{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:01:09Z","timestamp":1793275269406,"version":"4.5.0"},"reference-count":89,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82293642"],"award-info":[{"award-number":["82293642"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82230043"],"award-info":[{"award-number":["82230043"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82201576"],"award-info":[{"award-number":["82201576"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Aging"],"DOI":"10.1038\/s43587-025-00869-3","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T10:14:40Z","timestamp":1747736080000},"page":"1097-1113","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Activation of AMPK by GLP-1R agonists mitigates Alzheimer-related phenotypes in transgenic mice"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5878-6939","authenticated-orcid":false,"given":"Yun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqiu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7668-7350","authenticated-orcid":false,"given":"Yijia","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhao","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sipei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Bestard-Lorigados","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yili","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9928-889X","authenticated-orcid":false,"given":"Weihong","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"869_CR1","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/s41392-023-01484-7","volume":"8","author":"Y Zhang","year":"2023","unstructured":"Zhang, Y., Chen, H., Li, R., Sterling, K. & Song, W. Amyloid \u03b2-based therapy for Alzheimer\u2019s disease: challenges, successes and future. Signal Transduct. Target. Ther. 8, 248 (2023).","journal-title":"Signal Transduct. Target. Ther."},{"key":"869_CR2","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.pneurobio.2017.03.001","volume":"153","author":"Y Zhang","year":"2017","unstructured":"Zhang, Y. & Song, W. Islet amyloid polypeptide: another key molecule in Alzheimer\u2019s pathogenesis? Prog. Neurobiol. 153, 100\u2013120 (2017).","journal-title":"Prog. Neurobiol."},{"key":"869_CR3","doi-asserted-by":"publisher","first-page":"1962","DOI":"10.1111\/ejn.12235","volume":"37","author":"Y Deng","year":"2013","unstructured":"Deng, Y. et al. Amyloid-\u03b2 protein (A\u03b2) Glu11 is the major \u03b2-secretase site of \u03b2-site amyloid-\u03b2 precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to A\u03b2 Asp1 contributes to Alzheimer pathogenesis. Eur. J. Neurosci. 37, 1962\u20131969 (2013).","journal-title":"Eur. J. Neurosci."},{"key":"869_CR4","doi-asserted-by":"publisher","first-page":"6915","DOI":"10.1523\/JNEUROSCI.0340-17.2017","volume":"37","author":"S Zhang","year":"2017","unstructured":"Zhang, S. et al. BACE1 cleavage site selection critical for amyloidogenesis and Alzheimer\u2019s pathogenesis. J. Neurosci. 37, 6915\u20136925 (2017).","journal-title":"J. Neurosci."},{"key":"869_CR5","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/34910","volume":"391","author":"B De Strooper","year":"1998","unstructured":"De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387\u2013390 (1998).","journal-title":"Nature"},{"key":"869_CR6","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/35017108","volume":"2","author":"Z Zhang","year":"2000","unstructured":"Zhang, Z. et al. Presenilins are required for \u03b3-secretase cleavage of \u03b2-APP and transmembrane cleavage of Notch-1. Nat. Cell Biol. 2, 463\u2013465 (2000).","journal-title":"Nat. Cell Biol."},{"key":"869_CR7","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1111\/jdi.12087","volume":"4","author":"K Gudala","year":"2013","unstructured":"Gudala, K., Bansal, D., Schifano, F. & Bhansali, A. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J. Diabetes Investig. 4, 640\u2013650 (2013).","journal-title":"J. Diabetes Investig."},{"key":"869_CR8","doi-asserted-by":"publisher","first-page":"e14443","DOI":"10.1002\/alz.14443","volume":"21","author":"Y Kang","year":"2025","unstructured":"Kang, Y. et al. Identification of circulating risk biomarkers for cognitive decline in a large community-based population in Chongqing China. Alzheimers Dement. 21, e14443 (2025).","journal-title":"Alzheimers Dement."},{"key":"869_CR9","doi-asserted-by":"publisher","first-page":"1435276","DOI":"10.1155\/2019\/1435276","volume":"2019","author":"A Rorbach-Dolata","year":"2019","unstructured":"Rorbach-Dolata, A. & Piwowar, A. Neurometabolic evidence supporting the hypothesis of increased incidence of type 3 diabetes mellitus in the 21st century. Biomed Res. Int. 2019, 1435276 (2019).","journal-title":"Biomed Res. Int."},{"key":"869_CR10","doi-asserted-by":"publisher","first-page":"3165","DOI":"10.3390\/ijms21093165","volume":"21","author":"TT Nguyen","year":"2020","unstructured":"Nguyen, T. T., Ta, Q. T. H., Nguyen, T. K. O., Nguyen, T. T. D. & Giau, V. V. Type 3 diabetes and its role implications in Alzheimer\u2019s disease. Int. J. Mol. Sci. 21, 3165 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"869_CR11","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1038\/s41420-023-01732-3","volume":"9","author":"D Bano","year":"2023","unstructured":"Bano, D., Ehninger, D. & Bagetta, G. Decoding metabolic signatures in Alzheimer\u2019s disease: a mitochondrial perspective. Cell Death Discov. 9, 432 (2023).","journal-title":"Cell Death Discov."},{"key":"869_CR12","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.neuroscience.2013.07.009","volume":"250","author":"Y Yang","year":"2013","unstructured":"Yang, Y. & Song, W. Molecular links between Alzheimer\u2019s disease and diabetes mellitus. Neuroscience 250, 140\u2013150 (2013).","journal-title":"Neuroscience"},{"key":"869_CR13","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1007\/s00259-005-1762-7","volume":"32","author":"L Mosconi","year":"2005","unstructured":"Mosconi, L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer\u2019s disease. FDG-PET studies in MCI and AD. Eur. J. Nucl. Med. Mol. Imaging 32, 486\u2013510 (2005).","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"869_CR14","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/nrneurol.2017.185","volume":"14","author":"SE Arnold","year":"2018","unstructured":"Arnold, S. E. et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14, 168\u2013181 (2018).","journal-title":"Nat. Rev. Neurol."},{"key":"869_CR15","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.dadm.2019.03.004","volume":"11","author":"B Delikkaya","year":"2019","unstructured":"Delikkaya, B., Moriel, N., Tong, M., Gallucci, G. & de la Monte, S. M. Altered expression of insulin-degrading enzyme and regulator of calcineurin in the rat intracerebral streptozotocin model and human apolipoprotein E-\u03b54-associated Alzheimer\u2019s disease. Alzheimers Dement. (Amst.) 11, 392\u2013404 (2019).","journal-title":"Alzheimers Dement. (Amst.)"},{"key":"869_CR16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0069824","volume":"8","author":"Y Yang","year":"2013","unstructured":"Yang, Y., Wu, Y., Zhang, S. & Song, W. High glucose promotes A\u03b2 production by inhibiting APP degradation. PLoS ONE 8, e69824 (2013).","journal-title":"PLoS ONE"},{"key":"869_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2016.296","volume":"7","author":"E Lauretti","year":"2017","unstructured":"Lauretti, E., Li, J. G., Di Meco, A. & Pratico, D. Glucose deficit triggers tau pathology and synaptic dysfunction in a tauopathy mouse model. Transl. Psychiatry 7, e1020 (2017).","journal-title":"Transl. Psychiatry"},{"key":"869_CR18","doi-asserted-by":"publisher","first-page":"2614","DOI":"10.1007\/s11095-017-2199-y","volume":"34","author":"M Markowicz-Piasecka","year":"2017","unstructured":"Markowicz-Piasecka, M. et al. Metformin\u2014a future therapy for neurodegenerative diseases. Pharm. Res. 34, 2614\u20132627 (2017).","journal-title":"Pharm. Res."},{"key":"869_CR19","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1016\/S0140-6736(87)91194-9","volume":"2","author":"B Kreymann","year":"1987","unstructured":"Kreymann, B., Williams, G., Ghatei, M. A. & Bloom, S. R. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2, 1300\u20131304 (1987).","journal-title":"Lancet"},{"key":"869_CR20","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/0167-0115(95)00167-0","volume":"62","author":"JD Tucker","year":"1996","unstructured":"Tucker, J. D., Dhanvantari, S. & Brubaker, P. L. Proglucagon processing in islet and intestinal cell lines. Regul. Pept. 62, 29\u201335 (1996).","journal-title":"Regul. Pept."},{"key":"869_CR21","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1152\/physrev.00013.2014","volume":"95","author":"DA Sandoval","year":"2015","unstructured":"Sandoval, D. A. & D\u2019Alessio, D. A. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol. Rev. 95, 513\u2013548 (2015).","journal-title":"Physiol. Rev."},{"key":"869_CR22","first-page":"E981","volume":"273","author":"MA Nauck","year":"1997","unstructured":"Nauck, M. A. et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am. J. Physiol. 273, E981\u2013E988 (1997).","journal-title":"Am. J. Physiol."},{"key":"869_CR23","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.2337\/db13-1440","volume":"63","author":"P Richards","year":"2014","unstructured":"Richards, P. et al. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 63, 1224\u20131233 (2014).","journal-title":"Diabetes"},{"key":"869_CR24","doi-asserted-by":"publisher","first-page":"12412","DOI":"10.1002\/anie.201707200","volume":"56","author":"F Hausch","year":"2017","unstructured":"Hausch, F. Cryo-EM structures of class B GPCR reveal the activation mechanism. Angew. Chem. Int. Ed. Engl. 56, 12412\u201312414 (2017).","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"869_CR25","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.molmet.2019.09.010","volume":"30","author":"TD Muller","year":"2019","unstructured":"Muller, T. D. et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72\u2013130 (2019).","journal-title":"Mol. Metab."},{"key":"869_CR26","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1016\/j.ekir.2022.07.167","volume":"7","author":"DZI Cherney","year":"2022","unstructured":"Cherney, D. Z. I. et al. Hemoglobin A1c reduction with the GLP-1 receptor agonist semaglutide is independent of baseline eGFR: post hoc analysis of the SUSTAIN and PIONEER programs. Kidney Int. Rep. 7, 2345\u20132355 (2022).","journal-title":"Kidney Int. Rep."},{"key":"869_CR27","doi-asserted-by":"crossref","unstructured":"Rodriguez, P. J. et al. Semaglutide vs tirzepatide for weight loss in adults with overweight or obesity. JAMA Intern. Med. 184, 1056\u20131064 (2024).","DOI":"10.1001\/jamainternmed.2024.2525"},{"key":"869_CR28","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12268","volume":"8","author":"CH Norgaard","year":"2022","unstructured":"Norgaard, C. H. et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement. (N Y) 8, e12268 (2022).","journal-title":"Alzheimers Dement. (N Y)"},{"key":"869_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-020-04608-4","volume":"21","author":"GD Femminella","year":"2020","unstructured":"Femminella, G. D. et al. Correction to: Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer\u2019s disease: study protocol for a randomised controlled trial (ELAD study). Trials 21, 660 (2020).","journal-title":"Trials"},{"key":"869_CR30","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/j.bbrc.2017.11.114","volume":"495","author":"HY Cai","year":"2018","unstructured":"Cai, H. Y. et al. Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP\/PS1\/tau mouse model of Alzheimer\u2019s disease. Biochem. Biophys. Res. Commun. 495, 1034\u20131040 (2018).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"869_CR31","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.3390\/ijms21051746","volume":"21","author":"AI Duarte","year":"2020","unstructured":"Duarte, A. I. et al. Liraglutide protects against brain amyloid-\u03b21\u201342 accumulation in female mice with early Alzheimer\u2019s disease-like pathology by partially rescuing oxidative\/nitrosative stress and inflammation. Int. J. Mol. Sci. 21, 1746 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"869_CR32","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.neuropharm.2014.07.015","volume":"86","author":"PL McClean","year":"2014","unstructured":"McClean, P. L. & Holscher, C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer\u2019s disease. Neuropharmacology 86, 241\u2013258 (2014).","journal-title":"Neuropharmacology"},{"key":"869_CR33","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.2147\/NDT.S260160","volume":"16","author":"J Kong","year":"2020","unstructured":"Kong, J., Wan, L., Wang, Y., Zhang, H. & Zhang, W. Liraglutide attenuates A\u03b242 generation in APPswe\/SH-SY5Y cells through the regulation of autophagy. Neuropsychiatr. Dis. Treat. 16, 1817\u20131825 (2020).","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"869_CR34","doi-asserted-by":"publisher","first-page":"2781","DOI":"10.1084\/jem.20081588","volume":"205","author":"H Qing","year":"2008","unstructured":"Qing, H. et al. Valproic acid inhibits A\u03b2 production, neuritic plaque formation, and behavioral deficits in Alzheimer\u2019s disease mouse models. J. Exp. Med. 205, 2781\u20132789 (2008).","journal-title":"J. Exp. Med."},{"key":"869_CR35","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1172\/JCI64516","volume":"123","author":"PT Ly","year":"2013","unstructured":"Ly, P. T. et al. Inhibition of GSK3\u03b2-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J. Clin. Invest. 123, 224\u2013235 (2013).","journal-title":"J. Clin. Invest."},{"key":"869_CR36","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.ymgme.2010.12.005","volume":"102","author":"M He","year":"2011","unstructured":"He, M. et al. Identification and characterization of new long chain acyl-CoA dehydrogenases. Mol. Genet. Metab. 102, 418\u2013429 (2011).","journal-title":"Mol. Genet. Metab."},{"key":"869_CR37","unstructured":"Farzam, K. & Patel, P. Tirzepatide. StatPearls https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK585056\/ (2024)."},{"key":"869_CR38","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.cmet.2005.05.009","volume":"2","author":"SA Hawley","year":"2005","unstructured":"Hawley, S. A. et al. Calmodulin-dependent protein kinase kinase-\u03b2 is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9\u201319 (2005).","journal-title":"Cell Metab."},{"key":"869_CR39","doi-asserted-by":"publisher","first-page":"3329","DOI":"10.1073\/pnas.0308061100","volume":"101","author":"RJ Shaw","year":"2004","unstructured":"Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329\u20133335 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"869_CR40","doi-asserted-by":"publisher","first-page":"2357","DOI":"10.1002\/jnr.24706","volume":"98","author":"MR King","year":"2020","unstructured":"King, M. R. et al. Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin-4 treatment. J. Neurosci. Res. 98, 2357\u20132369 (2020).","journal-title":"J. Neurosci. Res."},{"key":"869_CR41","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1128\/MCB.24.2.865-874.2004","volume":"24","author":"MA Christensen","year":"2004","unstructured":"Christensen, M. A. et al. Transcriptional regulation of BACE1, the \u03b2-amyloid precursor protein \u03b2-secretase, by Sp1. Mol. Cell. Biol. 24, 865\u2013874 (2004).","journal-title":"Mol. Cell. Biol."},{"key":"869_CR42","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1017\/S1461145711000149","volume":"15","author":"CH Chen","year":"2012","unstructured":"Chen, C. H. et al. Increased NF-\u03baB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer\u2019s disease. Int. J. Neuropsychopharmacol. 15, 77\u201390 (2012).","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"869_CR43","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s40478-014-0078-x","volume":"2","author":"Y Tanaka","year":"2014","unstructured":"Tanaka, Y., Chambers, J. K., Matsuwaki, T., Yamanouchi, K. & Nishihara, M. Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice. Acta Neuropathol. Commun. 2, 78 (2014).","journal-title":"Acta Neuropathol. Commun."},{"key":"869_CR44","doi-asserted-by":"publisher","first-page":"4040","DOI":"10.1016\/j.apsb.2022.06.003","volume":"12","author":"J Pang","year":"2022","unstructured":"Pang, J., Feng, J. N., Ling, W. & Jin, T. The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs\u2014therapeutic potential exploration in lung injury. Acta Pharm. Sin. B 12, 4040\u20134055 (2022).","journal-title":"Acta Pharm. Sin. B"},{"key":"869_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103382","volume":"24","author":"F Zhang","year":"2021","unstructured":"Zhang, F. et al. Recombinant human GLP-1 beinaglutide regulates lipid metabolism of adipose tissues in diet-induced obese mice. iScience 24, 103382 (2021).","journal-title":"iScience"},{"key":"869_CR46","doi-asserted-by":"publisher","first-page":"4544","DOI":"10.3390\/cimb45060288","volume":"45","author":"A Petrovic","year":"2023","unstructured":"Petrovic, A. et al. The role of GLP1-RAs in direct modulation of lipid metabolism in hepatic tissue as determined using in vitro models of NAFLD. Curr. Issues Mol. Biol. 45, 4544\u20134556 (2023).","journal-title":"Curr. Issues Mol. Biol."},{"key":"869_CR47","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.3233\/JPD-230030","volume":"13","author":"T Panagaki","year":"2023","unstructured":"Panagaki, T., Randi, E. B., Szabo, C. & Holscher, C. Incretin mimetics restore the ER-mitochondrial axis and switch cell fate towards survival in LUHMES dopaminergic-like neurons: implications for novel therapeutic strategies in Parkinson\u2019s disease. J. Parkinsons Dis. 13, 1149\u20131174 (2023).","journal-title":"J. Parkinsons Dis."},{"key":"869_CR48","doi-asserted-by":"publisher","first-page":"457","DOI":"10.3949\/ccjm.89a.21110","volume":"89","author":"N Nachawi","year":"2022","unstructured":"Nachawi, N., Rao, P. P. & Makin, V. The role of GLP-1 receptor agonists in managing type 2 diabetes. Cleve. Clin. J. Med. 89, 457\u2013464 (2022).","journal-title":"Cleve. Clin. J. Med."},{"key":"869_CR49","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/S2213-8587(15)00482-9","volume":"4","author":"MA Nauck","year":"2016","unstructured":"Nauck, M. A. & Meier, J. J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 4, 525\u2013536 (2016).","journal-title":"Lancet Diabetes Endocrinol."},{"key":"869_CR50","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1530\/eje.0.1460863","volume":"146","author":"H Hui","year":"2002","unstructured":"Hui, H., Farilla, L., Merkel, P. & Perfetti, R. The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects. Eur. J. Endocrinol. 146, 863\u2013869 (2002).","journal-title":"Eur. J. Endocrinol."},{"key":"869_CR51","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1210\/jcem.87.3.8337","volume":"87","author":"JM Egan","year":"2002","unstructured":"Egan, J. M., Clocquet, A. R. & Elahi, D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J. Clin. Endocrinol. Metab. 87, 1282\u20131290 (2002).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"869_CR52","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1210\/jc.2010-2081","volume":"96","author":"T Blevins","year":"2011","unstructured":"Blevins, T. et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 96, 1301\u20131310 (2011).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"869_CR53","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.neurobiolaging.2020.01.004","volume":"89","author":"G Lietzau","year":"2020","unstructured":"Lietzau, G. et al. Dipeptidyl peptidase-4 inhibitors and sulfonylureas prevent the progressive impairment of the nigrostriatal dopaminergic system induced by diabetes during aging. Neurobiol. Aging 89, 12\u201323 (2020).","journal-title":"Neurobiol. Aging"},{"key":"869_CR54","doi-asserted-by":"publisher","first-page":"614884","DOI":"10.3389\/fnbeh.2020.614884","volume":"14","author":"CY Eren-Yazicioglu","year":"2020","unstructured":"Eren-Yazicioglu, C. Y., Yigit, A., Dogruoz, R. E. & Yapici-Eser, H. Can GLP-1 be a target for reward system related disorders? A qualitative synthesis and systematic review analysis of studies on palatable food, drugs of abuse, and alcohol. Front. Behav. Neurosci. 14, 614884 (2020).","journal-title":"Front. Behav. Neurosci."},{"key":"869_CR55","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1038\/s41380-024-02408-9","volume":"29","author":"E Spoleti","year":"2024","unstructured":"Spoleti, E. et al. Dopamine neuron degeneration in the ventral tegmental area causes hippocampal hyperexcitability in experimental Alzheimer\u2019s disease. Mol. Psychiatry 29, 1265\u20131280 (2024).","journal-title":"Mol. Psychiatry"},{"key":"869_CR56","doi-asserted-by":"publisher","first-page":"tgaa022","DOI":"10.1093\/texcom\/tgaa022","volume":"1","author":"G Murari","year":"2020","unstructured":"Murari, G. et al. Prefrontal GABA levels correlate with memory in older adults at high risk for Alzheimer\u2019s disease. Cereb. Cortex Commun. 1, tgaa022 (2020).","journal-title":"Cereb. Cortex Commun."},{"key":"869_CR57","doi-asserted-by":"publisher","first-page":"877","DOI":"10.3233\/JAD-143090","volume":"46","author":"HH Hansen","year":"2015","unstructured":"Hansen, H. H. et al. The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer\u2019s disease. J. Alzheimers Dis. 46, 877\u2013888 (2015).","journal-title":"J. Alzheimers Dis."},{"key":"869_CR58","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.brainres.2015.12.052","volume":"1634","author":"HH Hansen","year":"2016","unstructured":"Hansen, H. H. et al. The GLP-1 receptor agonist liraglutide reduces pathology-specific tau phosphorylation and improves motor function in a transgenic hTauP301L mouse model of tauopathy. Brain Res. 1634, 158\u2013170 (2016).","journal-title":"Brain Res."},{"key":"869_CR59","doi-asserted-by":"publisher","first-page":"101102","DOI":"10.1016\/j.molmet.2020.101102","volume":"46","author":"MA Nauck","year":"2021","unstructured":"Nauck, M. A., Quast, D. R., Wefers, J. & Meier, J. J. GLP-1 receptor agonists in the treatment of type 2 diabetes\u2014state-of-the-art. Mol. Metab. 46, 101102 (2021).","journal-title":"Mol. Metab."},{"key":"869_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2024.167060","volume":"1870","author":"R Shen","year":"2024","unstructured":"Shen, R. et al. GLP-1 receptor agonist attenuates tubular cell ferroptosis in diabetes via enhancing AMPK-fatty acid metabolism pathway through macropinocytosis. Biochim. Biophys. Acta Mol. Basis Dis. 1870, 167060 (2024).","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"869_CR61","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nrm.2017.95","volume":"19","author":"S Herzig","year":"2018","unstructured":"Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121\u2013135 (2018).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"869_CR62","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","volume":"66","author":"D Garcia","year":"2017","unstructured":"Garcia, D. & Shaw, R. J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789\u2013800 (2017).","journal-title":"Mol. Cell"},{"key":"869_CR63","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1111\/j.1471-4159.2011.07331.x","volume":"118","author":"A Salminen","year":"2011","unstructured":"Salminen, A., Kaarniranta, K., Haapasalo, A., Soininen, H. & Hiltunen, M. AMP-activated protein kinase: a potential player in Alzheimer\u2019s disease. J. Neurochem. 118, 460\u2013474 (2011).","journal-title":"J. Neurochem."},{"key":"869_CR64","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.bbi.2017.12.009","volume":"69","author":"Z Ou","year":"2018","unstructured":"Ou, Z. et al. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP\/PS1 mice. Brain Behav. Immun. 69, 351\u2013363 (2018).","journal-title":"Brain Behav. Immun."},{"key":"869_CR65","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1001\/jama.2019.20939","volume":"323","author":"BM Kuehn","year":"2020","unstructured":"Kuehn, B. M. In Alzheimer research, glucose metabolism moves to center stage. JAMA 323, 297\u2013299 (2020).","journal-title":"JAMA"},{"key":"869_CR66","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1001\/jamaneurol.2015.0613","volume":"72","author":"AA Willette","year":"2015","unstructured":"Willette, A. A. et al. Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease. JAMA Neurol. 72, 1013\u20131020 (2015).","journal-title":"JAMA Neurol."},{"key":"869_CR67","doi-asserted-by":"publisher","first-page":"e154595","DOI":"10.1172\/jci.insight.154595","volume":"7","author":"C He","year":"2022","unstructured":"He, C. et al. Recurrent moderate hypoglycemia accelerates the progression of Alzheimer\u2019s disease through impairment of the TRPC6\/GLUT3 pathway. JCI Insight 7, e154595 (2022).","journal-title":"JCI Insight"},{"key":"869_CR68","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-04927-z","volume":"22","author":"RA Fontanella","year":"2024","unstructured":"Fontanella, R. A. et al. Tirzepatide prevents neurodegeneration through multiple molecular pathways. J. Transl. Med. 22, 114 (2024).","journal-title":"J. Transl. Med."},{"key":"869_CR69","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.brainres.2011.10.046","volume":"1430","author":"J Yu","year":"2012","unstructured":"Yu, J. et al. IGF-1 induces hypoxia-inducible factor 1\u03b1-mediated GLUT3 expression through PI3K\/Akt\/mTOR dependent pathways in PC12 cells. Brain Res. 1430, 18\u201324 (2012).","journal-title":"Brain Res."},{"key":"869_CR70","doi-asserted-by":"publisher","first-page":"3240","DOI":"10.1093\/nar\/gks1227","volume":"41","author":"N Jin","year":"2013","unstructured":"Jin, N. et al. CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer\u2019s disease. Nucleic Acids Res. 41, 3240\u20133256 (2013).","journal-title":"Nucleic Acids Res."},{"key":"869_CR71","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1139\/apnm-2020-0005","volume":"45","author":"JF Halling","year":"2020","unstructured":"Halling, J. F. & Pilegaard, H. PGC-1\u03b1-mediated regulation of mitochondrial function and physiological implications. Appl. Physiol. Nutr. Metab. 45, 927\u2013936 (2020).","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"869_CR72","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1002\/alz.12683","volume":"19","author":"T Ashleigh","year":"2023","unstructured":"Ashleigh, T., Swerdlow, R. H. & Beal, M. F. The role of mitochondrial dysfunction in Alzheimer\u2019s disease pathogenesis. Alzheimers Dement. 19, 333\u2013342 (2023).","journal-title":"Alzheimers Dement."},{"key":"869_CR73","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1046\/j.1471-4159.1999.731674.x","volume":"73","author":"C Blazquez","year":"1999","unstructured":"Blazquez, C., Woods, A., de Ceballos, M. L., Carling, D. & Guzman, M. The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. J. Neurochem. 73, 1674\u20131682 (1999).","journal-title":"J. Neurochem."},{"key":"869_CR74","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1096\/fj.201500182","volume":"30","author":"J Thevenet","year":"2016","unstructured":"Thevenet, J. et al. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. FASEB J. 30, 1913\u20131926 (2016).","journal-title":"FASEB J."},{"key":"869_CR75","doi-asserted-by":"publisher","first-page":"101395","DOI":"10.1016\/j.redox.2019.101395","volume":"29","author":"P Rojas-Morales","year":"2020","unstructured":"Rojas-Morales, P., Pedraza-Chaverri, J. & Tapia, E. Ketone bodies, stress response, and redox homeostasis. Redox Biol. 29, 101395 (2020).","journal-title":"Redox Biol."},{"key":"869_CR76","doi-asserted-by":"publisher","first-page":"116373","DOI":"10.1016\/j.biopha.2024.116373","volume":"173","author":"Z Zhao","year":"2024","unstructured":"Zhao, Z., Yan, J., Huang, L. & Yang, X. Phytochemicals targeting Alzheimer\u2019s disease via the AMP-activated protein kinase pathway, effects, and mechanisms of action. Biomed. Pharmacother. 173, 116373 (2024).","journal-title":"Biomed. Pharmacother."},{"key":"869_CR77","doi-asserted-by":"publisher","first-page":"e78919","DOI":"10.1371\/journal.pone.0078919","volume":"8","author":"L Caberlotto","year":"2013","unstructured":"Caberlotto, L., Lauria, M., Nguyen, T. P. & Scotti, M. The central role of AMP-kinase and energy homeostasis impairment in Alzheimer\u2019s disease: a multifactor network analysis. PLoS ONE 8, e78919 (2013).","journal-title":"PLoS ONE"},{"key":"869_CR78","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1096\/fj.04-2572com","volume":"18","author":"DC Fewlass","year":"2004","unstructured":"Fewlass, D. C. et al. Obesity-related leptin regulates Alzheimer\u2019s A\u03b2. FASEB J. 18, 1870\u20131878 (2004).","journal-title":"FASEB J."},{"key":"869_CR79","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.3390\/ijms21051725","volume":"21","author":"S Jantrapirom","year":"2020","unstructured":"Jantrapirom, S. et al. Liraglutide suppresses tau hyperphosphorylation, amyloid beta accumulation through regulating neuronal insulin signaling and BACE-1 activity. Int. J. Mol. Sci. 21, 1725 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"869_CR80","doi-asserted-by":"publisher","first-page":"661","DOI":"10.17219\/acem\/121007","volume":"29","author":"CJ Yu","year":"2020","unstructured":"Yu, C. J. et al. The role of GLP-1\/GIP receptor agonists in Alzheimer\u2019s disease. Adv. Clin. Exp. Med. 29, 661\u2013668 (2020).","journal-title":"Adv. Clin. Exp. Med."},{"key":"869_CR81","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1007\/s11011-021-00879-1","volume":"37","author":"B Cao","year":"2022","unstructured":"Cao, B. et al. Neuroprotective effects of liraglutide against inflammation through the AMPK\/NF-\u03baB pathway in a mouse model of Parkinson\u2019s disease. Metab. Brain Dis. 37, 451\u2013462 (2022).","journal-title":"Metab. Brain Dis."},{"key":"869_CR82","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/s41392-024-01931-z","volume":"9","author":"Z Zheng","year":"2024","unstructured":"Zheng, Z. et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct. Target. Ther. 9, 234 (2024).","journal-title":"Signal Transduct. Target. Ther."},{"key":"869_CR83","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-024-01739-w","volume":"25","author":"G Lu","year":"2024","unstructured":"Lu, G. et al. AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization. J. Headache Pain 25, 29 (2024).","journal-title":"J. Headache Pain"},{"key":"869_CR84","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1038\/78682","volume":"6","author":"F Bard","year":"2000","unstructured":"Bard, F. et al. Peripherally administered antibodies against amyloid \u03b2-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916\u2013919 (2000).","journal-title":"Nat. Med."},{"key":"869_CR85","doi-asserted-by":"publisher","first-page":"8661","DOI":"10.1002\/alz.14313","volume":"20","author":"W Wang","year":"2024","unstructured":"Wang, W. et al. Associations of semaglutide with first-time diagnosis of Alzheimer\u2019s disease in patients with type 2 diabetes: target trial emulation using nationwide real-world data in the US. Alzheimers Dement. 20, 8661\u20138672 (2024).","journal-title":"Alzheimers Dement."},{"key":"869_CR86","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/s41392-024-01768-6","volume":"9","author":"Q Zhang","year":"2024","unstructured":"Zhang, Q. et al. Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential \u03b1-secretase cleavages, leading to autism-like phenotypes. Signal Transduct. Target. Ther. 9, 51 (2024).","journal-title":"Signal Transduct. Target. Ther."},{"key":"869_CR87","doi-asserted-by":"publisher","first-page":"18727","DOI":"10.1073\/pnas.0606298103","volume":"103","author":"X Sun","year":"2006","unstructured":"Sun, X. et al. Hypoxia facilitates Alzheimer\u2019s disease pathogenesis by up-regulating BACE1 gene expression. Proc. Natl Acad. Sci. USA 103, 18727\u201318732 (2006).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"869_CR88","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14543","volume":"21","author":"Y Feng","year":"2025","unstructured":"Feng, Y. et al. Inhibition of IFITM3 in cerebrovascular endothelium alleviates Alzheimer\u2019s-related phenotypes. Alzheimers Dement. 21, e14543 (2025).","journal-title":"Alzheimers Dement."},{"key":"869_CR89","first-page":"2831","volume":"26","author":"PT Ly","year":"2011","unstructured":"Ly, P. T., Cai, F. & Song, W. Detection of neuritic plaques in Alzheimer\u2019s disease mouse model. J. Vis. Exp. 26, 2831 (2011).","journal-title":"J. Vis. Exp."}],"container-title":["Nature Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-00869-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-00869-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-00869-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T13:02:22Z","timestamp":1750251742000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-00869-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":89,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["869"],"URL":"https:\/\/doi.org\/10.1038\/s43587-025-00869-3","relation":{},"ISSN":["2662-8465"],"issn-type":[{"value":"2662-8465","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,20]]},"assertion":[{"value":"12 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}