“FDA-approved carbonic anhydrase inhibitors reduce Amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness”

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective cure. Cerebrovascular and neurovascular pathology are early and causal hallmarks of AD, with cerebral amyloid angiopathy (CAA), the deposition of amyloid β (Aβ) at the cerebral vasculature, being present in about 90% of AD cases. Our previous work has uncovered the protective effect of carbonic anhydrase (CA) inhibition against Aβ-mediated mitochondrial dysfunction, production of reactive oxygen species (ROS) and apoptosis in vascular, glial and neuronal cells in culture and in mouse brains injected with Aβ. Here, we tested for the first time in a model of AD and cerebrovascular amyloidosis, the TgSwDI mice, a chronic regimen employing FDA-approved CA inhibitors (CAIs), methazolamide (MTZ) and acetazolamide (ATZ). These drugs are used in humans for the treatment of glaucoma, high altitude sickness, and other disorders, and are able to pass the blood-brain barrier. We found that both CAIs were non-toxic, significantly reduced cerebral amyloidosis, including vascular and glial Aβ accumulation, and ameliorated cognition. MTZ and ATZ treatment prevented caspase activation in endothelial cells, microglia and astrocytes, reverted capillary constriction, reduced gliosis, and induced protective pro-clearance pathways, which are likely responsible for the reduction of Aβ deposition. Importantly, we unveiled a key new drug target, showing that the mitochondrial isozyme CA-VB is upregulated in TgSwDI brains and in endothelial cells upon Aβ treatment, and that CA-VB silencing, mimicking CAIs effects, reduces endothelial cell apoptosis. Overall, this work paves the way to the potential application of CAIs in clinical trials for human AD and CAA.

HOMOCYSTEINE POTENTIATES AMYLOID Β-Induced CEREBRAL ENDOTHELIAL CELL APOPTOSIS, BLOOD BRAIN BARRIER DYSFUNCTION AND ANGIOGENIC IMPAIRMENT

“…Our data suggests that patients presenting with both amyloidosis (AD/CAA) and Hhcy should be considered at higher risk for these complications, due to their already highly compromised BBB function, and physicians should be cautious in prescribing Aβ immunotherapies in patients with these comorbidities. These findings also highlight the need to continue the search for alternative therapies which could be affective also in patients with cerebrovascular comorbidities (Canepa et al, 2023), which are among the most frequent AD associated comorbidities (Carey & Fossati, 2023).…”

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

“…Our data suggests that patients presenting with both amyloidosis (AD/CAA) and Hhcy should be considered at higher risk for these complications, due to their already highly compromised BBB function, and physicians should be cautious in prescribing Aβ immunotherapies in patients with these comorbidities. These findings also highlight the need to continue the search for alternative therapies which could be affective also in patients with cerebrovascular comorbidities (Canepa et al., 2023), which are among the most frequent AD associated comorbidities (Carey & Fossati, 2023).…”

Amyloid, a Jekyll and Hyde Molecule Inducing Neuronal Decline and Cognitive Dysfunction is Also a Unique Molecular Template used in Nano-electronics, Light Capture Photovoltaics, and Biosensors in Neuromorphic Computing.

“…Carbonic anhydrase inhibitors have been shown to reduce cerebral, vascular, and glial Aβ accumulation and amyloid fibril deposition and improved cognitive processes in mice. Carbonic anhydrase inhibitors may be useful in the treatment of AD and cerebral amyloid angiopathy [226]. Carbonic anhydrase occurs as 14 isozyme zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and have major roles in controlling acid-base balances and pH in tissues [227].…”