{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:42Z","timestamp":1787028582116,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cyprus Institute of Neurology and Genetics","award":["33173290"],"award-info":[{"award-number":["33173290"]}]},{"award":["33173290"],"award-info":[{"award-number":["33173290"]}],"id":[{"id":"https:\/\/ror.org\/01ggsp920","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease\u2019s progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced A\u03b240 and A\u03b242 levels, restored GLP-1 receptor expression, increased synaptophysin and \u03b2III-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required.<\/jats:p>","DOI":"10.3390\/ijms27125311","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:53:10Z","timestamp":1781247190000},"page":"5311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Semaglutide Selectively Improves Metabolic and Cognitive Function in 5xFAD Mice"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0791-2285","authenticated-orcid":false,"given":"Lucy","family":"Shahabian","sequence":"first","affiliation":[{"name":"Neuropathology Department, Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus"},{"name":"Cyprus Institute of Neurology and Genetics School, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1914-1340","authenticated-orcid":false,"given":"Demos","family":"Kynigopoulos","sequence":"additional","affiliation":[{"name":"Neuropathology Department, Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus"},{"name":"Cyprus Institute of Neurology and Genetics School, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revekka","family":"Papacharalambous","sequence":"additional","affiliation":[{"name":"Neuropathology Department, Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Ioannou","sequence":"additional","affiliation":[{"name":"Neuropathology Department, Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus"},{"name":"Cyprus Institute of Neurology and Genetics School, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2273-320X","authenticated-orcid":false,"given":"Sofia","family":"Dionysiou","sequence":"additional","affiliation":[{"name":"Neuropathology Department, Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus"},{"name":"Cyprus Institute of Neurology and Genetics School, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4394-1030","authenticated-orcid":false,"given":"Sylia","family":"Christou","sequence":"additional","affiliation":[{"name":"Neuropathology Department, Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus"},{"name":"Cyprus Institute of Neurology and Genetics School, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3562-8810","authenticated-orcid":false,"given":"Michalis","family":"Picolos","sequence":"additional","affiliation":[{"name":"Alithias Endocrinology Centre, 2324 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menelaos","family":"Pipis","sequence":"additional","affiliation":[{"name":"Neuropathology Department, Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Panayiotou","sequence":"additional","affiliation":[{"name":"Neuropathology Department, Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus"},{"name":"Cyprus Institute of Neurology and Genetics School, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25424823251341870","DOI":"10.1177\/25424823251341870","article-title":"Dual Impact of Neuroinflammation on Cognitive and Motor Impairments in Alzheimer\u2019s Disease","volume":"9","author":"Fakorede","year":"2025","journal-title":"J. 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