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

• Published in: Alzheimer's & dementia 2024-11, Vol.20 (11), p.7805-7818
• Main Authors: Tate, Mason, Wijeratne, H. R. Sagara, Kim, Byungwook, Philtjens, Stéphanie, You, Yanwen, Lee, Do‐Hun, Gutierrez, Daniela A., Sharify, Daniel, Wells, Megan, Perez‐Cardelo, Magdalena, Doud, Emma H., Fernandez‐Hernando, Carlos, Lasagna‐Reeves, Cristian, Mosley, Amber L., Kim, Jungsu
• Format: Article
• Language: English
• Subjects: ABCA1; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; amyloid; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; apolipoprotein E; Apolipoproteins E - genetics; ATP Binding Cassette Transporter 1 - genetics; ATP Binding Cassette Transporter 1 - metabolism; Brain - metabolism; Brain - pathology; Cell Movement; Disease Models, Animal; lipid metabolism; Mice; Mice, Transgenic; Microglia - metabolism; Microglia - pathology; MicroRNAs - genetics; MicroRNAs - metabolism; microRNA‐33; Phagocytosis; Phenotype; Presenilin-1 - genetics
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.14243

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 (Aβ) phagocytosis. RESULTS Mir‐33 deletion increases ABCA1 levels and reduces Aβ 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 Aβ phagocytosis. DISCUSSION These results suggest that miR‐33 might be a potential drug target by modulating ABCA1 level, apoE lipidation, Aβ level, and microglial function. Highlights Loss of microRNA‐33 (miR‐33) increased ABCA1 protein levels and the lipidation of apolipoprotein E. Loss of miR‐33 reduced amyloid beta (Aβ) levels, plaque deposition, and gliosis. mRNAs and proteins dysregulated by miR‐33 loss relate to microglia and Alzheimer's disease. Inhibition of miR‐33 increased microglial migration and Aβ phagocytosis in vitro.