{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:48:24Z","timestamp":1791478104425,"version":"4.3.4"},"reference-count":332,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Lodz","award":["503\/1-159-01\/503-11-001"],"award-info":[{"award-number":["503\/1-159-01\/503-11-001"]}]},{"name":"Medical University of Lodz","award":["503\/0-149-04\/503-01-001"],"award-info":[{"award-number":["503\/0-149-04\/503-01-001"]}]},{"name":"Polish Society of Metabolic Disorders","award":["503\/1-159-01\/503-11-001"],"award-info":[{"award-number":["503\/1-159-01\/503-11-001"]}]},{"name":"Polish Society of Metabolic Disorders","award":["503\/0-149-04\/503-01-001"],"award-info":[{"award-number":["503\/0-149-04\/503-01-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>This comprehensive review examines the therapeutic potential of metformin, a well-established diabetes medication, in treating neurodegenerative disorders. Originally used as a first-line treatment for type 2 diabetes, recent studies have begun investigating metformin\u2019s effects beyond metabolic disorders, particularly its neuroprotective capabilities against conditions like Parkinson\u2019s disease, Alzheimer\u2019s disease, Huntington\u2019s disease, and multiple sclerosis. Key findings demonstrate that metformin\u2019s neuroprotective effects operate through multiple pathways: AMPK activation enhancing cellular energy metabolism and autophagy; upregulation of antioxidant defenses; suppression of inflammation; inhibition of protein aggregation; and improvement of mitochondrial function. These mechanisms collectively address common pathological features in neurodegeneration and neuroinflammation, including oxidative stress, protein accumulation, and mitochondrial dysfunction. Clinical and preclinical evidence supporting metformin\u2019s association with improved cognitive performance, reduced risk of dementia, and modulation of pathological hallmarks of neurodegenerative diseases is critically evaluated. While metformin shows promise as a therapeutic agent, this review emphasizes the need for further investigation to fully understand its mechanisms and optimal therapeutic applications in neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/ph18040486","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T06:06:35Z","timestamp":1743141995000},"page":"486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Overview of Metformin and Neurodegeneration: A Comprehensive Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1699-8912","authenticated-orcid":false,"given":"Weronika","family":"Kruczkowska","sequence":"first","affiliation":[{"name":"Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, \u017beligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3377-4162","authenticated-orcid":false,"given":"Julia","family":"Ga\u0142\u0119ziewska","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, \u017beligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0608-1794","authenticated-orcid":false,"given":"Paulina","family":"Buczek","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, \u017beligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6682-0402","authenticated-orcid":false,"given":"El\u017cbieta","family":"P\u0142uciennik","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, \u017beligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8616-3825","authenticated-orcid":false,"given":"Mateusz","family":"Kciuk","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12\/16, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6864-0704","authenticated-orcid":false,"given":"Agnieszka","family":"\u015aliwi\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Nucleic Acid Biochemistry, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/s41574-023-00833-4","article-title":"Metformin: Update on mechanisms of action and repurposing potential","volume":"19","author":"Foretz","year":"2023","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: Historical overview","volume":"60","author":"Bailey","year":"2017","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1039\/CT9222101790","article-title":"CCXIV.\u2014The preparation of methylguanidine, and of \u03b2\u03b2-dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively","volume":"121","author":"Werner","year":"1922","journal-title":"J. Chem. Soc. Trans."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.4103\/1673-5374.385286","article-title":"Promising use of metformin in treating neurological disorders: Biomarker-guided therapies","volume":"19","author":"Loan","year":"2024","journal-title":"Neural Regen. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kciuk, M., Kruczkowska, W., Galeziewska, J., Wanke, K., Kaluzinska-Kolat, Z., Aleksandrowicz, M., and Kontek, R. (2024). Alzheimer\u2019s Disease as Type 3 Diabetes: Understanding the Link and Implications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252211955"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1007\/s11010-023-04771-7","article-title":"Metformin role in Parkinson\u2019s disease: A double-sword effect","volume":"479","author":"Alrouji","year":"2024","journal-title":"Mol. Cell. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Agostini, F., Masato, A., Bubacco, L., and Bisaglia, M. (2021). Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010398"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Battini, V., Cirnigliaro, G., Leuzzi, R., Rissotto, E., Mosini, G., Benatti, B., Pozzi, M., Nobile, M., Radice, S., and Carnovale, C. (2023). The potential effect of metformin on cognitive and other symptom dimensions in patients with schizophrenia and antipsychotic-induced weight gain: A systematic review, meta-analysis, and meta-regression. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1215807"},{"key":"ref_9","unstructured":"(2025, March 13). NCT04098666; Metformin in Alzheimer\u2019s Dementia Prevention (MAP), Jos\u00e9 A. Luchsinger, Columbia University, Available online: https:\/\/clinicaltrials.gov\/study\/NCT04098666."},{"key":"ref_10","unstructured":"(2025, March 13). NCT04826692; TEsting METformin Against Cognitive Decline in HD, Instituto de Investigacion Sanitaria La Fe, Available online: https:\/\/clinicaltrials.gov\/study\/NCT04826692."},{"key":"ref_11","unstructured":"(2025, March 13). NCT05781711; Clinical Study to Evaluate the Possible Efficacy of Metformin in Patients with Parkinson\u2019s Disease, Mostafa Bahaa, Tanta University, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05781711."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1080\/14737175.2021.1847645","article-title":"Metformin as a potential therapeutic for neurological disease: Mobilizing AMPK to repair the nervous system","volume":"21","author":"Demare","year":"2021","journal-title":"Expert Rev. Neurother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1210\/endrev\/bnad029","article-title":"Metformin, Cognitive Function, and Changes in the Gut Microbiome","volume":"45","year":"2024","journal-title":"Endocr. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/dom.15663","article-title":"Metformin: Therapeutic profile in the treatment of type 2 diabetes","volume":"26","author":"Bailey","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.2337\/dc20-0892","article-title":"Metformin Use Is Associated with Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults with Type 2 Diabetes: The Sydney Memory and Ageing Study","volume":"43","author":"Samaras","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1177\/02698811211057304","article-title":"The effect of metformin on cognitive function: A systematic review and meta-analysis","volume":"36","author":"Bandarian","year":"2022","journal-title":"J. Psychopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1016\/j.xphs.2017.04.078","article-title":"Transporters Involved in Metformin Pharmacokinetics and Treatment Response","volume":"106","author":"Liang","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1097\/FPC.0b013e3283559b22","article-title":"Metformin pathways: Pharmacokinetics and pharmacodynamics","volume":"22","author":"Gong","year":"2012","journal-title":"Pharmacogenet. Genom."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","article-title":"Clinical pharmacokinetics of metformin","volume":"50","author":"Graham","year":"2011","journal-title":"Clin. Pharmacokinet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Szymczak-Pajor, I., Wenclewska, S., and Sliwinska, A. (2022). Metabolic Action of Metformin. Pharmaceuticals, 15.","DOI":"10.3390\/ph15070810"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e17906","DOI":"10.1016\/j.heliyon.2023.e17906","article-title":"Effects of food on pharmacokinetics and safety of metformin hydrochloride tablets: A meta-analysis of pharmacokinetic, bioavailability, or bioequivalence studies","volume":"9","author":"Sun","year":"2023","journal-title":"Heliyon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1111\/dom.13264","article-title":"Pharmacokinetics of metformin in patients with gastrointestinal intolerance","volume":"20","author":"McCreight","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Fontaine, E. (2018). Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00753"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1038\/s41591-018-0125-4","article-title":"Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo","volume":"24","author":"Madiraju","year":"2018","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1210\/endrev\/bnaa023","article-title":"Cellular and Molecular Mechanisms of Metformin Action","volume":"42","author":"LaMoia","year":"2021","journal-title":"Endocr. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1042\/BJ20140620","article-title":"Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria","volume":"462","author":"Bridges","year":"2014","journal-title":"Biochem. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"482","DOI":"10.5603\/EP.2017.0050","article-title":"Metformin\u2014A new old drug","volume":"68","author":"Wrobel","year":"2017","journal-title":"Endokrynol. Pol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nature13270","article-title":"Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase","volume":"510","author":"Madiraju","year":"2014","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Apostolova, N., Iannantuoni, F., Gruevska, A., Muntane, J., Rocha, M., and Victor, V.M. (2020). Mechanisms of action of metformin in type 2 diabetes: Effects on mitochondria and leukocyte-endothelium interactions. Redox Biol., 34.","DOI":"10.1016\/j.redox.2020.101517"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e230015","DOI":"10.1530\/REM-23-0015","article-title":"Metformin and its redox-related mechanisms of action in type 2 diabetes","volume":"2023","author":"Vezza","year":"2023","journal-title":"Redox Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1074\/jbc.RA118.006670","article-title":"Low metformin causes a more oxidized mitochondrial NADH\/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism","volume":"294","author":"Alshawi","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, S., Washio, J., Sato, S., Abiko, Y., Shinohara, Y., Kobayashi, Y., Otani, H., Sasaki, S., Wang, X., and Takahashi, N. (2022). Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020989"},{"key":"ref_33","first-page":"CD002967","article-title":"Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus","volume":"2010","author":"Salpeter","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.4239\/wjd.v15.i6.1178","article-title":"Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis and management in critically ill patients","volume":"15","author":"See","year":"2024","journal-title":"World J. Diabetes"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"827","DOI":"10.5009\/gnl20367","article-title":"Effects of Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and Diabetes: Insights from the Cellular to Patient Levels","volume":"15","author":"Pinyopornpanish","year":"2021","journal-title":"Gut Liver"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1007\/s00125-013-2991-0","article-title":"Molecular mechanism of action of metformin: Old or new insights?","volume":"56","author":"Rena","year":"2013","journal-title":"Diabetologia"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Gumieniczek, A., Berecka-Rycerz, A., Mroczek, T., and Wojtanowski, A.K. (2019). Determination of Chemical Stability of Two Oral Antidiabetics, Metformin and Repaglinide in the Solid State and Solutions Using LC-UV, LC-MS, and FT-IR Methods. Molecules, 24.","DOI":"10.3390\/molecules24244430"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1107\/S2052520616017844","article-title":"Charge density analysis of metformin chloride, a biguanide anti-hyperglycemic agent","volume":"73","author":"Jelsch","year":"2017","journal-title":"Acta Crystallogr. Sect. B Struct. Sci. Cryst. Eng. Mater."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: From mechanisms of action to therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1002\/jps.23852","article-title":"Surfactant-mediated dissolution of metformin hydrochloride tablets: Wetting effects versus ion pairs diffusivity","volume":"103","author":"Desai","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"57","DOI":"10.5599\/admet.916","article-title":"In vitro pH dependent passive transport of ketoprofen and metformin","volume":"9","author":"Elezovic","year":"2021","journal-title":"ADMET DMPK"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.molstruc.2015.05.050","article-title":"Insulin-like action of novel metformin-containing vanadate as a new antidiabatic drug: Synthesis, characterization and crystal structure of [Metformin-H]2[V2O6]]\u00b7H2O","volume":"1098","author":"Ibrahim","year":"2015","journal-title":"J. Mol. Struct."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"An, Q., Xing, C., Wang, Z., Li, S., Wang, W., Yang, S., Kong, L., Yang, D., Zhang, L., and Du, G. (2024). Metformin-Mediated Improvement in Solubility, Stability, and Permeability of Nonsteroidal Anti-Inflammatory Drugs. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16030382"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Li, N., Zhou, T., and Fei, E. (2022). Actions of Metformin in the Brain: A New Perspective of Metformin Treatments in Related Neurological Disorders. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158281"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41531-022-00321-y","article-title":"Mechanisms of peripheral levodopa resistance in Parkinson\u2019s disease","volume":"8","author":"Beckers","year":"2022","journal-title":"NPJ Park. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"He, Q., Liu, J., Liang, J., Liu, X., Li, W., Liu, Z., Ding, Z., and Tuo, D. (2018). Towards Improvements for Penetrating the Blood-Brain Barrier-Recent Progress from a Material and Pharmaceutical Perspective. Cells, 7.","DOI":"10.3390\/cells7040024"},{"key":"ref_47","unstructured":"Chevalier, R. (2025, March 13). Available online: https:\/\/www.biorxiv.org\/content\/10.1101\/362541v2.abstract."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Sharma, S., Zhang, Y., Akter, K.A., Nozohouri, S., Archie, S.R., Patel, D., Villalba, H., and Abbruscato, T. (2023). Permeability of Metformin across an In Vitro Blood\u2013Brain Barrier Model during Normoxia and Oxygen-Glucose Deprivation Conditions: Role of Organic Cation Transporters (Octs). Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15051357"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1111\/j.1476-5381.2010.01101.x","article-title":"Metformin inhibits P-glycoprotein expression via the NF-\u03baB pathway and CRE transcriptional activity through AMPK activation","volume":"162","author":"Kim","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_50","first-page":"177","article-title":"Inhibition of P-glycoprotein expression and function by anti-diabetic drugs gliclazide, metformin, and pioglitazone in vitro and in situ","volume":"11","author":"Abbasi","year":"2016","journal-title":"Res. Pharm. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Huttunen, J., Peltokangas, S., Gynther, M., Natunen, T., Hiltunen, M., Auriola, S., Ruponen, M., Vellonen, K.S., and Huttunen, K.M. (2019). L-Type Amino Acid Transporter 1 (LAT1\/Lat1)-Utilizing Prodrugs Can Improve the Delivery of Drugs into Neurons, Astrocytes and Microglia. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-49009-z"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Singh, N., and Ecker, G.F. (2018). Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051278"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Sato, R., Ohmori, K., Umetsu, M., Takao, M., Tano, M., Grant, G., Porter, B., Bet, A., Terasaki, T., and Uchida, Y. (2021). An Atlas of the Quantitative Protein Expression of Anti-Epileptic-Drug Transporters, Metabolizing Enzymes and Tight Junctions at the Blood-Brain Barrier in Epileptic Patients. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13122122"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.addr.2011.12.003","article-title":"The transport of antiepileptic drugs by P-glycoprotein","volume":"64","author":"Zhang","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.4103\/1673-5374.313046","article-title":"Multiple hurdle mechanism and blood-brain barrier in epilepsy: Glucocorticoid receptor-heat shock proteins on drug regulation","volume":"16","author":"Ghosh","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1007\/s11095-017-2199-y","article-title":"Metformin\u2014A Future Therapy for Neurodegenerative Diseases: Theme: Drug Discovery, Development and Delivery in Alzheimer\u2019s Disease Guest Editor: Davide Brambilla","volume":"34","author":"Sikora","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"647","DOI":"10.2337\/dc20-1964","article-title":"Metformin Benefits: Another Example for Alternative Energy Substrate Mechanism?","volume":"44","author":"Giaccari","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_58","unstructured":"Crowley, M.J., Diamantidis, C.J., McDuffie, J.R., Cameron, B., Stanifer, J., Mock, C.K., Kosinski, A., Wang, X., Tang, S., and Williams, J.W. (2025, March 13). Metformin Use in Patients with Historical Contraindications or Precautions, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK409379\/."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.2147\/PPA.S211614","article-title":"Overcoming barriers to the use of metformin: Patient and provider perspectives","volume":"13","author":"Flory","year":"2019","journal-title":"Patient Prefer. Adherence"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/dom.15749","article-title":"Optimizing metformin therapy in practice: Tailoring therapy in specific patient groups to improve tolerability, efficacy and outcomes","volume":"26","author":"Silverii","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1055\/s-0043-1761215","article-title":"Predictors of Metformin Side Effects in Patients with Newly Diagnosed Type 2 Diabetes Mellitus","volume":"15","author":"Alibrahim","year":"2023","journal-title":"Ibnosina J. Med. Biomed. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"727","DOI":"10.2165\/11536790-000000000-00000","article-title":"Lactic acidosis induced by metformin: Incidence, management and prevention","volume":"33","author":"Lalau","year":"2010","journal-title":"Drug Saf."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"585","DOI":"10.4239\/wjd.v14.i5.585","article-title":"Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes","volume":"14","author":"Sayedali","year":"2023","journal-title":"World J. Diabetes"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"279","DOI":"10.5603\/cd.97473","article-title":"Beyond Diabetes Management: Unraveling Metformin\u2019s Long-Term Effects on Vitamin B12","volume":"12","author":"Bahl","year":"2023","journal-title":"Clin. Diabetol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1007\/s10787-023-01163-7","article-title":"Long-term use of metformin and Alzheimer\u2019s disease: Beneficial or detrimental effects","volume":"31","author":"Saad","year":"2023","journal-title":"Inflammopharmacology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"388","DOI":"10.14740\/jocmr2922e","article-title":"Effect of Metformin on Different Non-Diabetes Related Conditions, a Special Focus on Malignant Conditions: Review of Literature","volume":"9","author":"Abdelgadir","year":"2017","journal-title":"J. Clin. Med. Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Shen, D., Ye, X., Li, J., Hao, X., Jin, L., Jin, Y., Tong, L., and Gao, F. (2022). Metformin Preserves VE-Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF\/VEGFR2\/p-Src in an Intraventricular Hemorrhage Rat Model. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158552"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3513","DOI":"10.1111\/dom.15759","article-title":"Advances in metformin-delivery systems for diabetes and obesity management","volume":"26","author":"Abbasi","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Du, M.R., Gao, Q.Y., Liu, C.L., Bai, L.Y., Li, T., and Wei, F.L. (2022). Exploring the Pharmacological Potential of Metformin for Neurodegenerative Diseases. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.838173"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8599268","DOI":"10.1155\/2024\/8599268","article-title":"Neuroprotective Effects of Metformin and Berberine in Lipopolysaccharide-Induced Sickness-Like Behaviour in Mice","volume":"2024","author":"Kodi","year":"2024","journal-title":"Adv. Pharmacol. Pharm. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.ejpb.2022.10.018","article-title":"Design and optimization of metformin-loaded solid lipid nanoparticles for neuroprotective effects in a rat model of diffuse traumatic brain injury: A biochemical, behavioral, and histological study","volume":"181","author":"Ebrahimi","year":"2022","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"106348","DOI":"10.1016\/j.ejps.2022.106348","article-title":"Novel therapeutic mechanism of action of metformin and its nanoformulation in Alzheimer\u2019s disease and role of AKT\/ERK\/GSK pathway","volume":"181","author":"Kumar","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s42114-025-01227-y","article-title":"Intranasal delivery of metformin using metal-organic framework (MOF)-74-Mg nanocarriers","volume":"8","author":"Yuan","year":"2025","journal-title":"Adv. Compos. Hybrid Mater."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2022). 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care, 45, S17\u2013S38.","DOI":"10.2337\/dc22-S002"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"740","DOI":"10.7326\/M15-2650","article-title":"Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis","volume":"164","author":"Maruthur","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"446","DOI":"10.2337\/dc11-1465","article-title":"Quantifying the effect of metformin treatment and dose on glycemic control","volume":"35","author":"Hirst","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1001\/jama.2016.9400","article-title":"Comparison of Clinical Outcomes and Adverse Events Associated with Glucose-Lowering Drugs in Patients with Type 2 Diabetes: A Meta-analysis","volume":"316","author":"Palmer","year":"2016","journal-title":"JAMA"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Du, Y., Zhu, Y.J., Zhou, Y.X., Ding, J., and Liu, J.Y. (2022). Metformin in therapeutic applications in human diseases: Its mechanism of action and clinical study. Mol. Biomed., 3.","DOI":"10.1186\/s43556-022-00108-w"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.2337\/dc12-0413","article-title":"Management of hyperglycemia in type 2 diabetes: A patient-centered approach: Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)","volume":"35","author":"Inzucchi","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/dom.12854","article-title":"Understanding and overcoming metformin gastrointestinal intolerance","volume":"19","author":"Bonnet","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s10557-020-07050-5","article-title":"Metformin Lowers Body Weight But Fails to Increase Insulin Sensitivity in Chronic Heart Failure Patients without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study","volume":"35","author":"Larsen","year":"2021","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3634908","DOI":"10.1155\/2022\/3634908","article-title":"Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK\/NLRP3 Inflammasome Pathway","volume":"2022","author":"Yuan","year":"2022","journal-title":"Anal. Cell. Pathol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Deschemin, J.C., Foretz, M., Viollet, B., and Vaulont, S. (2017). AMPK is not required for the effect of metformin on the inhibition of BMP6-induced hepcidin gene expression in hepatocytes. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-12976-2"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1042\/CS20110386","article-title":"Cellular and molecular mechanisms of metformin: An overview","volume":"122","author":"Viollet","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.metabol.2019.06.002","article-title":"PPP1R3C mediates metformin-inhibited hepatic gluconeogenesis","volume":"98","author":"Ji","year":"2019","journal-title":"Metabolism"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Pavlovic, K., Krako Jakovljevic, N., Isakovic, A.M., Ivanovic, T., Markovic, I., and Lalic, N.M. (2022). Therapeutic vs. Suprapharmacological Metformin Concentrations: Different Effects on Energy Metabolism and Mitochondrial Function in Skeletal Muscle Cells in vitro. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.930308"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s11684-015-0384-0","article-title":"Metformin and metabolic diseases: A focus on hepatic aspects","volume":"9","author":"Zheng","year":"2015","journal-title":"Front. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s12031-007-9002-1","article-title":"Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons","volume":"34","author":"Detaille","year":"2008","journal-title":"J. Mol. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"5535","DOI":"10.1210\/jc.2004-0150","article-title":"Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin","volume":"89","author":"Marchetti","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1210\/en.2005-1433","article-title":"Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase-dependent reduction in GLUT4 endocytosis","volume":"147","author":"Yang","year":"2006","journal-title":"Endocrinology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.4161\/cc.10.11.15824","article-title":"The insulin receptor substrate (IRS) proteins: At the intersection of metabolism and cancer","volume":"10","author":"Shaw","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s12944-016-0342-0","article-title":"Revisiting the membrane-centric view of diabetes","volume":"15","author":"Pilon","year":"2016","journal-title":"Lipids Health Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"357","DOI":"10.15584\/ejcem.2023.2.19","article-title":"Relationship between obesity, insulin resistance and cell membrane properties","volume":"21","author":"Ahyayauch","year":"2023","journal-title":"Eur. J. Clin. Exp. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"S134","DOI":"10.2337\/diabetes.51.2007.S134","article-title":"Lipotoxicity in human pancreatic islets and the protective effect of metformin","volume":"51","author":"Lupi","year":"2002","journal-title":"Diabetes"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1038\/nm.4345","article-title":"Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug","volume":"23","author":"Wu","year":"2017","journal-title":"Nat. Med."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Cheng, M., Ren, L., Jia, X., Wang, J., and Cong, B. (2024). Understanding the action mechanisms of metformin in the gastrointestinal tract. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1347047"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S0006-291X(02)02565-2","article-title":"Enhanced secretion of glucagon-like peptide 1 by biguanide compounds","volume":"298","author":"Yasuda","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Goel, S., Singh, R., Singh, V., Singh, H., Kumari, P., Chopra, H., Sharma, R., Nepovimova, E., Valis, M., and Kuca, K. (2022). Metformin: Activation of 5\u2032 AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.1022739"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.2337\/db13-0368","article-title":"AMPK: A target for drugs and natural products with effects on both diabetes and cancer","volume":"62","author":"Hardie","year":"2013","journal-title":"Diabetes"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/s41574-019-0242-2","article-title":"Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus","volume":"15","author":"Foretz","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"5545","DOI":"10.2147\/JIR.S436147","article-title":"The Role and Mechanism of Metformin in Inflammatory Diseases","volume":"16","author":"Lin","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"54","DOI":"10.15171\/jrip.2019.11","article-title":"Metformin and its anti-inflammatory and anti-oxidative effects; new concepts","volume":"8","author":"Dehkordi","year":"2018","journal-title":"J. Ren. Inj. Prev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"268","DOI":"10.7150\/ijbs.7929","article-title":"Metformin plays a dual role in MIN6 pancreatic \u03b2 cell function through AMPK-dependent autophagy","volume":"10","author":"Jiang","year":"2014","journal-title":"Int. J. Biol. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Cao, G., Gong, T., Du, Y., Wang, Y., Ge, T., and Liu, J. (2022). Mechanism of metformin regulation in central nervous system: Progression and future perspectives. Biomed. Pharmacother., 156.","DOI":"10.1016\/j.biopha.2022.113686"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Chele, D., Sirbu, C.-A., Mitrica, M., Toma, M., Vasiliu, O., Sirbu, A.-M., Authier, F.J., Mischianu, D., and Munteanu, A.E. (2025). Metformin\u2019s Effects on Cognitive Function from a Biovariance Perspective: A Narrative Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26041783"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41586-022-04431-8","article-title":"Low-dose metformin targets the lysosomal AMPK pathway through PEN2","volume":"603","author":"Ma","year":"2022","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1089\/ars.2017.7409","article-title":"Does Metformin Modulate Endoplasmic Reticulum Stress and Autophagy in Type 2 Diabetic Peripheral Blood Mononuclear Cells?","volume":"28","author":"Iannantuoni","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"108082","DOI":"10.1016\/j.isci.2023.108082","article-title":"Metformin inhibits inflammatory response and endoplasmic reticulum stress to improve hypothalamic aging in obese mice","volume":"26","author":"Yang","year":"2023","journal-title":"iScience"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1161\/CIRCRESAHA.116.308445","article-title":"Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status","volume":"119","author":"Cameron","year":"2016","journal-title":"Circ. Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.2147\/CMAR.S200059","article-title":"The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances","volume":"11","author":"Saraei","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1007\/s00125-017-4337-9","article-title":"Impact of metformin on cardiovascular disease: A meta-analysis of randomised trials among people with type 2 diabetes","volume":"60","author":"Griffin","year":"2017","journal-title":"Diabetologia"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cmet.2016.05.011","article-title":"Metformin as a Tool to Target Aging","volume":"23","author":"Barzilai","year":"2016","journal-title":"Cell Metab."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1007\/s10238-023-01051-y","article-title":"Molecular mechanisms of action of metformin: Latest advances and therapeutic implications","volume":"23","author":"Zhu","year":"2023","journal-title":"Clin. Exp. Med."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Ricci, S., and Cacialli, P. (2021). Stem Cell Research Tools in Human Metabolic Disorders: An Overview. Cells, 10.","DOI":"10.3390\/cells10102681"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Ezzamouri, B., Rosario, D., Bidkhori, G., Lee, S., Uhlen, M., and Shoaie, S. (2023). Metabolic modelling of the human gut microbiome in type 2 diabetes patients in response to metformin treatment. NPJ Syst. Biol. Appl., 9.","DOI":"10.1038\/s41540-022-00261-6"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Wang, Y., Jia, X., and Cong, B. (2024). Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1396031"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1172\/JCI40671","article-title":"Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1\/AMPK pathway via a decrease in hepatic energy state","volume":"120","author":"Foretz","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"An, H., Wang, Y., Qin, C., Li, M., Maheshwari, A., and He, L. (2020). The importance of the AMPK gamma 1 subunit in metformin suppression of liver glucose production. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-67030-5"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Shibata, S., Sogabe, S., Miwa, M., Fujimoto, T., Takakura, N., Naotsuka, A., Kitamura, S., Kawamoto, T., and Soga, T. (2021). Identification of the first highly selective inhibitor of human lactate dehydrogenase B. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-00820-7"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s12041-018-0963-3","article-title":"Shared mechanisms among neurodegenerative diseases: From genetic factors to gene networks","volume":"97","author":"Arneson","year":"2018","journal-title":"J. Genet."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Li, P., Nie, Y., and Yu, J. (2015). An Effective Method to Identify Shared Pathways and Common Factors among Neurodegenerative Diseases. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143045"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Correale, J., Marrodan, M., and Ysrraelit, M.C. (2019). Mechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis. Biomedicines, 7.","DOI":"10.3390\/biomedicines7010014"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"4314","DOI":"10.1038\/s41467-022-31873-5","article-title":"Shared mechanisms across the major psychiatric and neurodegenerative diseases","volume":"13","author":"Wingo","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Hussain, R., Zubair, H., Pursell, S., and Shahab, M. (2018). Neurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches. Brain Sci., 8.","DOI":"10.3390\/brainsci8090177"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Olufunmilayo, E.O., Gerke-Duncan, M.B., and Holsinger, R.M.D. (2023). Oxidative Stress and Antioxidants in Neurodegenerative Disorders. Antioxidants, 12.","DOI":"10.3390\/antiox12020517"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Xu, S., Zhang, X., Liu, C., Liu, Q., Chai, H., Luo, Y., and Li, S. (2021). Role of Mitochondria in Neurodegenerative Diseases: From an Epigenetic Perspective. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.688789"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"e168554","DOI":"10.1172\/JCI168554","article-title":"Disruption of axonal transport in neurodegeneration","volume":"133","author":"Berth","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Giri, P.M., Banerjee, A., Ghosal, A., and Layek, B. (2024). Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25073995"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Muddapu, V.R., Dharshini, S.A.P., Chakravarthy, V.S., and Gromiha, M.M. (2020). Neurodegenerative Diseases\u2014Is Metabolic Deficiency the Root Cause?. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00213"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1038\/s41467-024-46554-8","article-title":"Neuropathogenesis-on-chips for neurodegenerative diseases","volume":"15","author":"Amartumur","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Sonninen, T.M., Goldsteins, G., Laham-Karam, N., Koistinaho, J., and Lehtonen, S. (2020). Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases. Cells, 9.","DOI":"10.3390\/cells9102183"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1186\/s12964-024-01791-8","article-title":"Misfolding and aggregation in neurodegenerative diseases: Protein quality control machinery as potential therapeutic clearance pathways","volume":"22","author":"Koszla","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-023-06328-6","article-title":"Mega-scale experimental analysis of protein folding stability in biology and design","volume":"620","author":"Tsuboyama","year":"2023","journal-title":"Nature"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"e2019631118","DOI":"10.1073\/pnas.2019631118","article-title":"Mechanism of misfolding of the human prion protein revealed by a pathological mutation","volume":"118","author":"Barritt","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/bs.apcsb.2019.10.001","article-title":"Combining molecular dynamics simulations and experimental analyses in protein misfolding","volume":"118","author":"Wille","year":"2019","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Diociaiuti, M., Bonanni, R., Cariati, I., Frank, C., and D\u2019Arcangelo, G. (2021). Amyloid Prefibrillar Oligomers: The Surprising Commonalities in Their Structure and Activity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126435"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Alibhai, J., Blanco, R.A., Barria, M.A., Piccardo, P., Caughey, B., Perry, V.H., Freeman, T.C., and Manson, J.C. (2016). Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration. PLoS Biol., 14.","DOI":"10.1371\/journal.pbio.1002579"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s40478-018-0587-0","article-title":"Rapid dissemination of \u03b1-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment","volume":"6","author":"Okuzumi","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"27","DOI":"10.20517\/evcna.2023.05","article-title":"Hijacking intercellular trafficking for the spread of protein aggregates in neurodegenerative diseases: A focus on tunneling nanotubes (TNTs)","volume":"4","author":"Chakraborty","year":"2023","journal-title":"Extracell. Vesicles Circ. Nucleic Acids"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Moda, F., Ciullini, A., Dellarole, I.L., Lombardo, A., Campanella, N., Bufano, G., Cazzaniga, F.A., and Giaccone, G. (2023). Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception. Front. Biosci., 28.","DOI":"10.31083\/j.fbl2810255"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41531-023-00618-6","article-title":"Cell-to-cell transmitted \u03b1-synuclein recapitulates experimental Parkinson\u2019s disease","volume":"10","author":"Prymaczok","year":"2024","journal-title":"NPJ Park. Dis."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13195-023-01178-w","article-title":"Initial levels of \u03b2-amyloid and tau deposition have distinct effects on longitudinal tau accumulation in Alzheimer\u2019s disease","volume":"15","author":"Cai","year":"2023","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1007\/s00018-023-04882-w","article-title":"Soluble mutant huntingtin drives early human pathogenesis in Huntington\u2019s disease","volume":"80","author":"Miguez","year":"2023","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Mosleth, E.F., Vedeler, C.A., Liland, K.H., McLeod, A., Bringeland, G.H., Kroondijk, L., Berven, F.S., Lysenko, A., Rawlings, C.J., and Eid, K.E. (2021). Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-82388-w"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Weids, A.J., Ibstedt, S., Tamas, M.J., and Grant, C.M. (2016). Distinct stress conditions result in aggregation of proteins with similar properties. Sci. Rep., 6.","DOI":"10.1038\/srep24554"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Dong, Z., and Cui, H. (2018). The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors. Cells, 8.","DOI":"10.3390\/cells8010004"},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Shahheydari, H., Ragagnin, A., Walker, A.K., Toth, R.P., Vidal, M., Jagaraj, C.J., Perri, E.R., Konopka, A., Sultana, J.M., and Atkin, J.D. (2017). Protein Quality Control and the Amyotrophic Lateral Sclerosis\/Frontotemporal Dementia Continuum. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00119"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"e18188","DOI":"10.1016\/j.heliyon.2023.e18188","article-title":"A bioinformatic investigation of proteasome and autophagy expression in the central nervous system","volume":"9","author":"Watanabe","year":"2023","journal-title":"Heliyon"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3988\/jcn.2022.0379","article-title":"Proteostasis and Ribostasis Impairment as Common Cell Death Mechanisms in Neurodegenerative Diseases","volume":"19","author":"Lim","year":"2023","journal-title":"J. Clin. Neurol."},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Feleciano, D.R., Juenemann, K., Iburg, M., Bras, I.C., Holmberg, C.I., and Kirstein, J. (2019). Crosstalk Between Chaperone-Mediated Protein Disaggregation and Proteolytic Pathways in Aging and Disease. Front. Aging Neurosci., 11.","DOI":"10.3389\/fnagi.2019.00009"},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Stojowska-Swedrzynska, K., Kuczynska-Wisnik, D., and Laskowska, E. (2024). Influence of N\u03b5-Lysine Acetylation on the Formation of Protein Aggregates and Antibiotic Persistence in E. coli. Molecules, 29.","DOI":"10.3390\/molecules29020383"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1039\/D3CB00145H","article-title":"Copper binding and protein aggregation: A journey from the brain to the human lens","volume":"4","author":"Posadas","year":"2023","journal-title":"RSC Chem. Biol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s40478-020-0894-0","article-title":"Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by \u03b1-synuclein","volume":"8","author":"McKinnon","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Yao, Q., Mascarenhas Dos Santos, A.C., Zhang, H., Manas, A., Hussaini, A., Kim, U., Xu, C., Basheer, S., Tasaki, S., and Xiang, J. (2023). Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax\u22062 in Alzheimer\u2019s Disease. Biomolecules, 13.","DOI":"10.3390\/biom13060970"},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Bonfanti, S., Lionetti, M.C., Fumagalli, M.R., Chirasani, V.R., Tiana, G., Dokholyan, N.V., Zapperi, S., and La Porta, C.A.M. (2019). Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-44151-0"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41419-023-05783-3","article-title":"Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis","volume":"14","author":"Zhou","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.tins.2022.01.006","article-title":"How do protein aggregates escape quality control in neurodegeneration?","volume":"45","author":"Koopman","year":"2022","journal-title":"Trends Neurosci."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1093\/brain\/awaa033","article-title":"Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum","volume":"143","author":"Cope","year":"2020","journal-title":"Brain"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s12974-021-02158-3","article-title":"Crosstalk between astrocytes and microglia results in increased degradation of \u03b1-synuclein and amyloid-\u03b2 aggregates","volume":"18","author":"Rostami","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s41392-023-01588-0","article-title":"Microglia in neurodegenerative diseases: Mechanism and potential therapeutic targets","volume":"8","author":"Gao","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_161","first-page":"2082145","article-title":"The Role of Oxidative Stress in Physiopathology and Pharmacological Treatment with Pro- and Antioxidant Properties in Chronic Diseases","volume":"2020","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Albano, G.D., Gagliardo, R.P., Montalbano, A.M., and Profita, M. (2022). Overview of the Mechanisms of Oxidative Stress: Impact in Inflammation of the Airway Diseases. Antioxidants, 11.","DOI":"10.3390\/antiox11112237"},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Afzal, S., Abdul Manap, A.S., Attiq, A., Albokhadaim, I., Kandeel, M., and Alhojaily, S.M. (2023). From imbalance to impairment: The central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1269581"},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Hajam, Y.A., Rani, R., Ganie, S.Y., Sheikh, T.A., Javaid, D., Qadri, S.S., Pramodh, S., Alsulimani, A., Alkhanani, M.F., and Harakeh, S. (2022). Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives. Cells, 11.","DOI":"10.3390\/cells11030552"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/01616412.2016.1251711","article-title":"Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders","volume":"39","author":"Islam","year":"2017","journal-title":"Neurol. Res."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"fcad356","DOI":"10.1093\/braincomms\/fcad356","article-title":"Role of oxidative stress in neurodegenerative disorders: A review of reactive oxygen species and prevention by antioxidants","volume":"6","author":"Houldsworth","year":"2024","journal-title":"Brain Commun."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Teleanu, D.M., Niculescu, A.G., Lungu, I.I., Radu, C.I., Vladacenco, O., Roza, E., Costachescu, B., Grumezescu, A.M., and Teleanu, R.I. (2022). An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23115938"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_169","doi-asserted-by":"crossref","unstructured":"Ihnatovych, I., Birkaya, B., Notari, E., and Szigeti, K. (2020). iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249668"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"e177002","DOI":"10.1172\/jci.insight.177002","article-title":"Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling","volume":"9","author":"Chang","year":"2024","journal-title":"JCI Insight"},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Li, X., Tong, H., Xu, S., Zhou, G., Yang, T., Yin, S., Yang, S., Li, X., and Li, S. (2024). Neuroinflammatory Proteins in Huntington\u2019s Disease: Insights into Mechanisms, Diagnosis, and Therapeutic Implications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252111787"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"RP96831","DOI":"10.7554\/eLife.96831.3","article-title":"Astrogliosis and neuroinflammation underlie scoliosis upon cilia dysfunction","volume":"13","author":"Djebar","year":"2024","journal-title":"eLife"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"368504211054985","DOI":"10.1177\/00368504211054985","article-title":"Inflammatory cytokines TNF\u03b1, IL-1\u03b2, and IL-6 are induced in endotoxin-stimulated microglia through different signaling cascades","volume":"104","author":"Ishijima","year":"2021","journal-title":"Sci. Prog."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"28","DOI":"10.4274\/tji.galenos.2024.76598","article-title":"Peripheral Expression of IL-6, TNF-\u03b1 and TGF-\u03b21 in Alzheimer\u2019s Disease Patients","volume":"12","author":"Lohmann","year":"2024","journal-title":"Turk. J. Immunol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s13195-024-01529-1","article-title":"Assessing blood-brain barrier dysfunction and its association with Alzheimer\u2019s pathology, cognitive impairment and neuroinflammation","volume":"16","author":"Preis","year":"2024","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_176","doi-asserted-by":"crossref","unstructured":"Mayer, M.G., and Fischer, T. (2024). Microglia at the blood brain barrier in health and disease. Front. Cell. Neurosci., 18.","DOI":"10.3389\/fncel.2024.1360195"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41392-023-01486-5","article-title":"Role of neuroinflammation in neurodegeneration development","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1186\/s12974-020-01930-1","article-title":"Transgenic inhibition of astroglial NF-\u03baB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma","volume":"17","author":"Yang","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_179","doi-asserted-by":"crossref","unstructured":"Garcia-Garcia, V.A., Alameda, J.P., Page, A., and Casanova, M.L. (2021). Role of NF-\u03baB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models. Cells, 10.","DOI":"10.3390\/cells10081906"},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Matejuk, A., and Ransohoff, R.M. (2020). Crosstalk Between Astrocytes and Microglia: An Overview. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01416"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/glia.24295","article-title":"Microglia and astrocyte activation is region-dependent in the \u03b1-synuclein mouse model of Parkinson\u2019s disease","volume":"71","author":"Basurco","year":"2023","journal-title":"Glia"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/jnr.25167","article-title":"The association of astrogliosis and microglial activation with aging and Alzheimer\u2019s disease pathology in the chimpanzee brain","volume":"101","author":"Edler","year":"2023","journal-title":"J. Neurosci. Res."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"5497046","DOI":"10.1155\/2020\/5497046","article-title":"Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress","volume":"2020","author":"Hohn","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1111\/cns.13116","article-title":"Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure","volume":"25","author":"Wang","year":"2019","journal-title":"CNS Neurosci. Ther."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s12640-018-9957-4","article-title":"Mutual Antagonism of PINK1\/Parkin and PGC-1\u03b1 Contributes to Maintenance of Mitochondrial Homeostasis in Rotenone-Induced Neurotoxicity","volume":"35","author":"Peng","year":"2019","journal-title":"Neurotox. Res."},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Van Acker, Z.P., Leroy, T., and Annaert, W. (2025). Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?. Bioessays, 47.","DOI":"10.1002\/bies.202400023"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"4902","DOI":"10.1038\/s41380-023-02251-4","article-title":"Mitochondrial DNA damage triggers spread of Parkinson\u2019s disease-like pathology","volume":"28","author":"Tresse","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_188","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Liu, B., Xu, L., Yu, S., Fu, J., Wang, J., Yan, X., and Su, J. (2021). ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression. Antioxidants, 10.","DOI":"10.3390\/antiox10121917"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1038\/s41467-022-30178-x","article-title":"Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism","volume":"13","author":"Huang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_190","doi-asserted-by":"crossref","unstructured":"Yan, X., Wang, B., Hu, Y., Wang, S., and Zhang, X. (2020). Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.00138"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40035-021-00278-7","article-title":"Excitotoxicity, calcium and mitochondria: A triad in synaptic neurodegeneration","volume":"11","author":"Verma","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_192","doi-asserted-by":"crossref","unstructured":"Brassard, R., Arutyunova, E., Takyi, E., Espinoza-Fonseca, L.M., Young, H.S., Touret, N., and Lemieux, M.J. (2025). Transmembrane Parkinson\u2019s disease mutation of PINK1 leads to altered mitochondrial anchoring. J. Biol. Chem., 301.","DOI":"10.1016\/j.jbc.2025.108253"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1038\/s41467-023-36945-8","article-title":"TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport","volume":"14","author":"Canty","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"4578","DOI":"10.1038\/s41467-021-24862-7","article-title":"Mitochondrial adaptor TRAK2 activates and functionally links opposing kinesin and dynein motors","volume":"12","author":"Fenton","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"102577","DOI":"10.1016\/j.arr.2024.102577","article-title":"Mitochondrial dysfunction as a therapeutic strategy for neurodegenerative diseases: Current insights and future directions","volume":"102","author":"Gu","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1080\/13543784.2020.1738383","article-title":"Brain insulin resistance: Role in neurodegenerative disease and potential for targeting","volume":"29","author":"Holscher","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"e20230032","DOI":"10.1590\/1980-5764-dn-2023-0032","article-title":"Brain insulin resistance and Alzheimer\u2019s disease: A systematic review","volume":"18","author":"Andrade","year":"2024","journal-title":"Dement. Neuropsychol."},{"key":"ref_198","doi-asserted-by":"crossref","unstructured":"Ansari, M.A., Al-Jarallah, A., and Babiker, F.A. (2023). Impaired Insulin Signaling Alters Mediators of Hippocampal Synaptic Dynamics\/Plasticity: A Possible Mechanism of Hyperglycemia-Induced Cognitive Impairment. Cells, 12.","DOI":"10.3390\/cells12131728"},{"key":"ref_199","doi-asserted-by":"crossref","unstructured":"Kleinridders, A. (2016). Deciphering Brain Insulin Receptor and Insulin-Like Growth Factor 1 Receptor Signalling. J. Neuroendocrinol., 28.","DOI":"10.1111\/jne.12433"},{"key":"ref_200","doi-asserted-by":"crossref","unstructured":"Pomytkin, I., and Pinelis, V. (2021). Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions. Life, 11.","DOI":"10.20944\/preprints202103.0372.v1"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.cmet.2018.08.014","article-title":"The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality","volume":"28","author":"Chaudhuri","year":"2018","journal-title":"Cell Metab."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.brainres.2015.04.026","article-title":"Exogenous \u03b2-amyloid peptide interferes with GLUT4 localization in neurons","volume":"1615","author":"Oliveira","year":"2015","journal-title":"Brain Res."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"788","DOI":"10.2337\/dc20-1549","article-title":"Insulin Resistance Is Associated with Enhanced Brain Glucose Uptake During Euglycemic Hyperinsulinemia: A Large-Scale PET Cohort","volume":"44","author":"Rebelos","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1038\/s41467-022-29722-6","article-title":"Insulin action and resistance are dependent on a GSK3\u03b2-FBXW7-ERR\u03b1 transcriptional axis","volume":"13","author":"Xia","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_205","doi-asserted-by":"crossref","unstructured":"Lauretti, E., Dincer, O., and Pratico, D. (2020). Glycogen synthase kinase-3 signaling in Alzheimer\u2019s disease. Biochim. Biophys. Acta Mol. Cell Res., 1867.","DOI":"10.1016\/j.bbamcr.2020.118664"},{"key":"ref_206","doi-asserted-by":"crossref","unstructured":"Sripetchwandee, J., Chattipakorn, N., and Chattipakorn, S.C. (2018). Links Between Obesity-Induced Brain Insulin Resistance, Brain Mitochondrial Dysfunction, and Dementia. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00496"},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"e01577","DOI":"10.1002\/brb3.1577","article-title":"Neurodegeneration in type 2 diabetes: Alzheimer\u2019s as a case study","volume":"10","author":"Madhusudhanan","year":"2020","journal-title":"Brain Behav."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s40265-016-0674-0","article-title":"Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer\u2019s Disease","volume":"77","year":"2017","journal-title":"Drugs"},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"e14821","DOI":"10.1111\/dme.14821","article-title":"Metformin and the risk of neurodegenerative diseases in patients with diabetes: A meta-analysis of population-based cohort studies","volume":"39","author":"Zhang","year":"2022","journal-title":"Diabet. Med."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"e024954","DOI":"10.1136\/bmjopen-2018-024954","article-title":"Effect of metformin on neurodegenerative disease among elderly adult US veterans with type 2 diabetes mellitus","volume":"9","author":"Shi","year":"2019","journal-title":"BMJ Open"},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ibneur.2022.12.006","article-title":"Molecular mechanisms underlying hyperglycemia associated cognitive decline","volume":"14","author":"Gupta","year":"2023","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.2337\/dc20-2881","article-title":"Comment on Samara et al. Metformin Use Is Associated with Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults with Type 2 Diabetes: The Sydney Memory and Ageing Study. Diabetes Care 2020;43:2691\u20132701","volume":"44","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_213","doi-asserted-by":"crossref","unstructured":"Khezri, M.R., Yousefi, K., Mahboubi, N., Hodaei, D., and Ghasemnejad-Berenji, M. (2022). Metformin in Alzheimer\u2019s disease: An overview of potential mechanisms, preclinical and clinical findings. Biochem. Pharmacol., 197.","DOI":"10.1016\/j.bcp.2022.114945"},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1007\/s10787-022-01043-6","article-title":"Metformin improves depressive-like behavior in experimental Parkinson\u2019s disease by inducing autophagy in the substantia nigra and hippocampus","volume":"30","author":"Mendonca","year":"2022","journal-title":"Inflammopharmacology"},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"e35752","DOI":"10.1016\/j.heliyon.2024.e35752","article-title":"Effects of chronic treatment with metformin on brain glucose hypometabolism and central insulin actions in transgenic mice with tauopathy","volume":"10","author":"Velazquez","year":"2024","journal-title":"Heliyon"},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1093\/bjd\/ljad305","article-title":"Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa","volume":"189","author":"Petrasca","year":"2023","journal-title":"Br. J. Dermatol."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/gtc.13098","article-title":"The anti-inflammatory effect of metformin: The molecular targets","volume":"29","author":"Sakata","year":"2024","journal-title":"Genes Cells"},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41392-023-01400-z","article-title":"Diabetic vascular diseases: Molecular mechanisms and therapeutic strategies","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_219","doi-asserted-by":"crossref","unstructured":"Chavda, V., Yadav, D., Patel, S., and Song, M. (2024). Effects of a Diabetic Microenvironment on Neurodegeneration: Special Focus on Neurological Cells. Brain Sci., 14.","DOI":"10.3390\/brainsci14030284"},{"key":"ref_220","doi-asserted-by":"crossref","unstructured":"Cui, W., Lv, C., Geng, P., Fu, M., Zhou, W., Xiong, M., and Li, T. (2024). Novel targets and therapies of metformin in dementia: Old drug, new insights. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1415740"},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"e2335","DOI":"10.1002\/brb3.2335","article-title":"Neuroprotective effects of metformin on cerebral ischemia-reperfusion injury by regulating PI3K\/Akt pathway","volume":"11","author":"Ruan","year":"2021","journal-title":"Brain Behav."},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.3233\/JAD-180263","article-title":"Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis","volume":"65","author":"Campbell","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_223","doi-asserted-by":"crossref","unstructured":"Papini, N., Giussani, P., and Tringali, C. (2024). Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168884"},{"key":"ref_224","doi-asserted-by":"crossref","unstructured":"Rotermund, C., Machetanz, G., and Fitzgerald, J.C. (2018). The Therapeutic Potential of Metformin in Neurodegenerative Diseases. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00400"},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"Rena","year":"2017","journal-title":"Diabetologia"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"e224","DOI":"10.1038\/emm.2016.16","article-title":"AMPK activators: Mechanisms of action and physiological activities","volume":"48","author":"Kim","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"3907","DOI":"10.1073\/pnas.0807991106","article-title":"Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer\u2019s amyloid peptides via up-regulating BACE1 transcription","volume":"106","author":"Chen","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.3233\/JAD-151200","article-title":"Metformin Facilitates Amyloid-\u03b2 Generation by \u03b2- and \u03b3-Secretases via Autophagy Activation","volume":"51","author":"Son","year":"2016","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.bbrc.2019.12.074","article-title":"Metformin reduces prion infection in neuronal cells by enhancing autophagy","volume":"523","author":"Abdelaziz","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.bbrc.2016.05.148","article-title":"Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury","volume":"477","author":"Wang","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_231","doi-asserted-by":"crossref","unstructured":"Tayara, K., Espinosa-Oliva, A.M., Garcia-Dominguez, I., Ismaiel, A.A., Boza-Serrano, A., Deierborg, T., Machado, A., Herrera, A.J., Venero, J.L., and de Pablos, R.M. (2018). Divergent Effects of Metformin on an Inflammatory Model of Parkinson\u2019s Disease. Front. Cell. Neurosci., 12.","DOI":"10.3389\/fncel.2018.00440"},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s12035-014-8866-7","article-title":"Chronic Metformin Preconditioning Provides Neuroprotection via Suppression of NF-\u03baB-Mediated Inflammatory Pathway in Rats with Permanent Cerebral Ischemia","volume":"52","author":"Zhu","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_233","doi-asserted-by":"crossref","unstructured":"Sportelli, C., Urso, D., Jenner, P., and Chaudhuri, K.R. (2020). Metformin as a Potential Neuroprotective Agent in Prodromal Parkinson\u2019s Disease-Viewpoint. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.00556"},{"key":"ref_234","doi-asserted-by":"crossref","unstructured":"Taheri, M., Roghani, M., and Sedaghat, R. (2024). Metformin Mitigates Trimethyltin-Induced Cognition Impairment and Hippocampal Neurodegeneration. Cell. Mol. Neurobiol., 44.","DOI":"10.1007\/s10571-024-01502-4"},{"key":"ref_235","doi-asserted-by":"crossref","unstructured":"Li, H., Liu, R., Liu, J., and Qu, Y. (2024). The Role and Mechanism of Metformin in the Treatment of Nervous System Diseases. Biomolecules, 14.","DOI":"10.3390\/biom14121579"},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/WAD.0000000000000202","article-title":"Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study","volume":"31","author":"Koenig","year":"2017","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"S355","DOI":"10.3233\/JAD-230899","article-title":"Effect of Metformin on Plasma and Cerebrospinal Fluid Biomarkers in Non-Diabetic Older Adults with Mild Cognitive Impairment Related to Alzheimer\u2019s Disease","volume":"99","author":"Weinberg","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_238","doi-asserted-by":"crossref","unstructured":"Poor, S.R., Ettcheto, M., Cano, A., Sanchez-Lopez, E., Manzine, P.R., Olloquequi, J., Camins, A., and Javan, M. (2021). Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer\u2019s Disease Treatment. Pharmaceuticals, 14.","DOI":"10.3390\/ph14090890"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s40001-023-01628-z","article-title":"Causal relationships between type 1 diabetes mellitus and Alzheimer\u2019s disease and Parkinson\u2019s disease: A bidirectional two-sample Mendelian randomization study","volume":"29","author":"Geng","year":"2024","journal-title":"Eur. J. Med. Res."},{"key":"ref_240","doi-asserted-by":"crossref","unstructured":"Szablewski, L. (2025). Associations Between Diabetes Mellitus and Neurodegenerative Diseases. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020542"},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/S2213-8587(13)70192-X","article-title":"Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: A post-hoc analysis of the Whitehall II cohort study","volume":"2","author":"Tuligenga","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_242","doi-asserted-by":"crossref","unstructured":"Wu, J., Fang, Y., Tan, X., Kang, S., Yue, X., Rao, Y., Huang, H., Liu, M., Qiu, S., and Yap, P.T. (2023). Detecting type 2 diabetes mellitus cognitive impairment using whole-brain functional connectivity. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-28163-5"},{"key":"ref_243","doi-asserted-by":"crossref","unstructured":"Chatterjee, S., and Mudher, A. (2018). Alzheimer\u2019s Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00383"},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1212\/WNL.0000000000004586","article-title":"Metformin vs sulfonylurea use and risk of dementia in US veterans aged \u226565 years with diabetes","volume":"89","author":"Orkaby","year":"2017","journal-title":"Neurology"},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1007\/s11357-022-00568-6","article-title":"Diabetic patients treated with metformin during early stages of Alzheimer\u2019s disease show a better integral performance: Data from ADNI study","volume":"44","author":"Pomilio","year":"2022","journal-title":"Geroscience"},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.3233\/JAD-220180","article-title":"Association Between Metformin and Alzheimer\u2019s Disease: A Systematic Review and Meta-Analysis of Clinical Observational Studies","volume":"88","author":"Luo","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1002\/alz.13480","article-title":"Heterogeneous treatment effects of metformin on risk of dementia in patients with type 2 diabetes: A longitudinal observational study","volume":"20","author":"Tang","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13195-023-01355-x","article-title":"A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: The MET-FINGER randomised controlled trial protocol","volume":"16","author":"Barbera","year":"2024","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_249","unstructured":"(2025, March 13). NCT00620191, Metformin in Amnestic Mild Cognitive Impairment (MCI), Jos\u00e9 A. Luchsinger, Columbia University, Available online: https:\/\/clinicaltrials.gov\/study\/NCT00620191."},{"key":"ref_250","unstructured":"(2025, March 13). NCT01965756, Effect of Insulin Sensitizer Metformin on AD Biomarkers, University of Pennsylvania, Available online: https:\/\/clinicaltrials.gov\/study\/NCT01965756."},{"key":"ref_251","unstructured":"(2025, March 13). NCT03757910; Brain Imaging in the Diabetes Prevention Program Outcomes Study (DPPOS-Brain), Jos\u00e9 A. Luchsinger, Columbia University, Available online: https:\/\/clinicaltrials.gov\/study\/NCT03757910."},{"key":"ref_252","doi-asserted-by":"crossref","unstructured":"Isop, L.M., Neculau, A.E., Necula, R.D., Kakucs, C., Moga, M.A., and Dima, L. (2023). Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders. Pharmaceuticals, 16.","DOI":"10.3390\/ph16121714"},{"key":"ref_253","doi-asserted-by":"crossref","unstructured":"El-Ghaiesh, S.H., Bahr, H.I., Ibrahiem, A.T., Ghorab, D., Alomar, S.Y., Farag, N.E., and Zaitone, S.A. (2020). Metformin Protects From Rotenone-Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis. Front. Mol. Neurosci., 13.","DOI":"10.3389\/fnmol.2020.00084"},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"eadd0499","DOI":"10.1126\/scitranslmed.add0499","article-title":"Enhanced mTORC1 signaling and protein synthesis in pathologic \u03b1-synuclein cellular and animal models of Parkinson\u2019s disease","volume":"15","author":"Khan","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_255","first-page":"582","article-title":"Parkin functionally interacts with PGC-1\u03b1 to preserve mitochondria and protect dopaminergic neurons","volume":"26","author":"Zheng","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_256","doi-asserted-by":"crossref","first-page":"e003036","DOI":"10.1136\/bmjdrc-2022-003036","article-title":"Comparative effect of metformin versus sulfonylureas with dementia and Parkinson\u2019s disease risk in US patients over 50 with type 2 diabetes mellitus","volume":"10","author":"Newby","year":"2022","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_257","doi-asserted-by":"crossref","unstructured":"Huang, K.H., Chang, Y.L., Gau, S.Y., Tsai, T.H., and Lee, C.Y. (2022). Dose-Response Association of Metformin with Parkinson\u2019s Disease Odds in Type 2 Diabetes Mellitus. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14050946"},{"key":"ref_258","doi-asserted-by":"crossref","first-page":"107132","DOI":"10.1016\/j.parkreldis.2024.107132","article-title":"Anti-diabetic drug use and reduced risk of Parkinson\u2019s disease: A community-based cohort study","volume":"128","author":"Rozani","year":"2024","journal-title":"Park. Relat. Disord."},{"key":"ref_259","unstructured":"(2025, March 13). NCT03685357; Correlation Between Idiopathic Parkinson\u2019s Disease and Diabetes Mellitus, Afnan Awad-Allah Elgnainy, Ain Shams University, Available online: https:\/\/www.clinicaltrials.gov\/study\/NCT03685357."},{"key":"ref_260","doi-asserted-by":"crossref","unstructured":"Boi, L., Pisanu, A., Palmas, M.F., Fusco, G., Carboni, E., Casu, M.A., Satta, V., Scherma, M., Janda, E., and Mocci, I. (2020). Modeling Parkinson\u2019s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human \u03b1-Synuclein Oligomers. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228535"},{"key":"ref_261","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/s41531-024-00798-9","article-title":"Circadian disruption promotes the neurotoxicity of oligomeric \u03b1-synuclein in mice","volume":"10","author":"Zhang","year":"2024","journal-title":"NPJ Park. Dis."},{"key":"ref_262","doi-asserted-by":"crossref","first-page":"e1209","DOI":"10.1038\/cddis.2014.175","article-title":"Metformin lowers Ser-129 phosphorylated \u03b1-synuclein levels via mTOR-dependent protein phosphatase 2A activation","volume":"5","author":"Hettich","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.neuropharm.2017.08.015","article-title":"Metformin lowers \u03b1-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson\u2019s disease","volume":"125","author":"Katila","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_264","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1038\/s41467-023-38401-z","article-title":"Redefining the role of AMPK in autophagy and the energy stress response","volume":"14","author":"Park","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_265","doi-asserted-by":"crossref","first-page":"26438","DOI":"10.1073\/pnas.2009838117","article-title":"Metformin rescues Parkinson\u2019s disease phenotypes caused by hyperactive mitochondria","volume":"117","author":"Mor","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_266","first-page":"3830861","article-title":"Evaluation of the Combination of Metformin and Rapamycin in an MPP(+)-Treated SH-SY5Y Model of Parkinson\u2019s Disease","volume":"2023","author":"Norradee","year":"2023","journal-title":"Adv. Pharmacol. Pharm. Sci."},{"key":"ref_267","doi-asserted-by":"crossref","first-page":"e001370","DOI":"10.1136\/bmjdrc-2020-001370","article-title":"Association between metformin and neurodegenerative diseases of observational studies: Systematic review and meta-analysis","volume":"8","author":"Ping","year":"2020","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_268","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1007\/s43440-020-00095-1","article-title":"Metformin protects rotenone-induced dopaminergic neurodegeneration by reducing lipid peroxidation","volume":"72","author":"Ozbey","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_269","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.neures.2019.12.017","article-title":"Neuroprotective effect of metformin on dopaminergic neurodegeneration and \u03b1-synuclein aggregation in C. elegans model of Parkinson\u2019s disease","volume":"162","author":"Saewanee","year":"2021","journal-title":"Neurosci. Res."},{"key":"ref_270","doi-asserted-by":"crossref","unstructured":"Van de Roovaart, H.J., Nguyen, N., and Veenstra, T.D. (2023). Huntington\u2019s Disease Drug Development: A Phase 3 Pipeline Analysis. Pharmaceuticals, 16.","DOI":"10.3390\/ph16111513"},{"key":"ref_271","doi-asserted-by":"crossref","first-page":"e38744","DOI":"10.7554\/eLife.38744","article-title":"Metformin reverses early cortical network dysfunction and behavior changes in Huntington\u2019s disease","volume":"7","author":"Arnoux","year":"2018","journal-title":"eLife"},{"key":"ref_272","doi-asserted-by":"crossref","first-page":"111670","DOI":"10.1016\/j.mad.2022.111670","article-title":"Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder","volume":"204","author":"Castera","year":"2022","journal-title":"Mech. Ageing Dev."},{"key":"ref_273","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s12017-016-8412-z","article-title":"Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics","volume":"18","author":"Jin","year":"2016","journal-title":"Neuromol. Med."},{"key":"ref_274","doi-asserted-by":"crossref","unstructured":"Ameen, O., Samaka, R.M., and Abo-Elsoud, R.A.A. (2022). Metformin alleviates neurocognitive impairment in aging via activation of AMPK\/BDNF\/PI3K pathway. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-20945-7"},{"key":"ref_275","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0264-9","article-title":"Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease","volume":"51","author":"Sanchis","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_276","doi-asserted-by":"crossref","unstructured":"Hervas, D., Fornes-Ferrer, V., Gomez-Escribano, A.P., Sequedo, M.D., Peiro, C., Millan, J.M., and Vazquez-Manrique, R.P. (2017). Metformin intake associates with better cognitive function in patients with Huntington\u2019s disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179283"},{"key":"ref_277","doi-asserted-by":"crossref","unstructured":"Narine, M., Azmi, M.A., Umali, M., Volz, A., and Colognato, H. (2023). The AMPK activator metformin improves recovery from demyelination by shifting oligodendrocyte bioenergetics and accelerating OPC differentiation. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1254303"},{"key":"ref_278","doi-asserted-by":"crossref","first-page":"102193","DOI":"10.1016\/j.coph.2022.102193","article-title":"The mechanistic target of rapamycin as a regulator of metabolic function in oligodendroglia during remyelination","volume":"63","author":"Mather","year":"2022","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_279","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/S0140-6736(18)30481-1","article-title":"Multiple sclerosis","volume":"391","author":"Thompson","year":"2018","journal-title":"Lancet"},{"key":"ref_280","doi-asserted-by":"crossref","unstructured":"Ursini, F., Russo, E., Pellino, G., D\u2019Angelo, S., Chiaravalloti, A., De Sarro, G., Manfredini, R., and De Giorgio, R. (2018). Metformin and Autoimmunity: A \u201cNew Deal\u201d of an Old Drug. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01236"},{"key":"ref_281","doi-asserted-by":"crossref","unstructured":"De Keersmaecker, A.V., Van Doninck, E., Popescu, V., Willem, L., Cambron, M., Laureys, G., D\u2019 Haeseleer, M., Bjerke, M., Roelant, E., and Lemmerling, M. (2024). A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): Study protocol for a multi-center randomized placebo controlled clinical trial. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1362629"},{"key":"ref_282","doi-asserted-by":"crossref","first-page":"148648","DOI":"10.1016\/j.brainres.2023.148648","article-title":"Metformin treatment reduces inflammation, dysmyelination and disease severity in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis","volume":"1822","author":"Gilbert","year":"2024","journal-title":"Brain Res."},{"key":"ref_283","doi-asserted-by":"crossref","first-page":"e230016","DOI":"10.57264\/cer-2023-0016","article-title":"Comparative efficacy of therapies for relapsing multiple sclerosis: A systematic review and network meta-analysis","volume":"12","author":"Samjoo","year":"2023","journal-title":"J. Comp. Eff. Res."},{"key":"ref_284","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1001\/jamaneurol.2015.4807","article-title":"Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis","volume":"73","author":"Negrotto","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_285","doi-asserted-by":"crossref","first-page":"e31230","DOI":"10.1002\/jcp.31230","article-title":"AMP-activated protein kinase as a mediator of mitochondrial dysfunction of multiple sclerosis in animal models: A systematic review","volume":"239","author":"Askari","year":"2024","journal-title":"J. Cell. Physiol."},{"key":"ref_286","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1111\/febs.16151","article-title":"AMPK in the brain: Its roles in glucose and neural metabolism","volume":"289","author":"Muraleedharan","year":"2022","journal-title":"FEBS J."},{"key":"ref_287","doi-asserted-by":"crossref","unstructured":"Lepez, A., Pirnay, T., Denanglaire, S., Perez-Morga, D., Vermeersch, M., Leo, O., and Andris, F. (2020). Long-term T cell fitness and proliferation is driven by AMPK-dependent regulation of reactive oxygen species. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-78715-2"},{"key":"ref_288","doi-asserted-by":"crossref","unstructured":"Wei, J., Raynor, J., Nguyen, T.L., and Chi, H. (2017). Nutrient and Metabolic Sensing in T Cell Responses. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00247"},{"key":"ref_289","doi-asserted-by":"crossref","unstructured":"Vakrakou, A.G., Alexaki, A., Brinia, M.E., Anagnostouli, M., Stefanis, L., and Stathopoulos, P. (2022). The mTOR Signaling Pathway in Multiple Sclerosis; from Animal Models to Human Data. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158077"},{"key":"ref_290","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s43440-019-00019-8","article-title":"Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK\/Nrf2\/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period","volume":"72","author":"Sanadgol","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_291","doi-asserted-by":"crossref","unstructured":"Zarrouk, M., Finlay, D.K., Foretz, M., Viollet, B., and Cantrell, D.A. (2014). Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106710"},{"key":"ref_292","doi-asserted-by":"crossref","unstructured":"Frasca, D., Diaz, A., Romero, M., and Blomberg, B.B. (2021). Metformin Enhances B Cell Function and Antibody Responses of Elderly Individuals with Type-2 Diabetes Mellitus. Front. Aging, 2.","DOI":"10.3389\/fragi.2021.715981"},{"key":"ref_293","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1038\/s41401-021-00759-5","article-title":"Metformin promotes microglial cells to facilitate myelin debris clearance and accelerate nerve repairment after spinal cord injury","volume":"43","author":"Wu","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_294","doi-asserted-by":"crossref","first-page":"92","DOI":"10.15616\/BSL.2019.25.1.92","article-title":"Anti-inflammatory Effects of Metformin on Neuro-inflammation and NLRP3 Inflammasome Activation in BV-2 Microglial Cells","volume":"25","author":"Ha","year":"2019","journal-title":"Biomed. Sci. Lett."},{"key":"ref_295","doi-asserted-by":"crossref","unstructured":"Liao, W., Xu, J., Li, B., Ruan, Y., Li, T., and Liu, J. (2021). Deciphering the Roles of Metformin in Alzheimer\u2019s Disease: A Snapshot. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.728315"},{"key":"ref_296","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1007\/s00415-023-12113-2","article-title":"The impact of metformin use on the outcomes of relapse-remitting multiple sclerosis patients receiving interferon beta 1a: An exploratory prospective phase II open-label randomized controlled trial","volume":"271","author":"Abdelgaied","year":"2024","journal-title":"J. Neurol."},{"key":"ref_297","unstructured":"(2025, March 13). NCT04121468; A Phase I Double Blind Study of Metformin Acting on Endogenous Neural Progenitor Cells in Children with Multiple Sclerosis, E. Ann Yeh, The Hospital for Sick Children, Available online: https:\/\/clinicaltrials.gov\/study\/NCT04121468?cond=Multiple%20Sclerosis&intr=Metformin&rank=1."},{"key":"ref_298","unstructured":"(2025, March 13). NCT06463743; Metformin as an Add-On or Monotherapy in Treatment of Aging People with Multiple Sclerosis (MS), Bianca Weinstock-Guttman, State University of New York at Buffalo, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06463743?cond=Multiple%20Sclerosis&intr=Metformin&rank=2."},{"key":"ref_299","unstructured":"(2025, March 13). NCT05893225; Metformin Add-On Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination and Neurodegeneration, University Hospital, Antwerp, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05893225?cond=Multiple%20Sclerosis&intr=Metformin&rank=3."},{"key":"ref_300","unstructured":"(2025, March 13). NCT06812585; The Effect of Metformin as an Adjuvant Therapy on Immunological Parameters in Egyptian Patients with RRMS: A Pilot Study, Mohamed Youssef Elsayed, German University in Cairo, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06812585?cond=Multiple%20Sclerosis&intr=Metformin&rank=4."},{"key":"ref_301","unstructured":"(2025, March 13). NCT05131828; CCMR Two: A Phase IIa, Randomised, Double-Blind, Placebo-Controlled Trial of the Ability of the Combination of Metformin and Clemastine to Promote Remyelination in People with Relapsing-Remitting Multiple Sclerosis Already on Disease-modifying Therapy, Nicholas Cunniffe, Cambridge University Hospitals NHS Foundation Trust, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05131828?cond=Multiple%20Sclerosis&intr=Metformin&rank=5."},{"key":"ref_302","unstructured":"(2025, March 13). NCT05298670; Drug Repurposing Using Metformin for Improving the Therapeutic Outcome in Multiple Sclerosis Patients, Mohamed Youssef Elsayed, German University in Cairo, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05298670?cond=Multiple%20Sclerosis&intr=Metformin&rank=6."},{"key":"ref_303","unstructured":"(2025, March 13). NCT05349474; Metformin Treatment in Progressive Multiple Sclerosis, Kevin Patel, University of California, Los Angeles, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05349474?cond=Multiple%20Sclerosis&intr=Metformin&rank=7."},{"key":"ref_304","first-page":"360","article-title":"Metformin improves memory via AMPK\/mTOR-dependent route in a rat model of Alzheimer\u2019s disease","volume":"27","author":"Babaei","year":"2024","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_305","doi-asserted-by":"crossref","unstructured":"Rai, S.N., Singh, P., Steinbusch, H.W.M., Vamanu, E., Ashraf, G., and Singh, M.P. (2021). The Role of Vitamins in Neurodegenerative Disease: An Update. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101284"},{"key":"ref_306","doi-asserted-by":"crossref","unstructured":"Ha, J., Choi, D.W., Kim, K.J., Cho, S.Y., Kim, H., Kim, K.Y., Koh, Y., Nam, C.M., and Kim, E. (2021). Association of metformin use with Alzheimer\u2019s disease in patients with newly diagnosed type 2 diabetes: A population-based nested case-control study. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-03406-5"},{"key":"ref_307","doi-asserted-by":"crossref","first-page":"216","DOI":"10.12775\/JEHS.2023.46.01.015","article-title":"The effect of antioxidants on the course and prevention of Alzheimer\u2019s disease on the example of vitamin E","volume":"46","author":"Cholewa","year":"2023","journal-title":"J. Educ. Health Sport"},{"key":"ref_308","doi-asserted-by":"crossref","first-page":"745","DOI":"10.2337\/db08-1028","article-title":"Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: A preliminary study","volume":"58","author":"Becker","year":"2009","journal-title":"Diabetes"},{"key":"ref_309","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.diabres.2015.05.003","article-title":"SLC47A1 gene rs2289669 G>A variants enhance the glucose-lowering effect of metformin via delaying its excretion in Chinese type 2 diabetes patients","volume":"109","author":"He","year":"2015","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_310","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/ng.2236","article-title":"The role of ATM in response to metformin treatment and activation of AMPK","volume":"44","author":"Yee","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_311","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1056\/NEJMoa066224","article-title":"Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy","volume":"355","author":"Kahn","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_312","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1177\/193229681300700112","article-title":"A novel fasting blood test for insulin resistance and prediabetes","volume":"7","author":"Cobb","year":"2013","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_313","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/j.1464-5491.2005.01755.x","article-title":"The effect of obesity on glycaemic response to metformin or sulphonylureas in Type 2 diabetes","volume":"23","author":"Donnelly","year":"2006","journal-title":"Diabet. Med."},{"key":"ref_314","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1139\/H07-100","article-title":"Non-obese patients with type 2 diabetes and prediabetic subjects: Distinct phenotypes requiring special diabetes treatment and (or) prevention?","volume":"32","author":"Vaag","year":"2007","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_315","doi-asserted-by":"crossref","first-page":"705","DOI":"10.2337\/dc17-1827","article-title":"Precision Medicine in Type 2 Diabetes: Clinical Markers of Insulin Resistance Are Associated with Altered Short- and Long-term Glycemic Response to DPP-4 Inhibitor Therapy","volume":"41","author":"Dennis","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_316","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1056\/NEJMoa012512","article-title":"Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin","volume":"346","author":"Knowler","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_317","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13024-022-00524-0","article-title":"Solving neurodegeneration: Common mechanisms and strategies for new treatments","volume":"17","author":"Wareham","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_318","doi-asserted-by":"crossref","unstructured":"D\u2019Ambrosi, N., Cozzolino, M., and Apolloni, S. (2022). The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges. Cells, 11.","DOI":"10.3390\/cells11020193"},{"key":"ref_319","doi-asserted-by":"crossref","first-page":"4138","DOI":"10.7150\/thno.83066","article-title":"New strategies of neurodegenerative disease treatment with extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs)","volume":"13","author":"Palanisamy","year":"2023","journal-title":"Theranostics"},{"key":"ref_320","first-page":"567","article-title":"CRISPR\/Cas9 genome editing for neurodegenerative diseases","volume":"22","author":"Erguder","year":"2023","journal-title":"EXCLI J."},{"key":"ref_321","doi-asserted-by":"crossref","first-page":"261","DOI":"10.4155\/fmc-2018-0249","article-title":"Multitarget-directed ligands for neurodegenerative diseases: Real opportunity or blurry mirage?","volume":"11","author":"Benchekroun","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_322","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41593-020-00778-1","article-title":"Gene-based therapies for neurodegenerative diseases","volume":"24","author":"Sun","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_323","doi-asserted-by":"crossref","first-page":"e70050","DOI":"10.1111\/cns.70050","article-title":"Antisense oligonucleotides as a precision therapy for developmental and epileptic encephalopathies","volume":"30","author":"Quilon","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_324","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.stem.2023.03.017","article-title":"Advancing cell therapy for neurodegenerative diseases","volume":"30","author":"Temple","year":"2023","journal-title":"Cell Stem Cell"},{"key":"ref_325","first-page":"e68921","article-title":"The Role of Wearable Devices in Chronic Disease Monitoring and Patient Care: A Comprehensive Review","volume":"16","author":"Jafleh","year":"2024","journal-title":"Cureus"},{"key":"ref_326","doi-asserted-by":"crossref","unstructured":"Wang, Y. (2024). Editorial: Understanding the link between lifestyle and neurodegenerative diseases. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1365734"},{"key":"ref_327","first-page":"e47861","article-title":"The Role of Gut Microbiota in Neurodegenerative Diseases: Current Insights and Therapeutic Implications","volume":"15","author":"Jain","year":"2023","journal-title":"Cureus"},{"key":"ref_328","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.bbamcr.2015.01.017","article-title":"Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-\u03baB activation: Use of insulin to attenuate metformin\u2019s effect","volume":"1853","author":"Picone","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_329","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.2337\/dc13-0229","article-title":"Increased risk of cognitive impairment in patients with diabetes is associated with metformin","volume":"36","author":"Moore","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_330","doi-asserted-by":"crossref","first-page":"37","DOI":"10.14336\/AD.2017.1202","article-title":"Metformin and the Risk of Dementia in Type 2 Diabetes Patients","volume":"10","year":"2019","journal-title":"Aging Dis."},{"key":"ref_331","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.pnpbp.2017.06.002","article-title":"Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus","volume":"79 Pt B","author":"Kuan","year":"2017","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_332","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.2337\/db14-0287","article-title":"Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease","volume":"63","author":"Yarchoan","year":"2014","journal-title":"Diabetes"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/4\/486\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:04:07Z","timestamp":1760029447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/4\/486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,28]]},"references-count":332,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ph18040486"],"URL":"https:\/\/doi.org\/10.3390\/ph18040486","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,28]]}}}