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GLP-1 and the Degenerating Brain: Exploring Mechanistic Insights and Therapeutic Potential
Osama Sobhi Moaket, Sarah Eyad Obaid, Fawaz Eyad Obaid, Yusuf Abdulkarim Shakeeb, Samir Mohammed Elsharief, Afrin Tania, Radwan Darwish, Alexandra E Butler et al.. International journal of molecular sciences, 2025-11-05
Topic: Gut, metabolism and diet
Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades-cAMP/PKA, PI3K/Akt, and MAPK pathways-that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood-brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications.
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APA 7th
Moaket, O. S., Obaid, S. E., Obaid, F. E., Shakeeb, Y. A., Elsharief, S. M., Tania, A., et al. (2025). GLP-1 and the Degenerating Brain: Exploring Mechanistic Insights and Therapeutic Potential. International journal of molecular sciences. https://doi.org/10.3390/ijms262110743
Vancouver
Moaket OS, Obaid SE, Obaid FE, Shakeeb YA, Elsharief SM, Tania A, et al. GLP-1 and the Degenerating Brain: Exploring Mechanistic Insights and Therapeutic Potential. International journal of molecular sciences. 2025. doi:10.3390/ijms262110743. PMID: 41226780.
BibTeX
@article{moaket2025-41226780,
author = {Moaket, Osama Sobhi and Obaid, Sarah Eyad and Obaid, Fawaz Eyad and Shakeeb, Yusuf Abdulkarim and Elsharief, Samir Mohammed and Tania, Afrin and Darwish, Radwan and Butler, Alexandra E and others},
title = {{GLP-1 and the Degenerating Brain: Exploring Mechanistic Insights and Therapeutic Potential}},
journal = {International journal of molecular sciences},
year = {2025},
doi = {10.3390/ijms262110743},
pmid = {41226780},
url = {https://doi.org/10.3390/ijms262110743}
}
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Key findings
- Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent.
- Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors.
- Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood-brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials.
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Study details
- Evidence strengthLow
How this study scored 43/100
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. We have no data on journal's citation record, 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, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (International journal of molecular sciences) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | — / 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 | 2 / 2 | Indexed in PubMed (PMID 41226780) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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