Apolipoprotein E dysfunction in Alzheimer’s disease: a study on miRNA regulation, glial markers, and amyloid pathology

Our findings demonstrated that miRNA levels were generally lower in 3-month-old <i>Apoe</i>-ko mice but increased in 9-month-old mice across five distinct brain regions, as well as in eye tissue and tear fluid. A high-fat diet further enhanced miRNA dysregulation in brain and eye tissues, but not in tear fluid. Target mRNAs were generally higher in the neocortex-hippocampus and eye tissue of 3-month-old <i>Apoe</i>-ko mice but decreased with age, except for glial cell mRNAs like <i>Gfap</i> and <i>Aif1</i>. Protein analysis revealed elevated Gfap expression, and increased APP/Aβ peptide accumulation in the neocortex-hippocampus, including brain endothelial cells at the meninges, as well as in the retina of 9-month-old <i>Apoe</i>-ko mice. These findings highlight ApoE's pivotal role in AD, demonstrating its impact on inflammatory and amyloidogenic/angiogenic miRNA expression, glial homeostasis, and APP/Aβ peptide clearance. The observed upregulation of proinflammatory miR-146a and anti-amyloidogenic/angiogenic miR-15a in 9-month-old <i>Apoe</i>-ko mice suggests their potential as tear-based biomarkers for ApoE dysfunction.