Abstract
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.
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This post is Copyright: Mason Tate,
H. R. Sagara Wijeratne,
Byungwook Kim,
Stéphanie Philtjens,
Yanwen You,
Do‐Hun Lee,
Daniela A. Gutierrez,
Daniel Sharify,
Megan Wells,
Magdalena Perez‐Cardelo,
Emma H. Doud,
Carlos Fernandez‐Hernando,
Cristian Lasagna‐Reeves,
Amber L. Mosley,
Jungsu Kim | September 30, 2024