Microrna-33 regulates apoe lipidation and amyloid-β metabolism in the brain

Jaekwang Kim, Hyejin Yoon, Takahiro Horie, Jack M. Burchett, Jessica L. Restivo, Noemi Rotllan, Cristina M. Ramírez, Philip B. Verghese, Masafumi Ihara, Hyang Sook Hoe, Christine Esau, Carlos Fernández-Hernando, David M. Holtzman, John R. Cirrito, Koh Ono, Jungsu Kim

Research output: Contribution to journalArticlepeer-review

99 Scopus citations


Dysregulation of amyloid-β (Aβ) metabolism is critical for Alzheimer’s disease (AD) pathogenesis. Mounting evidence suggests that apolipoprotein E (ApoE) is involved in Aβ metabolism. ATP-binding cassette transporter A1 (ABCA1) is a key regulator of ApoE lipidation, which affects Aβ levels. Therefore, identifying regulatory mechanisms of ABCA1 expression in the brain may provide new therapeutic targets for AD. Here, we demonstrate that microRNA-33 (miR-33) regulates ABCA1 and Aβ levels in the brain. Overexpression of miR-33 impaired cellular cholesterol efflux and dramatically increased extracellular Aβ levels by promoting Aβ secretion and impairing Aβ clearance in neural cells. In contrast, genetic deletion of mir-33 in mice dramatically increased ABCA1 levels and ApoE lipidation, but it decreased endogenous Aβ levels in cortex. Most importantly, pharmacological inhibition of miR-33 via antisense oligonucleotide specifically in the brain markedly decreased Aβ levels in cortex of APP/PS1 mice, representing a potential therapeutic strategy for AD.

Original languageEnglish
Pages (from-to)14717-14726
Number of pages10
JournalJournal of Neuroscience
Issue number44
StatePublished - Nov 4 2015


  • ABCA1
  • Abeta
  • Alzheimer’s disease
  • ApoE
  • MiR-33


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