Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer's mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic signaling impairment.
- 1Temple University Lewis Katz School of Medicine
Abstract
FDA-approved carbonic anhydrase inhibitors (CAIs) have shown robust efficacy in reducing amyloid- beta pathology, neurodegeneration, and cerebrovascular dysfunction in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA) models, highlighting carbonic anhydrases (CAs) as a promising, previously untapped therapeutic target for AD and the vascular contribution to dementia. We have recently shown that amyloid- beta aggregates disrupt neuro-signaling and deplete neurotrophic factors (particularly BDNF) in the heart of AD mouse models and human subjects. In this study, we present the first in-depth examination of CAI therapy (acetazolamide, ATZ) in Tg2576 mice, a well-established model of AD and CAA. We confirm that progressive cardiac fibrosis and amyloid- beta deposition in 13-month-old mice severely impair the cardiac neuro-signaling system, marked by a drastic decrease in BDNF and reductions in adrenergic fibers and regenerating nerve endings (TH and GAP-43 markers), leading to significant declines in ejection fraction and fractional shortening compared to age-matched WT littermates. Critically, this study demonstrates that long-term ATZ treatment in Tg2576 mice significantly reduces cardiac amyloid- beta burden, prevents adverse neuro-signaling remodeling, and restores heart physiological function, as assessed via speckle tracking strain echocardiography. These in vivo findings were corroborated in human cardiomyocytes, in which CA inhibition reduced human amyloid- beta40 oligomer-dependent disruption of CREB signaling, thus preserving BDNF expression. Together, these results reveal a previously unrecognized cardio-neuroprotective role for CAIs in preventing amyloid- beta-induced cardiovascular remodeling and neuro-signaling disruption in the Tg2576-AD model. Given the established benefits of CAIs on cerebrovascular function and cognition, our findings further support advancing repurposing efforts into clinical trials. CAIs such as ATZ could offer a dual-action therapy approach, addressing both the central nervous system and cardiac pathologies associated with AD and, potentially, the systemic effects of amyloidosis.
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BibTeX
@misc{elia2026carbonic,
title = {{Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer's mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic signaling impairment.}},
author = {A. Elia and R. Vazquez-Torres and A. Carey and M. Wolf and V. R. Gade and M. Alves and S. Fossati},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757731},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757731v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer's mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic signaling impairment.
AU - A. Elia
AU - R. Vazquez-Torres
AU - A. Carey
AU - M. Wolf
AU - V. R. Gade
AU - M. Alves
AU - S. Fossati
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757731
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757731v1
AB - FDA-approved carbonic anhydrase inhibitors (CAIs) have shown robust efficacy in reducing amyloid- beta pathology, neurodegeneration, and cerebrovascular dysfunction in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA) models, highlighting carbonic anhydrases (CAs) as a promising, previously untapped therapeutic target for AD and the vascular contribution to dementia. We have recently shown that amyloid- beta aggregates disrupt neuro-signaling and deplete neurotrophic factors (particularly BDNF) in the heart of AD mouse models and human subjects. In this study, we present the first in-depth examination of CAI therapy (acetazolamide, ATZ) in Tg2576 mice, a well-established model of AD and CAA. We confirm that progressive cardiac fibrosis and amyloid- beta deposition in 13-month-old mice severely impair the cardiac neuro-signaling system, marked by a drastic decrease in BDNF and reductions in adrenergic fibers and regenerating nerve endings (TH and GAP-43 markers), leading to significant declines in ejection fraction and fractional shortening compared to age-matched WT littermates. Critically, this study demonstrates that long-term ATZ treatment in Tg2576 mice significantly reduces cardiac amyloid- beta burden, prevents adverse neuro-signaling remodeling, and restores heart physiological function, as assessed via speckle tracking strain echocardiography. These in vivo findings were corroborated in human cardiomyocytes, in which CA inhibition reduced human amyloid- beta40 oligomer-dependent disruption of CREB signaling, thus preserving BDNF expression. Together, these results reveal a previously unrecognized cardio-neuroprotective role for CAIs in preventing amyloid- beta-induced cardiovascular remodeling and neuro-signaling disruption in the Tg2576-AD model. Given the established benefits of CAIs on cerebrovascular function and cognition, our findings further support advancing repurposing efforts into clinical trials. CAIs such as ATZ could offer a dual-action therapy approach, addressing both the central nervous system and cardiac pathologies associated with AD and, potentially, the systemic effects of amyloidosis.
ER -