Deletion of miR-33, a regulator of the ABCA1-APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice

INTRODUCTION: Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). ABCA1 facilitates the lipidation of apolipoprotein E (apoE). This study investigated whether microRNA-33 (miR-33)-mediated regulation of this ABCA1-APOE pathway affects phenotypes of an amyloid mouse model. METHODS: We generated mir-33(+/+);APP/PS1 and mir-33(-/-);APP/PS1 mice to determine changes in amyloid pathology using biochemical and histological analyses. We used RNA sequencing and mass spectrometry to identify the transcriptomic and proteomic changes between our genotypes. We also performed mechanistic experiments by determining the role of miR-33 in microglial migration and amyloid beta (A beta) phagocytosis. RESULTS: Mir-33 deletion increases ABCA1 levels and reduces A beta accumulation and glial activation. Multi-omics studies suggested miR-33 regulates the activation and migration of microglia. We confirm that the inhibition of miR-33 significantly increases microglial migration and A beta phagocytosis. DISCUSSION: These results suggest that miR-33 might be a potential drug target by modulating ABCA1 level, apoE lipidation, A beta level, and microglial function.