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Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ 1–42 -induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease
Mehdi Alami, Echarki Zerif, Abdelouahed Khalil, Nabil Hajji, Charles Ramassamy, Guy Lacombe, Benoît Laurent, Alan A. Cohen et al.. Journal of Alzheimer s Disease, 2025-03-20
Topic: Brain proteins, microglia and lab models
Background Alzheimer's disease (AD) is a chronic brain degenerative disease that leads to dementia. Objective The aim of the present study is to investigate the neuroprotective impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) (empagliflozin and dapagliflozin) on tau phosphorylation, oxidative stress, and neuroinflammation. Methods We used MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, annexin-V-FITC kit, and DCFH-DA (dichloro-dihydro-fluorescein diacetate) to respectively evaluate the effect of the SGLT2i (empagliflozin and dapagliflozin) on amyloid-β (Aβ) 1–42 -induced neuronal death, apoptosis, and oxidative stress. The expression of NLRP3-inflammasome, phospho-Tau181, glycogen synthase kinase-3 beta (GSK-3β), cyclin-dependent kinase 5 (CdK5), and histone deacetylase 6 (HDAC6), was quantified by flow cytometry. Drug distribution in the mice's brains was assessed by liquid chromatography-mass spectrometry (LC-MS). Results Aβ 1–42 significantly reduced cell viability and increased apoptosis, which was reversed by using gliflozins. SGLT2i significantly reduced Aβ 1–42 -induced reactive oxygen species generation, downregulated NLRP3-inflammasome, and diminished tau pathology. Mechanistically, the last effect involved the modulation of GSK-3β and CdK5 protein expression. However, the tested treatments did not modify the Aβ 1–42 -stimulating effect of HDAC6. Gliflozins are substrates of drug transporters ATP-binding cassette sub-family B member 1 and/or ATP binding cassette subfamily G member 2 (ABCB1 and ABCG2), and Elacridar significantly enhances their brain distribution. Conclusions SGLT2i empagliflozin and dapagliflozin exhibited neuroprotective actions against human Aβ 1–42 -induced neurotoxicity.
Key findings
- Results Aβ 1–42 significantly reduced cell viability and increased apoptosis, which was reversed by using gliflozins.
- SGLT2i significantly reduced Aβ 1–42 -induced reactive oxygen species generation, downregulated NLRP3-inflammasome, and diminished tau pathology.
- Gliflozins are substrates of drug transporters ATP-binding cassette sub-family B member 1 and/or ATP binding cassette subfamily G member 2 (ABCB1 and ABCG2), and Elacridar significantly enhances their brain distribution.
Why it matters
In cell models, the diabetes drugs empagliflozin and dapagliflozin reduced amyloid-induced cell death, oxidative stress, inflammasome markers and tau pathology. These are laboratory findings, and the study also found that a transporter-blocking compound increased the drugs' entry into mouse brain, so effects in people remain unknown.
Study details
- Evidence strengthLow
How this study scored 41/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Alzheimer s Disease) |
| Journal's citation record | 2 / 4 | Journal of Alzheimer s Disease: journal h-index 218 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 13 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 7.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 13 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Hicham Berrougui: h-index 29 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Columbia University: institution h-index 1,824 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 7 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40111935) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 41 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Alami, M., Zerif, E., Khalil, A., Hajji, N., Ramassamy, C., Lacombe, G., et al. (2025). Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ 1–42 -induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease. Journal of Alzheimer s Disease. https://doi.org/10.1177/13872877251329474
Vancouver
Alami M, Zerif E, Khalil A, Hajji N, Ramassamy C, Lacombe G, et al. Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ 1–42 -induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease. Journal of Alzheimer s Disease. 2025. doi:10.1177/13872877251329474. PMID: 40111935.
BibTeX
@article{alami2025-40111935,
author = {Alami, Mehdi and Zerif, Echarki and Khalil, Abdelouahed and Hajji, Nabil and Ramassamy, Charles and Lacombe, Guy and Laurent, Benoît and Cohen, Alan A. and others},
title = {{Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ 1–42 -induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease}},
journal = {Journal of Alzheimer s Disease},
year = {2025},
doi = {10.1177/13872877251329474},
pmid = {40111935},
url = {https://doi.org/10.1177/13872877251329474}
}
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