| First Author | Kim J | Year | 2015 |
| Journal | J Neurosci | Volume | 35 |
| Issue | 44 | Pages | 14717-26 |
| PubMed ID | 26538644 | Mgi Jnum | J:227051 |
| Mgi Id | MGI:5699619 | Doi | 10.1523/JNEUROSCI.2053-15.2015 |
| Citation | Kim J, et al. (2015) microRNA-33 Regulates ApoE Lipidation and Amyloid-beta Metabolism in the Brain. J Neurosci 35(44):14717-26 |
| abstractText | Dysregulation of amyloid-beta (Abeta) metabolism is critical for Alzheimer's disease (AD) pathogenesis. Mounting evidence suggests that apolipoprotein E (ApoE) is involved in Abeta metabolism. ATP-binding cassette transporter A1 (ABCA1) is a key regulator of ApoE lipidation, which affects Abeta 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 Abeta levels in the brain. Overexpression of miR-33 impaired cellular cholesterol efflux and dramatically increased extracellular Abeta levels by promoting Abeta secretion and impairing Abeta clearance in neural cells. In contrast, genetic deletion of mir-33 in mice dramatically increased ABCA1 levels and ApoE lipidation, but it decreased endogenous Abeta levels in cortex. Most importantly, pharmacological inhibition of miR-33 via antisense oligonucleotide specifically in the brain markedly decreased Abeta levels in cortex of APP/PS1 mice, representing a potential therapeutic strategy for AD. SIGNIFICANCE STATEMENT: Brain lipid metabolism, in particular Apolipoprotein E (ApoE) lipidation, is critical to Abeta metabolism and Alzheimer's disease (AD). Brain lipid metabolism is largely separated from the periphery due to blood-brain barrier and different repertoire of lipoproteins. Therefore, identifying the novel regulatory mechanism of brain lipid metabolism may provide a new therapeutic strategy for AD. Although there have been studies on brain lipid metabolism, its regulation, in particular by microRNAs, is relatively unknown. Here, we demonstrate that inhibition of microRNA-33 increases lipidation of brain ApoE and reduces Abeta levels by inducing ABCA1. We provide a unique approach for AD therapeutics to increase ApoE lipidation and reduce Abeta levels via pharmacological inhibition of microRNA in vivo. |
