{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:03:44Z","timestamp":1792512224843,"version":"4.5.0"},"reference-count":160,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neurodegenerative disorders, including Alzheimer\u2019s disease (AD), Parkinson\u2019s 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\u2014cAMP\/PKA, PI3K\/Akt, and MAPK pathways\u2014that 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-\u03b2 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\u2013brain 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.<\/jats:p>","DOI":"10.3390\/ijms262110743","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T13:19:29Z","timestamp":1762348769000},"page":"10743","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["GLP-1 and the Degenerating Brain: Exploring Mechanistic Insights and Therapeutic Potential"],"prefix":"10.3390","volume":"26","author":[{"given":"Osama Sobhi","family":"Moaket","sequence":"first","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8674-2534","authenticated-orcid":false,"given":"Sarah Eyad","family":"Obaid","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1530-3391","authenticated-orcid":false,"given":"Fawaz Eyad","family":"Obaid","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9426-8540","authenticated-orcid":false,"given":"Yusuf Abdulkarim","family":"Shakeeb","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir Mohammed","family":"Elsharief","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afrin","family":"Tania","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3419-4118","authenticated-orcid":false,"given":"Radwan","family":"Darwish","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-3917","authenticated-orcid":false,"given":"Alexandra E.","family":"Butler","sequence":"additional","affiliation":[{"name":"Research Department, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5342-2501","authenticated-orcid":false,"given":"Abu Saleh Md","family":"Moin","sequence":"additional","affiliation":[{"name":"Research Department, Royal College of Surgeons in Ireland-Bahrain, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Reich, N., and H\u00f6lscher, C. (2022). 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