| Abstrakt: |
Background: Most of Alzheimer's disease (AD) cases present cerebrovascular dysfunction (CVD) and neuroinflammation, at both early and late stages of AD progression. Dysfunctional vasculature and glial cells favor Aβ deposition, inducing brain cell stress, neuroinflammation, impaired clearance/ metabolic waste accumulation, blood‐brain barrier permeability, and ultimately leading to neurodegenerative processes and cognitive impairment. Endothelial cells (ECs) and microglial cells are major players in mediating vascular and glial fitness, and therefore clearance and inflammatory response. Our previous findings in vitro demonstrated that Aβ elicits mitochondrial dysregulation and caspase‐mediated apoptosis in ECs and glial cells. We also showed that FDA‐approved carbonic anhydrase inhibitors (CAIs), acetazolamide (ATZ) and methazolamide (MTZ), employed in non‐AD related conditions, hinder these pathological events. Method: TgSwDI mice, expressing human Amyloid‐β Precursor Protein, APP, carrying the Swedish, Dutch and Iowa mutations, were employed as AD/CAA (Cerebral Amyloid Angiopathy) model. The model is characterized by fibrillar Aβ burden in the cerebral microvasculature and in the parenchyma, starting at 6 months, as well as abundant gliosis. 8‐month‐old Tg animals were fed 8‐month‐CAI‐diet, following which we harvested the brains for biochemical and immunohistochemical assessments. Result: CAIs significantly reduced brain amyloidosis, and vascular and microglial Aβ accumulation. In addition, CAIs prevented caspase‐3 activation in ECs and microglia, ameliorating vascular and glial fitness, as we observed less microhemorrhages, reduced microgliosis, and microglial pro‐clearance phenotype. We also unveiled a critical novel druggable target, showing that the mitochondrial isozyme Carbonic Anhydrase (CA)‐VB is specifically upregulated in human cerebral endothelial and microglial cells challenged by Aβ, and most importantly is overexpressed in TgSwDI mouse brains, and in human brains of CAA and AD (with CAA) patients. Conclusion: CAIs promote vascular health, glial anti‐inflammatory/pro‐healing phenotype and Aβ phagocytosis, which may underlie Aβ deposition reduction. This work paves the way for the application of CAIs in clinical trials for AD and CAA, and uncovers CA‐VB as a mediator of cerebral Aβ toxicity in endothelial and microglial cells. [ABSTRACT FROM AUTHOR] |
