Abstract Body: Background: The linkage between atherosclerosis and vascular dementia, including its ties to Alzheimer’s disease (AD), is well-established. This research explores how small cerebral vessel damages, a less recognized consequence of atherosclerosis, contribute to the development of tau pathology, a key AD hallmark.
Methods and Results: Through the ApoE-/- mouse model, we evaluated the impact of hypercholesterolemia and AngII infusion on tau pathology. The regimen included an atherogenic diet for three months and subsequent AngII infusion (1mg/kg/min) for 28 days in three-month-old mice. Key outcomes measured were phosphorylated tau (AT8), cerebral microbleeds, blood component deposition, and oxidative stress markers. Results indicated a synergistic effect of diet and AngII on increasing microbleeds, vascular leakage, and oxidative stress, which coincided with heightened p-tau in affected brain regions. A specific focus on endothelial glutaredoxin-1 (Glrx) deficiency revealed its critical role in moderating these pathological changes, linking endothelial oxidative stress directly with tau pathology.
Conclusion: Our research highlights the significant role of small cerebral vessel damage in advancing tau pathology in atherosclerosis, with endothelial oxidative stress as a key mediator. This underscores novel pathways through which vascular health influences AD pathology.