{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:16:07Z","timestamp":1790694967289,"version":"4.1.0"},"reference-count":100,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T00:00:00Z","timestamp":1769212800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T00:00:00Z","timestamp":1769212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004909","name":"Universidade Federal Do Rio Grande Do Sul","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004909","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurochem Res"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Familial hypercholesterolemia (FH), caused by mutations in the low-density lipoprotein receptor (LDLr) gene, has been increasingly associated with neurodegenerative and mood disorders. Studies with LDLR knockout mice (LDLr\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) showed that neuroinflammation is a key event in FH-related brain dysfunction. Because mTOR inhibition has been shown to mitigate brain alterations in this model, we hypothesized that metformin, a drug reported to influence cellular energy metabolism, could attenuate FH-associated brain changes. To test this, adult LDLr\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice received daily oral doses of metformin (200\u00a0mg\/Kg) or vehicle for 30 days. During the final week, behavioral assessments were conducted, including the open-field test, novel object recognition and object reallocation tasks, and the tail suspension test (depressive-like behavior). Body weight, total cholesterol and glucose plasma levels were analyzed. Hippocampal astrocyte and microglial density, as well as the expression of genes related to neuroinflammation and synaptic plasticity, were evaluated. Metformin did not alter total cholesterol levels but significantly improved cognitive performance and reduced depressive-like behavior. The treatment also attenuated hippocampal astrogliosis without affecting microglial reactivity. Molecular analysis revealed reduced hippocampal TGF-\u03b2 gene expression and increased PSD-95 gene expression and protein content in metformin-treated LDLr\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Although a slight, non-significant reduction in the phosphorylated-to-total mTOR ratio was detected, no clear evidence of AMPK\/mTOR pathway modulation was observed. Overall, metformin improved memory function and astrocyte reactivity in LDLr\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice independently of cholesterol reduction and without demonstrable involvement of the AMPK\/mTOR pathway, suggesting its potential as a therapeutic strategy for FH-associated brain dysfunction.\n                  <\/jats:p>","DOI":"10.1007\/s11064-025-04658-7","type":"journal-article","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T03:54:20Z","timestamp":1769226860000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metformin Ameliorates Cognitive Deficits and Neuroinflammation in a Mouse Model of Familial Hypercholesterolemia"],"prefix":"10.1007","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6820-7452","authenticated-orcid":false,"given":"Nat\u00e1lia Baltazar","family":"do Nascimento","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4918-4982","authenticated-orcid":false,"given":"H\u00e9melin Resende","family":"Farias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8330-3485","authenticated-orcid":false,"given":"Tain\u00e1","family":"Schons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5068-9299","authenticated-orcid":false,"given":"Alex Paulo Zeferino","family":"Padilha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2455-9833","authenticated-orcid":false,"given":"Mariana Viana","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1987-3261","authenticated-orcid":false,"given":"Ariadni Mesquita","family":"Peres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8296-0248","authenticated-orcid":false,"given":"Lucas dos Santos","family":"da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0590-8221","authenticated-orcid":false,"given":"Ricardo Maia","family":"Dantas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1213-4519","authenticated-orcid":false,"given":"Jessica Marques Obelar","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7794-6588","authenticated-orcid":false,"given":"Matheus Scarpatto","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0360-2747","authenticated-orcid":false,"given":"Fernanda","family":"Telles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2369-7739","authenticated-orcid":false,"given":"F\u00e1tima Theresinha Costa Rodrigues","family":"Guma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0619-4913","authenticated-orcid":false,"given":"Jos\u00e9 Cl\u00e1udio Fonseca","family":"Moreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6217-1647","authenticated-orcid":false,"given":"Rachel Krolow Santos Silva","family":"Bast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1090-5244","authenticated-orcid":false,"given":"Andreza Fabro","family":"de Bem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1454-2866","authenticated-orcid":false,"given":"Jade","family":"de Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,24]]},"reference":[{"key":"4658_CR1","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1136\/bmj.322.7300.1447","volume":"322","author":"M Kivipelto","year":"2001","unstructured":"Kivipelto M, Helkala EL, Laakso MP, H\u00e4nninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A (2001) Midlife vascular risk factors and Alzheimer\u2019s disease in later life: longitudinal, population-based study. BMJ 322:1447\u20131451. https:\/\/doi.org\/10.1136\/bmj.322.7300.1447","journal-title":"BMJ"},{"key":"4658_CR2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1159\/000231980","volume":"28","author":"A Solomon","year":"2009","unstructured":"Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA (2009) Midlife serum cholesterol and increased risk of Alzheimer\u2019s and vascular dementia three decades later. Dement Geriatr Cogn Disord 28:75\u201380. https:\/\/doi.org\/10.1159\/000231980","journal-title":"Dement Geriatr Cogn Disord"},{"key":"4658_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/1476-511X-8-10","volume":"8","author":"S Tyrovolas","year":"2009","unstructured":"Tyrovolas S, Lionis C, Zeimbekis A, Bountziouka V, Micheli M, Katsarou A, Papairakleous N, Metallinos G, Makri K, Polychronopoulos E, Panagiotakos DB (2009) Increased body mass and depressive symptomatology are associated with hypercholesterolemia among elderly individuals: results from the MEDIS study. Lipids Health Dis 8:10. https:\/\/doi.org\/10.1186\/1476-511X-8-10","journal-title":"Lipids Health Dis"},{"key":"4658_CR4","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.bbi.2015.02.015","volume":"48","author":"T Strekalova","year":"2015","unstructured":"Strekalova T, Evans M, Costa-Nunes J, Bachurin S, Yeritsyan N, Couch Y, Steinbusch HMW, K\u00f6hler SE, Lesch KP, Anthony DC (2015) Tlr4 upregulation in the brain accompanies depression- and anxiety-like behaviors induced by a high-cholesterol diet. Brain Behav Immun 48:42\u201347. https:\/\/doi.org\/10.1016\/j.bbi.2015.02.015","journal-title":"Brain Behav Immun"},{"key":"4658_CR5","doi-asserted-by":"publisher","first-page":"215","DOI":"10.3233\/JAD-160826","volume":"56","author":"KJ Anstey","year":"2017","unstructured":"Anstey KJ, Ashby-Mitchell K, Peters R (2017) Updating the evidence on the association between serum cholesterol and risk of late-life dementia: review and meta-analysis. J Alzheimers Dis 56:215\u2013228. https:\/\/doi.org\/10.3233\/JAD-160826","journal-title":"J Alzheimers Dis"},{"key":"4658_CR6","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/S0140-6736(24)01296-0","volume":"404","author":"G Livingston","year":"2024","unstructured":"Livingston G, Huntley J, Liu KY, Costafreda SG, Selb\u00e6k G, Alladi S, Ames D, Banerjee S, Burns A, Brayne C, Fox NC, Ferri CP, Gitlin LN, Howard R, Kales HC, Kivim\u00e4ki M, Larson EB, Nakasujja N, Rockwood K, Samus Q, Shirai K, Singh-Manoux A, Schneider LS, Walsh S, Yao Y, Sommerlad A, Mukadam N (2024) Dementia prevention, intervention, and care: 2024 report of the lancet standing commission. Lancet 404:572\u2013628. https:\/\/doi.org\/10.1016\/S0140-6736(24)01296-0","journal-title":"Lancet"},{"key":"4658_CR7","doi-asserted-by":"publisher","first-page":"e29","DOI":"10.1016\/j.ejim.2016.05.009","volume":"34","author":"M Ariza","year":"2016","unstructured":"Ariza M, Cuenca N, Mauri M, Jurado MA, Garolera M (2016) Neuropsychological performance of young Familial hypercholesterolemia patients. Eur J Intern Med 34:e29\u2013e31. https:\/\/doi.org\/10.1016\/j.ejim.2016.05.009","journal-title":"Eur J Intern Med"},{"key":"4658_CR8","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.amjmed.2009.08.015","volume":"123","author":"D Zamb\u00f3n","year":"2010","unstructured":"Zamb\u00f3n D, Quintana M, Mata P, Alonso R, Benavent J, Cruz-S\u00e1nchez F, Gich J, Pocov\u00ed M, Civeira F, Capurro S, Bachman D, Sambamurti K, Nicholas J, Pappolla MA (2010) Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am J Med 123:267\u2013274. https:\/\/doi.org\/10.1016\/j.amjmed.2009.08.015","journal-title":"Am J Med"},{"key":"4658_CR9","doi-asserted-by":"publisher","first-page":"3007","DOI":"10.1001\/jama.1990.03450230043027","volume":"264","author":"JP Kane","year":"1990","unstructured":"Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ (1990) Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 264:3007\u20133012. https:\/\/doi.org\/10.1001\/jama.1990.03450230043027","journal-title":"JAMA"},{"key":"4658_CR10","doi-asserted-by":"publisher","first-page":"707","DOI":"10.3389\/fphar.2018.00707","volume":"9","author":"M Mytilinaiou","year":"2018","unstructured":"Mytilinaiou M, Kyrou I, Khan M, Grammatopoulos DK, Randeva HS (2018) Familial hypercholesterolemia: new horizons for diagnosis and effective management. Front Pharmacol 9:707. https:\/\/doi.org\/10.3389\/fphar.2018.00707","journal-title":"Front Pharmacol"},{"key":"4658_CR11","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.bbr.2016.05.029","volume":"311","author":"DF Engel","year":"2016","unstructured":"Engel DF, de Oliveira J, Lopes JB, Santos DB, Moreira ELG, Farina M, Rodrigues ALS, de Souza Brocardo P, de Bem AF (2016) Is there an association between hypercholesterolemia and depression? Behavioral evidence from the LDLr<Superscript>\u2212\/\u2212<\/Superscript> mouse experimental model. Behav Brain Res 311:31\u201338. https:\/\/doi.org\/10.1016\/j.bbr.2016.05.029","journal-title":"Behav Brain Res"},{"key":"4658_CR12","doi-asserted-by":"publisher","first-page":"97","DOI":"10.3233\/JAD-200541","volume":"78","author":"J de Oliveira","year":"2020","unstructured":"de Oliveira J, Engel DF, De Paula GC, Dos Santos DB, Lopes JB, Farina M, Moreira ELG, de Bem AF (2020) High cholesterol diet exacerbates blood-brain barrier disruption in LDLr<Superscript>\u2212\/\u2212<\/Superscript> mice: impact on cognitive function. J Alzheimers Dis 78:97\u2013115. https:\/\/doi.org\/10.3233\/JAD-200541","journal-title":"J Alzheimers Dis"},{"key":"4658_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.102149","volume":"93","author":"J de Oliveira","year":"2024","unstructured":"de Oliveira J, Moreira ELG, de Bem AF (2024) Beyond cardiovascular risk: implications of familial hypercholesterolemia on cognition and brain function. Ageing Res Rev 93:102149. https:\/\/doi.org\/10.1016\/j.arr.2023.102149","journal-title":"Ageing Res Rev"},{"key":"4658_CR14","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3233\/JAD-132228","volume":"41","author":"J de Oliveira","year":"2014","unstructured":"de Oliveira J, Moreira ELG, Dos Santos DB, Piermartiri TC, Dutra RC, Pinton S, Tasca CI, Farina M, Prediger RDS, de Bem AF (2014) Increased susceptibility to amyloid-\u03b2-induced neurotoxicity in mice lacking the low-density lipoprotein receptor. J Alzheimers Dis 41:43\u201360. https:\/\/doi.org\/10.3233\/JAD-132228","journal-title":"J Alzheimers Dis"},{"key":"4658_CR15","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1111\/jnc.15952","volume":"168","author":"MS Rodrigues","year":"2024","unstructured":"Rodrigues MS, do Nascimento NB, Farias HR, Schons T, Machado AG, Behenck E, Mesquita A, Krolow Bast R, Budni J, Engblom D, de Bem AF, de Oliveira J (2024) Microglia contribute to cognitive decline in hypercholesterolemic LDLr<Superscript>\u2212\/\u2212<\/Superscript> mice. J Neurochem 168:1565\u20131586. https:\/\/doi.org\/10.1111\/jnc.15952","journal-title":"J Neurochem"},{"key":"4658_CR16","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1177\/0271678X17705973","volume":"38","author":"JB Jahrling","year":"2018","unstructured":"Jahrling JB, Lin AL, DeRosa N, Hussong SA, Van Skike CE, Girotti M, Javors M, Zhao Q, Maslin LA, Asmis R, Galvan V (2018) mTOR drives cerebral blood flow and memory deficits in LDLR<Superscript>\u2212\/\u2212<\/Superscript> mice modeling atherosclerosis and vascular cognitive impairment. J Cereb Blood Flow Metab 38:58\u201374. https:\/\/doi.org\/10.1177\/0271678X17705973","journal-title":"J Cereb Blood Flow Metab"},{"key":"4658_CR17","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.molcel.2008.03.003","volume":"30","author":"DM Gwinn","year":"2008","unstructured":"Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214\u2013226. https:\/\/doi.org\/10.1016\/j.molcel.2008.03.003","journal-title":"Mol Cell"},{"key":"4658_CR18","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1210\/me.2009-0474","volume":"24","author":"J Ning","year":"2010","unstructured":"Ning J, Clemmons DR (2010) AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation. Mol Endocrinol 24:1218\u20131230. https:\/\/doi.org\/10.1210\/me.2009-0474","journal-title":"Mol Endocrinol"},{"key":"4658_CR19","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a019141","volume":"7","author":"SK Hindupur","year":"2015","unstructured":"Hindupur SK, Gonz\u00e1lez A, Hall MN (2015) The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb Perspect Biol 7:a019141. https:\/\/doi.org\/10.1101\/cshperspect.a019141","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"4658_CR20","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1111\/bcp.13852","volume":"85","author":"S Amin","year":"2019","unstructured":"Amin S, Lux A, O\u2019Callaghan F (2019) The journey of Metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth. Br J Clin Pharmacol 85:37\u201346. https:\/\/doi.org\/10.1111\/bcp.13852","journal-title":"Br J Clin Pharmacol"},{"key":"4658_CR21","doi-asserted-by":"publisher","first-page":"2549","DOI":"10.1007\/s00221-020-05911-x","volume":"238","author":"RW Du","year":"2020","unstructured":"Du RW, Bu WG (2020) Metformin improves depressive-like symptoms in mice via inhibition of peripheral and central NF-\u03baB\u2013NLRP3 inflammation activation. Exp Brain Res 238:2549\u20132556. https:\/\/doi.org\/10.1007\/s00221-020-05911-x","journal-title":"Exp Brain Res"},{"key":"4658_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e17873","volume":"9","author":"S Rabieipoor","year":"2023","unstructured":"Rabieipoor S, Zare M, Ettcheto M, Camins A, Javan M (2023) Metformin restores cognitive dysfunction and histopathological deficits in an animal model of sporadic Alzheimer\u2019s disease. Heliyon 9:e17873. https:\/\/doi.org\/10.1016\/j.heliyon.2023.e17873","journal-title":"Heliyon"},{"key":"4658_CR23","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13277","volume":"20","author":"M Kodali","year":"2021","unstructured":"Kodali M, Attaluri S, Madhu LN, Shuai B, Upadhya R, Gonzalez JJ, Rao X, Shetty AK (2021) Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus. Aging Cell 20:e13277. https:\/\/doi.org\/10.1111\/acel.13277","journal-title":"Aging Cell"},{"key":"4658_CR24","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1093\/cvr\/cvaa171","volume":"117","author":"A Seneviratne","year":"2020","unstructured":"Seneviratne A, Cave L, Hyde G, Moestrup SK, Carling D, Mason JC, Haskard DO, Boyle JJ (2020) Metformin directly suppresses atherosclerosis in normoglycaemic mice via Haematopoietic AMP-activated protein kinase. Cardiovasc Res 117:1295. https:\/\/doi.org\/10.1093\/cvr\/cvaa171","journal-title":"Cardiovasc Res"},{"key":"4658_CR25","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.3233\/JAD-181240","volume":"68","author":"SA Farr","year":"2019","unstructured":"Farr SA, Roesler E, Niehoff ML, Roby DA, McKee A, Morley JE (2019) Metformin improves learning and memory in the SAMP8 mouse model of Alzheimer\u2019s disease. J Alzheimers Dis 68:1699\u20131710. https:\/\/doi.org\/10.3233\/JAD-181240","journal-title":"J Alzheimers Dis"},{"key":"4658_CR26","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s11011-024-01422-8","volume":"40","author":"HA Abosharaf","year":"2024","unstructured":"Abosharaf HA, Elsonbaty Y, Tousson E, Mohamed TM (2024) Metformin effectively alleviates the symptoms of alzheimer in rats by Lowering amyloid \u03b2 deposition and enhancing the insulin signal. Metab Brain Dis 40:41. https:\/\/doi.org\/10.1007\/s11011-024-01422-8","journal-title":"Metab Brain Dis"},{"key":"4658_CR27","doi-asserted-by":"publisher","first-page":"585","DOI":"10.3233\/JAD-190742","volume":"73","author":"J de Oliveira","year":"2020","unstructured":"de Oliveira J, Engel DF, de Paula GC, Melo HM, Lopes SC, Ribeiro CT, Delanogare E, Moreira JCF, Gelain DP, Prediger RD, Gabilan NH, Moreira ELG, Ferreira ST, de Bem AF (2020) LDL receptor deficiency does not alter brain amyloid-\u03b2 levels but causes an exacerbation of apoptosis. J Alzheimers Dis 73:585\u2013596. https:\/\/doi.org\/10.3233\/JAD-190742","journal-title":"J Alzheimers Dis"},{"key":"4658_CR28","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0014-2999(03)01272-X","volume":"463","author":"L Prut","year":"2003","unstructured":"Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3\u201333. https:\/\/doi.org\/10.1016\/S0014-2999(03)01272-X","journal-title":"Eur J Pharmacol"},{"key":"4658_CR29","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.3233\/JAD-2010-1308","volume":"19","author":"SJ Greco","year":"2010","unstructured":"Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Wesson Ashford J, Johnston JM, Tezapsidis N, Casadesus G (2010) Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer\u2019s disease. J Alzheimers Dis 19:1155\u20131167. https:\/\/doi.org\/10.3233\/JAD-2010-1308","journal-title":"J Alzheimers Dis"},{"key":"4658_CR30","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.bbr.2009.06.005","volume":"204","author":"FL Assini","year":"2009","unstructured":"Assini FL, Duzzioni M, Takahashi RN (2009) Object location memory in mice: pharmacological validation and further evidence of hippocampal CA1 participation. Behav Brain Res 204:206\u2013211. https:\/\/doi.org\/10.1016\/j.bbr.2009.06.005","journal-title":"Behav Brain Res"},{"key":"4658_CR31","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/BF00428203","volume":"85","author":"L Steru","year":"1985","unstructured":"Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367\u2013370. https:\/\/doi.org\/10.1007\/BF00428203","journal-title":"Psychopharmacology"},{"key":"4658_CR32","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.ijdevneu.2016.03.001","volume":"50","author":"DM Arcego","year":"2016","unstructured":"Arcego DM, Krolow R, Lampert C, Toniazzo AP, Berlitz C, Lazzaretti C, Schmitz F, Rodrigues AF, Wyse ATS, Dalmaz C (2016) Early life adversities or high fat diet intake reduce cognitive function and alter BDNF signaling in adult rats: interplay of these factors changes these effects. Int J Dev Neurosci 50:16\u201325. https:\/\/doi.org\/10.1016\/j.ijdevneu.2016.03.001","journal-title":"Int J Dev Neurosci"},{"key":"4658_CR33","doi-asserted-by":"publisher","first-page":"5718","DOI":"10.1007\/s12035-024-03912-3","volume":"61","author":"L Santos","year":"2024","unstructured":"Santos L, Behrens L, Barbosa C, Tiefensee-Ribeiro C, Rosa-Silva H, Somensi N, Brum PO, Silveira AK, Rodrigues MS, de Oliveira J, Gelain DP, Almeida RF, Moreira JCF (2024) Histone 3 trimethylation patterns are associated with resilience or stress susceptibility in a rat model of major depression disorder. Mol Neurobiol 61:5718\u20135737. https:\/\/doi.org\/10.1007\/s12035-024-03912-3","journal-title":"Mol Neurobiol"},{"key":"4658_CR34","doi-asserted-by":"publisher","first-page":"e29","DOI":"10.1161\/CIR.0000000000000152","volume":"131","author":"D Mozaffarian","year":"2015","unstructured":"Mozaffarian D, Benjamin EJ, Go AS et al (2015) Heart disease and stroke statistics\u20142015 update: a report from the American Heart Association. Circulation 131:e29\u2013e39. https:\/\/doi.org\/10.1161\/CIR.0000000000000152","journal-title":"Circulation"},{"key":"4658_CR35","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2017-016461","volume":"7","author":"LE Akioyamen","year":"2017","unstructured":"Akioyamen LE, Genest J, Shan SD, Reel RL, Albaum JM, Chu A, Tu JV (2017) Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open 7:e016461. https:\/\/doi.org\/10.1136\/bmjopen-2017-016461","journal-title":"BMJ Open"},{"key":"4658_CR36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19113426","volume":"19","author":"A Benito-Vicente","year":"2018","unstructured":"Benito-Vicente A, Uribe KB, Jebari S, Galicia-Garcia U, Ostolaza H, Martin C (2018) Familial hypercholesterolemia: the most frequent cholesterol metabolism disorder caused disease. Int J Mol Sci 19:3426. https:\/\/doi.org\/10.3390\/ijms19113426","journal-title":"Int J Mol Sci"},{"key":"4658_CR37","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1111\/j.1471-4159.2008.05415.x","volume":"106","author":"L Thirumangalakudi","year":"2008","unstructured":"Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, Bhat NR (2008) High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J Neurochem 106:475\u2013485. https:\/\/doi.org\/10.1111\/j.1471-4159.2008.05415.x","journal-title":"J Neurochem"},{"key":"4658_CR38","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.neuroscience.2011.09.009","volume":"197","author":"J de Oliveira","year":"2011","unstructured":"de Oliveira J, Hort MA, Moreira ELG, Glaser V, Ribeiro-do-Valle RM, Prediger RD, Farina M, Latini A, de Bem AF (2011) Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: relevance of cortico-cerebral mitochondrial dysfunction and oxidative stress. Neuroscience 197:99\u2013106. https:\/\/doi.org\/10.1016\/j.neuroscience.2011.09.009","journal-title":"Neuroscience"},{"key":"4658_CR39","doi-asserted-by":"publisher","first-page":"2055","DOI":"10.11124\/JBISRIR-2016-003258","volume":"15","author":"JM Campbell","year":"2017","unstructured":"Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E (2017) Metformin and Alzheimer\u2019s disease, dementia and cognitive impairment: a systematic review protocol. JBI Database Syst Rev Implement Rep 15:2055\u20132059. https:\/\/doi.org\/10.11124\/JBISRIR-2016-003258","journal-title":"JBI Database Syst Rev Implement Rep"},{"key":"4658_CR40","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1172\/JCI13505","volume":"108","author":"G Zhou","year":"2001","unstructured":"Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in the mechanism of Metformin action. J Clin Invest 108:1167\u20131174. https:\/\/doi.org\/10.1172\/JCI13505","journal-title":"J Clin Invest"},{"key":"4658_CR41","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1053\/meta.2001.24192","volume":"50","author":"CJ Glueck","year":"2001","unstructured":"Glueck CJ, Fontaine RN, Wang P, Subbiah MTR, Weber K, Illig E, Streicher P, Sieve-Smith L, Tracy TM, Lang JE, McCullough P (2001) Metformin reduces weight, centripetal obesity, insulin, leptin, and LDL cholesterol in nondiabetic, morbidly obese subjects with BMI\u2009>\u200930. Metabolism 50:856\u2013861. https:\/\/doi.org\/10.1053\/meta.2001.24192","journal-title":"Metabolism"},{"key":"4658_CR42","doi-asserted-by":"publisher","first-page":"1858","DOI":"10.2337\/dc15-0658","volume":"38","author":"T Xu","year":"2015","unstructured":"Xu T, Brandmaier S, Messias AC et al (2015) Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care 38:1858\u20131867. https:\/\/doi.org\/10.2337\/dc15-0658","journal-title":"Diabetes Care"},{"key":"4658_CR43","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1111\/dom.12840","volume":"19","author":"JR Petrie","year":"2017","unstructured":"Petrie JR, Chaturvedi N, Ford I et al (2017) Metformin in adults with type 1 diabetes: design and methods of REMOVAL, an international multicentre trial. Diabetes Obes Metab 19:509\u2013516. https:\/\/doi.org\/10.1111\/dom.12840","journal-title":"Diabetes Obes Metab"},{"key":"4658_CR44","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.jdiacomp.2017.01.013","volume":"31","author":"CP Wang","year":"2017","unstructured":"Wang CP, Lorenzo C, Habib SL, Jo B, Espinoza SE (2017) Differential effects of metformin on age-related comorbidities in older men with type 2 diabetes. J Diabetes Complications 31:679\u2013686. https:\/\/doi.org\/10.1016\/j.jdiacomp.2017.01.013","journal-title":"J Diabetes Complications"},{"key":"4658_CR45","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1055\/s-0032-1327734","volume":"121","author":"C Seifarth","year":"2013","unstructured":"Seifarth C, Schehler B, Schneider HJ (2013) Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes 121:27\u201331. https:\/\/doi.org\/10.1055\/s-0032-1327734","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"4658_CR46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1365-2796.2004.01328.x","volume":"256","author":"MG Wulffel\u00e9","year":"2004","unstructured":"Wulffel\u00e9 MG, Kooy A, de Zeeuw D, Stehouwer CDA, Gansevoort RT (2004) The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes: a systematic review. J Intern Med 256:1\u201314. https:\/\/doi.org\/10.1111\/j.1365-2796.2004.01328.x","journal-title":"J Intern Med"},{"key":"4658_CR47","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.5551\/jat.48223","volume":"26","author":"A Asai","year":"2019","unstructured":"Asai A, Shuto Y, Nagao M, Kawahara M, Miyazawa T, Sugihara H, Oikawa S (2019) Metformin attenuates early-stage atherosclerosis in mildly hyperglycemic Oikawa\u2013Nagao mice. J Atheroscler Thromb 26:1075\u20131083. https:\/\/doi.org\/10.5551\/jat.48223","journal-title":"J Atheroscler Thromb"},{"key":"4658_CR48","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1038\/s12276-024-01297-w","volume":"56","author":"JY Sung","year":"2024","unstructured":"Sung JY, Kim SG, Park SY, Kim JR, Choi HC (2024) Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent phosphorylation of PGC-1\u03b1. Exp Mol Med 56:1967\u20131979. https:\/\/doi.org\/10.1038\/s12276-024-01297-w","journal-title":"Exp Mol Med"},{"key":"4658_CR49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0254321","volume":"16","author":"N Yan","year":"2021","unstructured":"Yan N, Wang L, Li Y, Wang T, Yang L, Yan R, Wang H, Jia S (2021) Metformin intervention ameliorates atherosclerosis in ApoE\u2212\/\u2212 mice through restoring gut dysbiosis and anti-inflammation. PLoS One 16:e0254321. https:\/\/doi.org\/10.1371\/journal.pone.0254321","journal-title":"PLoS One"},{"key":"4658_CR50","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd10020054","volume":"10","author":"X Chen","year":"2023","unstructured":"Chen X, Wang S, Xu W, Zhao M, Zhang Y, Xiao H (2023) Metformin directly binds to MMP-9 to improve plaque stability. J Cardiovasc Dev Dis 10:54. https:\/\/doi.org\/10.3390\/jcdd10020054","journal-title":"J Cardiovasc Dev Dis"},{"key":"4658_CR51","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.bbrc.2021.04.029","volume":"557","author":"H Wu","year":"2021","unstructured":"Wu H, Feng K, Zhang C, Zhang H, Zhang J, Hua Y, Dong Z, Zhu Y, Yang S, Ma C (2021) Metformin attenuates atherosclerosis and plaque vulnerability by upregulating KLF2-mediated autophagy in ApoE\u2013\/\u2013 mice. Biochem Biophys Res Commun 557:334\u2013341. https:\/\/doi.org\/10.1016\/j.bbrc.2021.04.029","journal-title":"Biochem Biophys Res Commun"},{"key":"4658_CR52","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1038\/s41598-017-02080-w","volume":"7","author":"F Luo","year":"2017","unstructured":"Luo F, Guo Y, Ruan GY et al (2017) Combined use of Metformin and Atorvastatin attenuates atherosclerosis in rabbits fed a high-cholesterol diet. Sci Rep 7:2080. https:\/\/doi.org\/10.1038\/s41598-017-02080-w","journal-title":"Sci Rep"},{"key":"4658_CR53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbr.2015.12.012","volume":"301","author":"JS Allard","year":"2015","unstructured":"Allard JS, Perez EJ, Fukui K, Carpenter P, Ingram DK, de Cabo R (2015) Prolonged metformin treatment reduces transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL\/6J mice. Behav Brain Res 301:1\u201310. https:\/\/doi.org\/10.1016\/j.bbr.2015.12.012","journal-title":"Behav Brain Res"},{"key":"4658_CR54","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.neuropharm.2015.07.023","volume":"101","author":"F Chen","year":"2016","unstructured":"Chen F, Dong RR, Zhong KL et al (2016) Antidiabetic drugs restore abnormal transport of amyloid-\u03b2 across the blood\u2013brain barrier and memory impairment in db\/db mice. Neuropharmacology 101:123\u2013136. https:\/\/doi.org\/10.1016\/j.neuropharm.2015.07.023","journal-title":"Neuropharmacology"},{"key":"4658_CR55","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.lfs.2012.08.017","volume":"91","author":"H Pintana","year":"2012","unstructured":"Pintana H, Apaijai N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC (2012) Effects of metformin on learning and memory behaviors and brain mitochondrial function in high-fat-diet-induced insulin-resistant rats. Life Sci 91:409\u2013414. https:\/\/doi.org\/10.1016\/j.lfs.2012.08.017","journal-title":"Life Sci"},{"key":"4658_CR56","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2021.111608","volume":"201","author":"MS Rodrigues","year":"2021","unstructured":"Rodrigues MS, de Paula GC, Duarte MB et al (2021) Nanotechnology as a therapeutic strategy to prevent neuropsychomotor alterations associated with hypercholesterolemia. Colloids Surf B Biointerfaces 201:111608. https:\/\/doi.org\/10.1016\/j.colsurfb.2021.111608","journal-title":"Colloids Surf B Biointerfaces"},{"key":"4658_CR57","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1111\/1440-1681.12265","volume":"41","author":"M Guo","year":"2014","unstructured":"Guo M, Mi J, Jiang QM et al (2014) Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharmacol Physiol 41:650\u2013656. https:\/\/doi.org\/10.1111\/1440-1681.12265","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"4658_CR58","doi-asserted-by":"publisher","first-page":"5935","DOI":"10.1523\/JNEUROSCI.2904-18.2019","volume":"39","author":"J Zemdegs","year":"2019","unstructured":"Zemdegs J, Martin H, Pintana H et al (2019) Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J Neurosci 39:5935\u20135948. https:\/\/doi.org\/10.1523\/JNEUROSCI.2904-18.2019","journal-title":"J Neurosci"},{"key":"4658_CR59","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.604150","volume":"14","author":"AF de Bem","year":"2021","unstructured":"de Bem AF, Krolow R, Farias HR et al (2021) Animal models of metabolic disorders in the study of neurodegenerative diseases: an overview. Front Neurosci 14:604150. https:\/\/doi.org\/10.3389\/fnins.2020.604150","journal-title":"Front Neurosci"},{"key":"4658_CR60","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1089\/rej.2011.1302","volume":"15","author":"LW Harries","year":"2012","unstructured":"Harries LW, Bradley-Smith RM, Llewellyn DJ et al (2012) Leukocyte CCR2 expression is associated with Mini-Mental State Examination score in older adults. Rejuvenation Res 15:395\u2013404. https:\/\/doi.org\/10.1089\/rej.2011.1302","journal-title":"Rejuvenation Res"},{"key":"4658_CR61","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.cca.2005.06.015","volume":"364","author":"V Solfrizzi","year":"2006","unstructured":"Solfrizzi V, D\u2019Introno A, Colacicco AM et al (2006) Circulating biomarkers of cognitive decline and dementia. Clin Chim Acta 364:91\u2013112. https:\/\/doi.org\/10.1016\/j.cca.2005.06.015","journal-title":"Clin Chim Acta"},{"key":"4658_CR62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030525","volume":"7","author":"K Westin","year":"2012","unstructured":"Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S, Hansson O (2012) CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer\u2019s disease. PLoS One 7:e30525. https:\/\/doi.org\/10.1371\/journal.pone.0030525","journal-title":"PLoS One"},{"key":"4658_CR63","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.pnpbp.2017.03.010","volume":"77","author":"ML Garcez","year":"2017","unstructured":"Garcez ML, Mina F, Bellettini-Santos T, Carneiro FG, Luz AP, Schiavo GL, Andrighetti MS, Scheid MG, Bolfe RP, Budni J (2017) Minocycline reduces inflammatory parameters in brain structures and serum and reverses memory impairment caused by amyloid-\u03b2(1\u201342) administration in mice. Prog Neuropsychopharmacol Biol Psychiatry 77:23\u201331. https:\/\/doi.org\/10.1016\/j.pnpbp.2017.03.010","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"4658_CR64","doi-asserted-by":"publisher","first-page":"3242","DOI":"10.1007\/s12035-018-1211-9","volume":"56","author":"ML Garcez","year":"2019","unstructured":"Garcez ML, Mina F, Bellettini-Santos T, Pereira da Luz A, Schiavo GL, Macieski JMC, Medeiros EB, Marques AO, Magnus NQ, Budni J (2019) Involvement of NLRP3 in the effects of minocycline in an alzheimer\u2019s disease-like pathology induced by \u03b2-amyloid oligomers in mice. Mol Neurobiol 56:3242\u20133257. https:\/\/doi.org\/10.1007\/s12035-018-1211-9","journal-title":"Mol Neurobiol"},{"key":"4658_CR65","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1111\/j.1749-6632.2000.tb06384.x","volume":"903","author":"DL Sparks","year":"2000","unstructured":"Sparks DL, Kuo YM, Roher A, Martin T, Lukas RJ (2000) Alterations of alzheimer\u2019s disease in the cholesterol-fed rabbit, including vascular inflammation: preliminary observations. Ann N Y Acad Sci 903:335\u2013344. https:\/\/doi.org\/10.1111\/j.1749-6632.2000.tb06384.x","journal-title":"Ann N Y Acad Sci"},{"key":"4658_CR66","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1007\/s001090050097","volume":"75","author":"WJ Streit","year":"1997","unstructured":"Streit WJ, Sparks DL (1997) Activation of microglia in brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med 75:130\u2013138. https:\/\/doi.org\/10.1007\/s001090050097","journal-title":"J Mol Med"},{"key":"4658_CR67","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2025.115272","volume":"390","author":"S Kaye","year":"2025","unstructured":"Kaye S, Gold A, Lin D, Chen M, Zhu J, Gao J (2025) Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques. Exp Neurol 390:115272. https:\/\/doi.org\/10.1016\/j.expneurol.2025.115272","journal-title":"Exp Neurol"},{"key":"4658_CR68","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.neuron.2014.11.018","volume":"85","author":"H Lian","year":"2015","unstructured":"Lian H, Yang L, Cole A, Sun L, Chiang ACA, Fowler SW, Shim DJ, Rodriguez-Rivera J, Taglialatela G, Jankowsky JL, Lu HC, Zheng H (2015) NF-\u03baB\u2013activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer\u2019s disease. Neuron 85:101\u2013115. https:\/\/doi.org\/10.1016\/j.neuron.2014.11.018","journal-title":"Neuron"},{"key":"4658_CR69","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00112","volume":"8","author":"I Morales","year":"2014","unstructured":"Morales I, Guzm\u00e1n-Mart\u00ednez L, Cerda-Troncoso C, Far\u00edas GA, Maccioni RB (2014) Neuroinflammation in the pathogenesis of Alzheimer\u2019s disease: a rational framework for the search of novel therapeutic approaches. Front Cell Neurosci 8:112. https:\/\/doi.org\/10.3389\/fncel.2014.00112","journal-title":"Front Cell Neurosci"},{"key":"4658_CR70","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.neuroscience.2015.12.039","volume":"316","author":"YL Chen","year":"2016","unstructured":"Chen YL, Wang LM, Chen Y, Gao JY, Marshall C, Cai ZY, Hu G, Xiao M (2016) Changes in astrocyte functional markers and proteins related to \u03b2-amyloid metabolism in early hypercholesterolemia. Neuroscience 316:178\u2013191. https:\/\/doi.org\/10.1016\/j.neuroscience.2015.12.039","journal-title":"Neuroscience"},{"key":"4658_CR71","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1042\/BST20140155","volume":"42","author":"EC Phillips","year":"2014","unstructured":"Phillips EC, Croft CL, Kurbatskaya K, O\u2019Neill MJ, Hutton ML, Hanger DP, Garwood CJ, Noble W (2014) Astrocytes and neuroinflammation in Alzheimer\u2019s disease. Biochem Soc Trans 42:1321\u20131325. https:\/\/doi.org\/10.1042\/BST20140155","journal-title":"Biochem Soc Trans"},{"key":"4658_CR72","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.ceb.2015.02.004","volume":"32","author":"EM Hol","year":"2015","unstructured":"Hol EM, Pekny M (2015) Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in central nervous system diseases. Curr Opin Cell Biol 32:121\u2013130. https:\/\/doi.org\/10.1016\/j.ceb.2015.02.004","journal-title":"Curr Opin Cell Biol"},{"key":"4658_CR73","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.brainres.2016.05.013","volume":"1644","author":"WH de Oliveira","year":"2016","unstructured":"de Oliveira WH, de Santana Nunes AK, de Fran\u00e7a MER, dos Santos LA, L\u00f3s DB, Rocha SWS, de Sousa Barbosa KP, Rodrigues GB, Peixoto CA (2016) Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice. Brain Res 1644:149\u2013160. https:\/\/doi.org\/10.1016\/j.brainres.2016.05.013","journal-title":"Brain Res"},{"key":"4658_CR74","doi-asserted-by":"publisher","first-page":"2821","DOI":"10.1007\/s00221-021-06176-8","volume":"239","author":"WH Oliveira","year":"2021","unstructured":"Oliveira WH, Braga CF, L\u00f3s DB, Ara\u00fajo SMR, Fran\u00e7a MER, Duarte-Silva E, Rodrigues GB, Rocha SWS, Peixoto CA (2021) Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice. Exp Brain Res 239:2821\u20132839. https:\/\/doi.org\/10.1007\/s00221-021-06176-8","journal-title":"Exp Brain Res"},{"key":"4658_CR75","doi-asserted-by":"publisher","first-page":"108415","DOI":"10.1016\/j.intimp.2021.108415","volume":"102","author":"IP Mendon\u00e7a","year":"2022","unstructured":"Mendon\u00e7a IP, Paiva IHR, Duarte-Silva EP, Melo MG, Silva RS, Oliveira WH, Costa BL, Peixoto CA (2022) Metformin and Fluoxetine improve depressive-like behavior in a murine model of parkinson\u2019s disease through modulation of neuroinflammation, neurogenesis and neuroplasticity. Int Immunopharmacol 102:108415. https:\/\/doi.org\/10.1016\/j.intimp.2021.108415","journal-title":"Int Immunopharmacol"},{"key":"4658_CR76","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1007\/s12640-022-00499-2","volume":"40","author":"M Sabzali","year":"2022","unstructured":"Sabzali M, Eidi A, Khaksari M, Khastar H (2022) Anti-inflammatory, antioxidant, and antiapoptotic actions of metformin attenuate ethanol neurotoxicity in an animal model of fetal alcohol spectrum disorders. Neurotox Res 40:605\u2013613. https:\/\/doi.org\/10.1007\/s12640-022-00499-2","journal-title":"Neurotox Res"},{"key":"4658_CR77","doi-asserted-by":"publisher","first-page":"488","DOI":"10.3389\/fncel.2018.00488","volume":"12","author":"S Bachiller","year":"2018","unstructured":"Bachiller S, Jim\u00e9nez-Ferrer I, Paulus A, Yang Y, Swanberg M, Deierborg T, Boza-Serrano A (2018) Microglia in neurological diseases: a roadmap to brain disease\u2013dependent inflammatory response. Front Cell Neurosci 12:488. https:\/\/doi.org\/10.3389\/fncel.2018.00488","journal-title":"Front Cell Neurosci"},{"key":"4658_CR78","doi-asserted-by":"publisher","first-page":"129","DOI":"10.3389\/fncel.2014.00129","volume":"8","author":"RC Paolicelli","year":"2014","unstructured":"Paolicelli RC, Bisht K, Tremblay M\u00c8 (2014) Fractalkine regulation of microglial physiology and consequences for the brain and behavior. Front Cell Neurosci 8:129. https:\/\/doi.org\/10.3389\/fncel.2014.00129","journal-title":"Front Cell Neurosci"},{"key":"4658_CR79","doi-asserted-by":"publisher","first-page":"3458","DOI":"10.1016\/j.neuron.2022.07.013","volume":"110","author":"RC Paolicelli","year":"2022","unstructured":"Paolicelli RC, Sierra A, Stevens B et al (2022) Microglia States and nomenclature: a field at its crossroads. Neuron 110:3458\u20133483. https:\/\/doi.org\/10.1016\/j.neuron.2022.07.013","journal-title":"Neuron"},{"key":"4658_CR80","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.3389\/fphar.2019.01008","volume":"10","author":"L Guzman-Martinez","year":"2019","unstructured":"Guzman-Martinez L, Maccioni RB, Andrade V, Navarrete LP, Pastor MG, Ramos-Escobar N (2019) Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol 10:1008. https:\/\/doi.org\/10.3389\/fphar.2019.01008","journal-title":"Front Pharmacol"},{"key":"4658_CR81","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.bbi.2021.02.011","volume":"95","author":"X Ma","year":"2021","unstructured":"Ma X, Xiao W, Li H, Pang P, Xue F, Wan L, Pei L, Yan H (2021) Metformin restores hippocampal neurogenesis and learning and memory by regulating gut microbiota in obese mice. Brain Behav Immun 95:68\u201383. https:\/\/doi.org\/10.1016\/j.bbi.2021.02.011","journal-title":"Brain Behav Immun"},{"key":"4658_CR82","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/s41392-024-01764-w","volume":"9","author":"Z Deng","year":"2024","unstructured":"Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J (2024) TGF-\u03b2 signaling in health, disease, and therapeutics. Signal Transduct Target Ther 9:61. https:\/\/doi.org\/10.1038\/s41392-024-01764-w","journal-title":"Signal Transduct Target Ther"},{"key":"4658_CR83","doi-asserted-by":"publisher","first-page":"887497","DOI":"10.3389\/fphar.2022.887497","volume":"13","author":"Y Wang","year":"2022","unstructured":"Wang Y, Wang Z, Yang H, Chen S, Zheng D, Liu X, Jiang Q, Chen Y (2022) Metformin ameliorates chronic colitis-related intestinal fibrosis by inhibiting TGF-\u03b21\/Smad3 signaling. Front Pharmacol 13:887497. https:\/\/doi.org\/10.3389\/fphar.2022.887497","journal-title":"Front Pharmacol"},{"key":"4658_CR84","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04649-4","volume":"13","author":"Q Xiao","year":"2022","unstructured":"Xiao Q, Xiao J, Liu J, Liu J, Shu G, Yin G (2022) Metformin suppresses colorectal cancer growth by targeting INHBA to inhibit TGF-\u03b2\/PI3K\/AKT signaling. Cell Death Dis 13:202. https:\/\/doi.org\/10.1038\/s41419-022-04649-4","journal-title":"Cell Death Dis"},{"key":"4658_CR85","doi-asserted-by":"publisher","first-page":"E6983","DOI":"10.1073\/pnas.1517045112","volume":"112","author":"X Chen","year":"2015","unstructured":"Chen X, Levy JM, Hou A, Winters C, Azzam R, Sousa AA, Leapman RD, Nicoll RA, Reese TS (2015) PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density. Proc Natl Acad Sci U S A 112:E6983\u2013E6992. https:\/\/doi.org\/10.1073\/pnas.1517045112","journal-title":"Proc Natl Acad Sci U S A"},{"key":"4658_CR86","doi-asserted-by":"publisher","DOI":"10.1186\/s12868-021-00683-8","volume":"22","author":"Z Qin","year":"2021","unstructured":"Qin Z, Zhou C, Xiao X, Guo C (2021) Metformin attenuates sepsis-induced neuronal injury and cognitive impairment. BMC Neurosci 22:6. https:\/\/doi.org\/10.1186\/s12868-021-00683-8","journal-title":"BMC Neurosci"},{"key":"4658_CR87","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1038\/mp.2014.161","volume":"20","author":"PJ Fitzgerald","year":"2015","unstructured":"Fitzgerald PJ, Pinard CR, Camp MC, Feyder M, Sah A, Bergstrom HC, Graybeal C, Liu Y, Schl\u00fcter OM, Grant SG, Singewald N, Xu W, Holmes A (2015) Durable fear memories require PSD-95. Mol Psychiatry 20:901\u2013912. https:\/\/doi.org\/10.1038\/mp.2014.161","journal-title":"Mol Psychiatry"},{"key":"4658_CR88","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23133-9","volume":"12","author":"B Compans","year":"2021","unstructured":"Compans B, Camus C, Kallergi E, Sposini S, Martineau M, Butler C, Kechkar A, Klaassen RV, Retailleau N, Sejnowski TJ, Smit AB, Sibarita JB, Bartol TM Jr, Perrais D, Nikoletopoulou V, Choquet D, Hosy E (2021) NMDAR-dependent long-term depression is associated with increased short-term plasticity through autophagy-mediated loss of PSD-95. Nat Commun 12:2849. https:\/\/doi.org\/10.1038\/s41467-021-23133-9","journal-title":"Nat Commun"},{"key":"4658_CR89","doi-asserted-by":"publisher","first-page":"170","DOI":"10.3389\/fncel.2020.00170","volume":"14","author":"YL Wang","year":"2020","unstructured":"Wang YL, Zhao JH, Guo FL et al (2020) Metformin ameliorates synaptic defects in a mouse model of alzheimer\u2019s disease by inhibiting Cdk5 activity. Front Cell Neurosci 14:170. https:\/\/doi.org\/10.3389\/fncel.2020.00170","journal-title":"Front Cell Neurosci"},{"key":"4658_CR90","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-024-02755-9","volume":"14","author":"SY Cho","year":"2024","unstructured":"Cho SY, Kim EW, Park SJ et al (2024) Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer\u2019s model mice. Transl Psychiatry 14:27. https:\/\/doi.org\/10.1038\/s41398-024-02755-9","journal-title":"Transl Psychiatry"},{"key":"4658_CR91","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2024.110262","volume":"265","author":"Q Wu","year":"2025","unstructured":"Wu Q, Jia XY, Zhang SH, Wu YZ, Xu LS, Han JG, Yu W, Zhou QH (2025) Metformin activates the PI3K\/AKT\/BDNF axis to attenuate postoperative cognitive dysfunction. Neuropharmacology 265:110262. https:\/\/doi.org\/10.1016\/j.neuropharm.2024.110262","journal-title":"Neuropharmacology"},{"key":"4658_CR92","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.jad.2019.09.013","volume":"260","author":"W Fang","year":"2020","unstructured":"Fang W, Zhang J, Hong L, Huang W, Dai X, Ye Q, Chen X (2020) Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK\/CREB-mediated histone acetylation. J Affect Disord 260:302\u2013313. https:\/\/doi.org\/10.1016\/j.jad.2019.09.013","journal-title":"J Affect Disord"},{"key":"4658_CR93","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1111\/acel.12075","volume":"12","author":"O Moiseeva","year":"2013","unstructured":"Moiseeva O, Desch\u00eanes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar AE, Bourdeau V, Pollak MN, Ferbeyre G (2013) Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK\/NF-\u03baB activation. Aging Cell 12:489\u2013498. https:\/\/doi.org\/10.1111\/acel.12075","journal-title":"Aging Cell"},{"key":"4658_CR94","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.neuroscience.2012.06.054","volume":"223","author":"J Halloran","year":"2012","unstructured":"Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, Austad SN, Strong R, Richardson A, Hart MJ, Galvan V (2012) Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience 223:102\u2013113. https:\/\/doi.org\/10.1016\/j.neuroscience.2012.06.054","journal-title":"Neuroscience"},{"key":"4658_CR95","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009979","volume":"5","author":"P Spilman","year":"2010","unstructured":"Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-\u03b2 levels in a mouse model of Alzheimer\u2019s disease. PLoS One 5:e9979. https:\/\/doi.org\/10.1371\/journal.pone.0009979","journal-title":"PLoS One"},{"key":"4658_CR96","doi-asserted-by":"publisher","first-page":"4305","DOI":"10.1523\/JNEUROSCI.2144-20.2021","volume":"41","author":"CE Van Skike","year":"2021","unstructured":"Van Skike CE, Hussong SA, Hernandez SF, Banh AQ, DeRosa N, Galvan V (2021) MTOR attenuation with rapamycin reverses neurovascular uncoupling and memory deficits in mice modeling Alzheimer\u2019s disease. J Neurosci 41:4305\u20134320. https:\/\/doi.org\/10.1523\/JNEUROSCI.2144-20.2021","journal-title":"J Neurosci"},{"key":"4658_CR97","doi-asserted-by":"publisher","first-page":"753","DOI":"10.3389\/fendo.2018.00753","volume":"9","author":"E Fontaine","year":"2018","unstructured":"Fontaine E (2018) Metformin-induced mitochondrial complex I inhibition: facts, uncertainties, and consequences. Front Endocrinol (Lausanne) 9:753. https:\/\/doi.org\/10.3389\/fendo.2018.00753","journal-title":"Front Endocrinol (Lausanne)"},{"key":"4658_CR98","doi-asserted-by":"publisher","first-page":"123803","DOI":"10.1016\/j.lfs.2025.123803","volume":"378","author":"N Gonz\u00e1lez P\u00e9rez","year":"2025","unstructured":"Gonz\u00e1lez P\u00e9rez N, Bellotto M, Porte Alc\u00f3n S, Bentivegna M, Arcucci L, Vinuesa \u00c1, Presa J, Brites F, P\u00e9rez Sirkin D, Beauquis J, Saravia F, Pomilio C (2025) Metformin protects against insulin resistance-related dementia risk involving restored microglial homeostasis. Life Sci 378:123803. https:\/\/doi.org\/10.1016\/j.lfs.2025.123803","journal-title":"Life Sci"},{"key":"4658_CR99","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cmet.2016.05.011","volume":"23","author":"N Barzilai","year":"2016","unstructured":"Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (2016) Metformin as a tool to target aging. Cell Metab 23:1060\u20131065. https:\/\/doi.org\/10.1016\/j.cmet.2016.05.011","journal-title":"Cell Metab"},{"key":"4658_CR100","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.cmet.2010.03.014","volume":"11","author":"A Kalender","year":"2010","unstructured":"Kalender A, Selvaraj A, Kim SY, Gulati P, Br\u00fbl\u00e9 S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, Marette A, Kozma SC, Thomas G (2010) Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 11:390\u2013401. https:\/\/doi.org\/10.1016\/j.cmet.2010.03.014","journal-title":"Cell Metab"}],"container-title":["Neurochemical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11064-025-04658-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11064-025-04658-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11064-025-04658-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T10:12:20Z","timestamp":1772619140000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11064-025-04658-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,24]]},"references-count":100,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["4658"],"URL":"https:\/\/doi.org\/10.1007\/s11064-025-04658-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-7436605\/v1","asserted-by":"object"}]},"ISSN":["0364-3190","1573-6903"],"issn-type":[{"value":"0364-3190","type":"print"},{"value":"1573-6903","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,24]]},"assertion":[{"value":"22 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 January 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}},{"value":"All applicable international, national, and\/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}}],"article-number":"60"}}