期刊
JOURNAL OF NEUROSCIENCE
卷 35, 期 44, 页码 14717-14726出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2053-15.2015
关键词
ABCA1; abeta; Alzheimer's disease; ApoE; miR-33
资金
- Washington University McDonnell Center for Cellular and Molecular Neurobiology
- GHR Foundation
- Mayo Clinic Center for Individualized Medicine
- Alzheimer's Association
- National Institutes of Health [NS069329, AG016574, AG005681, AG042513, HL107953, AG039708, AG13956]
- Mayo Graduate School
- BrightFocus Foundation [A2010613, A2012421]
- Grants-in-Aid for Scientific Research [15H04271] Funding Source: KAKEN
Dysregulation of amyloid-beta (A beta) metabolism is critical for Alzheimer's disease (AD) pathogenesis. Mounting evidence suggests that apolipoprotein E (ApoE) is involved in A beta metabolism. ATP-binding cassette transporter A1 (ABCA1) is a key regulator of ApoE lipidation, which affects A beta 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 A beta levels in the brain. Overexpression of miR-33 impaired cellular cholesterol efflux and dramatically increased extracellular A beta levels by promoting A beta secretion and impairing A beta clearance in neural cells. In contrast, genetic deletion of mir-33 in mice dramatically increased ABCA1 levels and ApoE lipidation, but it decreased endogenous A beta levels in cortex. Most importantly, pharmacological inhibition of miR-33 via antisense oligonucleotide specifically in the brain markedly decreased A beta levels in cortex of APP/PS1 mice, representing a potential therapeutic strategy for AD.
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