microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain

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.