Endothelial mitochondrial dysfunction during Cerebral Amyloid Angiopathy and Hyperhomocysteinemia

Hyperhomocysteinemia (HHcy), or high levels of homocysteine, is considered a risk factor for vascular disease. Cardiovascular (CV) risk factors, such as HHcy, may lead to exacerbation of cerebral amyloid angiopathy (CAA) due to their detrimental effects on cerebrovascular function. Cerebrovascular function is regulated, in part, by endothelial cells (EC), the most important cellular component of the blood‐brain barrier (BBB). Dysfunctional ECs may lead to deficits in vascular perfusion, clearance, and may eventually result in neuroinflammation, microhemorrhages, and neurodegeneration. EC mitochondria serve as sensors of cellular damage and mediate downstream pathways such as cell death and inflammation. In ECs, mitochondrial dysfunction may lie as the point of convergence of CV risk factors and amyloid β (Aβ)‐induced neurovascular dysfunction. Understanding the mitochondrial deficits elicited by CV risk factors, Aβ, or their combination, may open roads to new therapeutics aimed at preserving mitochondrial function. Indeed, we have previously shown that carbonic anhydrase inhibitors (CAi) reduce amyloid‐induced cell death and mitochondrial dysfunction. Here, we aim to understand the changes occurring in EC mitochondria during Aβ‐ and mixed (Aβ+HHcy)‐ vascular pathologies. In addition, we will assess the therapeutic potential of CAi in such pathologies.