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- Title
TOM1 Regulates Neuronal Accumulation of Amyloid-β Oligomers by FcγRIIb2 Variant in Alzheimer's Disease.
- Authors
Youngdae Gwon; Tae-In Karri; Seo-Hyun Kim; Sungmin Song; Hyejin Park; Bitna Lim; Haneul Lee; Weontae Lee; Dong-Gyu Jo; Yong-Keun Jung
- Abstract
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 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 knockout 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 down-regulated in the hippocampus of male 3x Tg-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 3x Tg-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 3x Tg-AD mice and memory deficits in male 3x Tg-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.
- Subjects
ALZHEIMER'S disease; OLIGOMERS; AMYLOID plaque
- Publication
Journal of Neuroscience, 2018, Vol 38, Issue 42, p9001
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1996-17.2018