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Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer’s mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic-signaling impairment
Elia A, Vazquez-Torres R, Carey A, Wolf M, Gade VR, Alves M, Fossati S.. bioRxiv, 2026-10-09
Topic: Disease mechanisms in lab and animal studies
FDA-approved carbonic anhydrase inhibitors (CAIs) have shown robust efficacy in reducing amyloid-β (Aβ) pathology, neurodegeneration, and cerebrovascular dysfunction in Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) models, highlighting carbonic anhydrase (CAs) as a promising, previously untapped therapeutic target for AD and vascular contribution to dementia. We have recently shown that Aβ 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 Aβ 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 Aβ 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 Aβ40 oligomer-dependent disruption of CREB signaling, thus preserving BDNF expression. Together, these results reveal a previously unrecognized cardio-neuroprotective role for CAIs in preventing Aβ-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. Graphical Abstract Effect of Carbonic Anhydrase Inhibition on Cardiac Aβ Pathology in the Tg2576 Heart. Long-term acetazolamide (ATZ) treatment reduces Aβ deposition and fibrosis in Tg2576-AD mouse hearts, preserving cardiac function (↑EF, ↑FS) and the cardiac neuro-signaling pathway (↑BDNF, ↑TH+, ↑GAP-43+), thereby promoting cardiomyocyte homeostasis and long-term cardiac resilience.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Elia, A., Vazquez-Torres, R., Carey, A., Wolf, M., Gade, V. R., Alves, M., et al. (2026). Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer’s mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic-signaling impairment. bioRxiv. https://doi.org/10.64898/2026.10.08.757731
Vancouver
Elia A, Vazquez-Torres R, Carey A, Wolf M, Gade VR, Alves M, et al. Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer’s mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic-signaling impairment. bioRxiv. 2026. doi:10.64898/2026.10.08.757731.
BibTeX
@article{elia2026-32eba34d,
author = {Elia, A. and Vazquez-Torres, R. and Carey, A. and Wolf, M. and Gade, V. R. and Alves, M. and Fossati, S.},
title = {{Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer’s mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic-signaling impairment}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.08.757731},
url = {https://doi.org/10.64898/2026.10.08.757731}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- We have recently shown that Aβ aggregates disrupt neuro-signaling and deplete neurotrophic factors (particularly BDNF) in the heart of AD mouse models and human subjects.
- We confirm that progressive cardiac fibrosis and Aβ 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 Aβ burden, prevents adverse neuro-signaling remodeling, and restores heart physiological function, as assessed via speckle tracking strain echocardiography.
- Together, these results reveal a previously unrecognized cardio-neuroprotective role for CAIs in preventing Aβ-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.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “tg2576”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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