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Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway
Yanyu Zhai, Kaili Lu, Yuan Yuan, Ziyao Zhang, Lixia Xue, Fei Zhao, Xiaofeng Xu, Hongmei Wang. Journal of Alzheimer s Disease, 2025-03-28
Topic: Brain proteins, microglia and lab models
BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.
Key findings
- Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.
Why it matters
In a mouse model of Alzheimer's-like pathology, semaglutide reduced amyloid buildup and improved cognitive function, apparently by activating AMPK and suppressing the TLR4/NF-κB inflammatory pathway. These are animal results only, so it is not yet known whether semaglutide helps people with Alzheimer's disease.
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 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 | Laboratory or animal study (title names “app/ps1”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 20 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 11.0× 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 | 2 / 4 | Cited 20 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Hongmei Wang: h-index 26 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Shanghai Jiao Tong University: institution h-index 975 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40151913) |
| 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 →
Read the original
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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 names 8 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.
APA 7th
Zhai, Y., Lu, K., Yuan, Y., Zhang, Z., Xue, L., Zhao, F., et al. (2025). Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway. Journal of Alzheimer s Disease. https://doi.org/10.1177/13872877251329439
Vancouver
Zhai Y, Lu K, Yuan Y, Zhang Z, Xue L, Zhao F, et al. Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway. Journal of Alzheimer s Disease. 2025. doi:10.1177/13872877251329439. PMID: 40151913.
BibTeX
@article{zhai2025-40151913,
author = {Zhai, Yanyu and Lu, Kaili and Yuan, Yuan and Zhang, Ziyao and Xue, Lixia and Zhao, Fei and Xu, Xiaofeng and Wang, Hongmei},
title = {{Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway}},
journal = {Journal of Alzheimer s Disease},
year = {2025},
doi = {10.1177/13872877251329439},
pmid = {40151913},
url = {https://doi.org/10.1177/13872877251329439}
}
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