta(1-42) internalization was Fc gamma RIIb2 di-leucine motif-dependent and attenuated by TOM1, a Fc gamma RIIb2-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 A beta(1-42). In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented A beta uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of A beta in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of A beta-uptake-defective Fcgr2b mutant. Our findings suggest that Fc gamma RIIb2 is essential for neuropathic uptake of A beta in AD.