| First Author | Gwon Y | Year | 2018 |
| Journal | J Neurosci | Volume | 38 |
| Issue | 42 | Pages | 9001-9018 |
| PubMed ID | 30185465 | Mgi Jnum | J:266518 |
| Mgi Id | MGI:6209307 | Doi | 10.1523/JNEUROSCI.1996-17.2018 |
| Citation | Gwon Y, et al. (2018) TOM1 Regulates Neuronal Accumulation of Amyloid-beta Oligomers by FcgammaRIIb2 Variant in Alzheimer's Disease. J Neurosci 38(42):9001-9018 |
| abstractText | Emerging evidences suggest that intraneuronal Abeta correlates with the onset of Alzheimer's disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for Abeta uptake in AD pathology needs to be clarified. Here, we report that FcgammaRIIb2, a variant of Fcgamma-receptor IIb (FcgammaRIIb), functions in neuronal uptake of pathogenic Abeta. Cellular accumulation of oligomeric Abeta1-42, not monomeric Abeta1-42 or oligomeric Abeta1-40, was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. Abeta1-42 internalization was FcgammaRIIb2 di-leucine motif-dependent and attenuated by TOM1, a FcgammaRIIb2-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 Abeta1-42 In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented Abeta uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of Abeta in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of Abeta-uptake-defective Fcgr2b mutant. Our findings suggest that FcgammaRIIb2 is essential for neuropathic uptake of Abeta in AD.SIGNIFICANCE STATEMENT Accumulating evidences suggest that intraneuronal Abeta 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 FcgammaRIIb2 variant is responsible for both neuronal uptake and intraneuronal distribution of pathogenic Abeta linked to memory deficits in AD mice, showing a pathologic significance of the internalized Abeta. Further, Abeta internalization is attenuated by TOM1, a novel FcgammaRIIb2-binding protein. Together, we provide a molecular mechanism responsible for neuronal uptake of pathogenic Abeta found in AD. |
