TOM1 regulates neuronal accumulation of amyloid-β oligomers by FcγrIIb2 variant in Alzheimer’s disease

Youngdae Gwon, Tae In Kam, Seo Hyun Kim, Sungmin Song, Hyejin Park, Bitna Lim, Haneul Lee, Weontae Lee, Dong Gyu Jo, Yong Keun Jung

Research output: Contribution to journalArticle

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 Fcγ-receptor IIb (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 knock-out 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 downregulated in the hippocampus of male 3xTg-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 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.

Original languageEnglish (US)
Pages (from-to)9001-9018
Number of pages18
JournalJournal of Neuroscience
Volume38
Issue number42
DOIs
StatePublished - Oct 17 2018

Keywords

  • Alzheimer’s disease
  • Amyloid beta (Aβ)
  • Fcγ-receptor IIb
  • Intraneuronal Aβ
  • MiR-126
  • TOM1

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Gwon, Y., Kam, T. I., Kim, S. H., Song, S., Park, H., Lim, B., Lee, H., Lee, W., Jo, D. G., & Jung, Y. K. (2018). TOM1 regulates neuronal accumulation of amyloid-β oligomers by FcγrIIb2 variant in Alzheimer’s disease. Journal of Neuroscience, 38(42), 9001-9018. https://doi.org/10.1523/JNEUROSCI.1996-17.2018