Carbonic anhydrase inhibitors: a novel pharmacological strategy to rescue Aβ‐induced neurovascular pathology and gliosis in vivo

Abstract

AbstractBackgroundCerebrovascular dysfunction (CVD) and neuroinflammation are associated and contribute to Alzheimer's disease (AD) progression. Most AD cases also present cerebral amyloid angiopathy (CAA), characterized by amyloid beta (Aβ) deposits at the brain vasculature, which trigger CVD and dysregulated brain clearance. In addition, CVD and altered clearance worsen vascular Aβ deposition, inducing cellular stress, neuroinflammation, metabolic waste accumulation, vascular permeability, infiltration of blood‐borne cells, and eventually leading to neurodegenerative processes and cognitive impairment. Endothelial cells (ECs) and glial cells are major players in mediating vascular fitness and brain clearance, promoting the removal of toxic material from the brain, including Aβ. Our previous findings demonstrated that Aβ elicits mitochondrial dysregulation and caspase‐mediated apoptosis in ECs and glial cells. Moreover, we showed that acetazolamide (ATZ) and methazolamide (MTZ), FDA‐approved carbonic anhydrase inhibitors (CAIs), employed in non‐AD related conditions, hinder these pathological events.MethodsTgSwDI mice, expressing human Amyloid‐β Precursor Protein, APP, carrying the Swedish, Dutch and Iowa mutations, were employed as AD/CAA model. Tg mice, which develop, starting at 6 months, fibrillar Aβ burden, primarily in the cerebral microvasculature, and gliosis, were fed a CAI‐diet (from 8 to 16 months of age), following which we tested cognitive function, and harvested the brains for biochemical and immunohistochemical analyses.ResultsATZ‐ and MTZ‐diet improve behavioral performances, and decrease total brain Aβ burden and caspase‐3 activation. Specifically, CAIs reduce Aβ accumulation in ECs, astrocytes and microglia, and the cell‐specific Aβ‐initiated caspase activity, promoting vascular health, glial anti‐inflammatory/pro‐healing phenotype and perivascular Aβ phagocytosis, which may underlie cerebral Aβ reduction.ConclusionsOur results show that CAIs foster endothelial and glial proper function, improving Aβ clearance, and ultimately providing neuroprotection, and indicate CAIs as a novel pharmacological strategy to rescue Aβ‐induced neurovascular pathology and gliosis in AD/CAA pathology.