Mitochondria as a possible target for cerebral amyloid angiopathy‐mediated endothelial dysfunction in the presence of hyperhomocysteinemia. (December 2021)

• Record Type: Journal Article
• Authors: Parodi‐Rullan, Rebecca M; Lemon, Nicole L; Carey, Ashley M; Fossati, Silvia
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.054397
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Cardiovascular (CV) risk factors may potentiate cerebral amyloid angiopathy (CAA) pathology and neurovascular dysfunction, worsening neurodegeneration. The role of the mitochondria, key regulators of cell survival and death, in mediating cerebral endothelial cell (EC) dysfunction during CAA complicated with CV risk factors is unknown. Our lab has demonstrated that carbonic anhydrase inhibitors (CAi) reduce amyloid‐induced cell death and mitochondrial dysfunction in EC. Here, we aim to understand the role of the mitochondria in the pathogenesis of mixed AD and vascular dementias. Furthermore, we seek to understand the effects of pan‐CAi and CAi with high selectivity for mitochondria‐localized isoforms (mCAi) in preventing the toxic effects of amyloid β (Aβ) and hyperhomocysteinemia (HHcy). Methods: Human ECs were challenged with Aβ, Hcy, or the combination in the presence or absence of CAi. Cell death, mitochondrial function, and blood‐brain barrier (BBB) resistance effects were evaluated. Results: The presence of Aβ and/or HHcy induced EC apoptosis, mediated by death receptors activation and mitochondrial dysfunction, and attenuated by CAi and mCAi. BBB permeability was increased by both Aβ and HHcy, and HHcy worsened amyloid‐induced barrier permeability. These effects were prevented by CAi and mCAi. Conclusion: Both HHcy and Aβ had detrimental effects on EC mitochondrial function and BBB permeability, and HHcy worsened the effects of Aβ. These effects were prevented by CAi and mCAi. The ability of mCAi to protect against Aβ and/or HHcy suggests a central role of the mitochondria in mediating vascular dysfunction in the presence of Aβ and/or HHcy. Our studies support the importance of better understanding mitochondrial and EC pathways responsible for cerebrovascular dysfunction in CAA and mixed dementias.