%0 Journal Article
%T TOM1 Regulates Neuronal Accumulation of Amyloid-¦Â Oligomers by Fc¦ÃRIIb2 Variant in Alzheimer's Disease
%A Bitna Lim
%A Dong-Gyu Jo
%A Haneul Lee
%A Hyejin Park
%A Seo-Hyun Kim
%A Sungmin Song
%A Tae-In Kam
%A Weontae Lee
%A Yong-Keun Jung
%A Youngdae Gwon
%J The Journal of Neurosience
%D 2018
%R 10.1523/JNEUROSCI.1996-17.2018
%X Emerging evidences suggest that intraneuronal A¦Â correlates with the onset of Alzheimer's disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for A¦Â uptake in AD pathology needs to be clarified. Here, we report that Fc¦ÃRIIb2, a variant of Fc¦Ã-receptor IIb (Fc¦ÃRIIb), functions in neuronal uptake of pathogenic A¦Â. Cellular accumulation of oligomeric A¦Â1¨C42, not monomeric A¦Â1¨C42 or oligomeric A¦Â1¨C40, was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. A¦Â1¨C42 internalization was Fc¦ÃRIIb2 di-leucine motif-dependent and attenuated by TOM1, a Fc¦ÃRIIb2-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¦Â1¨C42. In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented A¦Â uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of A¦Â in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of A¦Â-uptake-defective Fcgr2b mutant. Our findings suggest that Fc¦ÃRIIb2 is essential for neuropathic uptake of A¦Â in AD.

SIGNIFICANCE STATEMENT Accumulating evidences suggest that intraneuronal A¦Â 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 Fc¦ÃRIIb2 variant is responsible for both neuronal uptake and intraneuronal distribution of pathogenic A¦Â linked to memory deficits in AD mice, showing a pathologic significance of the internalized A¦Â. Further, A¦Â internalization is attenuated by TOM1, a novel Fc¦ÃRIIb2-binding protein. Together, we provide a molecular mechanism responsible for neuronal uptake of pathogenic A¦Â found in AD
%U http://www.jneurosci.org/content/38/42/9001