Mitochondrial carbonic anhydrase–VB inhibition rescues brain endothelial stress and memory in Alzheimer’s disease models
- 1Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
- 2Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Temple University, Philadelphia, PA, USA.
Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CAs) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial CA isoform CA-VB by pharmacological and genetic manipulation in human cerebral microvascular endothelial cells (hCMEC), and we confirm the protective effects of the CA-V inhibitor in AD mice. CA-V inhibition and CA-VB KO prevent Aβ induced mitochondria-mediated endothelial apoptosis, loss of barrier resistance, and hCMEC inflammatory activation. Strikingly, CA-V inhibition also mitigates caspase activation and endothelial cell activation in the brains of 3xTg AD mice, resulting in preserved memory function. Our results demonstrate that selective CA-V inhibition is an effective and promising strategy against AD-mediated cerebrovascular pathology, neuroinflammation and cognitive impairment.
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BibTeX
@article{lemon2026mitochondrial,
title = {{Mitochondrial carbonic anhydrase–VB inhibition rescues brain endothelial stress and memory in Alzheimer’s disease models}},
author = {Nicole L. Lemon and Elisa Canepa and Rafael Vázquez-Torres and Rebecca Parodi-Rullán and Tina Hirt and Lisa M. Petersohn and Tashnuva Rifat and Maryam H. Abyaneh and Marc A. Ilies and Silvia Fossati},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.ady1161},
url = {https://www.science.org/doi/10.1126/sciadv.ady1161},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Mitochondrial carbonic anhydrase–VB inhibition rescues brain endothelial stress and memory in Alzheimer’s disease models
AU - Nicole L. Lemon
AU - Elisa Canepa
AU - Rafael Vázquez-Torres
AU - Rebecca Parodi-Rullán
AU - Tina Hirt
AU - Lisa M. Petersohn
AU - Tashnuva Rifat
AU - Maryam H. Abyaneh
AU - Marc A. Ilies
AU - Silvia Fossati
PY - 2026
DA - 2026/10/14
JO - Science Advances
DO - 10.1126/sciadv.ady1161
UR - https://www.science.org/doi/10.1126/sciadv.ady1161
AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CAs) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial CA isoform CA-VB by pharmacological and genetic manipulation in human cerebral microvascular endothelial cells (hCMEC), and we confirm the protective effects of the CA-V inhibitor in AD mice. CA-V inhibition and CA-VB KO prevent Aβ induced mitochondria-mediated endothelial apoptosis, loss of barrier resistance, and hCMEC inflammatory activation. Strikingly, CA-V inhibition also mitigates caspase activation and endothelial cell activation in the brains of 3xTg AD mice, resulting in preserved memory function. Our results demonstrate that selective CA-V inhibition is an effective and promising strategy against AD-mediated cerebrovascular pathology, neuroinflammation and cognitive impairment.
SN - 2375-2548
ER -