The Neuroprotective Effects of GLP-1 Analogues on Alzheimer's Disease – A Literature Review
DOI:
https://doi.org/10.12775/JEHS.2025.80.59398Keywords
Alzheimer's disease, GLP-1, glucagon like peptide 1, neuroprotectionAbstract
Alzheimer’s disease (AD), often referred to as type 3 diabetes, is characterized by neuroinflammation, oxidative stress, mitochondrial dysfunction, and brain insulin resistance, leading to cognitive decline. GLP-1 receptor agonists, originally developed for type 2 diabetes, demonstrate neuroprotective properties that address these pathologies. They improve insulin sensitivity, reduce amyloid-beta deposition, tau hyperphosphorylation, and neuronal apoptosis while enhancing synaptic plasticity, autophagy, and neural stem cell proliferation. Studies highlight their potential as innovative AD therapies. However, further research is needed to confirm their efficacy and long-term safety in combating neurodegeneration.
References
1. Talbot K, Wang HY. The nature, significance, and glucagon-like peptide-1 analog treatment of brain insulin resistance in Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2014;10(1 Suppl):S12-25. doi:10.1016/j.jalz.2013.12.007
2. Nguyen TT, Nguyen TTD, Nguyen TKO, Vo TK, Vo VG. Advances in developing therapeutic strategies for Alzheimer’s disease. Biomed Pharmacother Biomedecine Pharmacother. 2021;139:111623. doi:10.1016/j.biopha.2021.111623
3. The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention - PubMed. Accessed December 9, 2024. https://pubmed.ncbi.nlm.nih.gov/34101789/
4. Abeysinghe AADT, Deshapriya RDUS, Udawatte C. Alzheimer’s disease; a review of the pathophysiological basis and therapeutic interventions. Life Sci. 2020;256:117996. doi:10.1016/j.lfs.2020.117996
5. Clark K, Leung YY, Lee WP, Voight B, Wang LS. Polygenic Risk Scores in Alzheimer’s Disease Genetics: Methodology, Applications, Inclusion, and Diversity. J Alzheimers Dis. 89(1):1-12. doi:10.3233/JAD-220025
6. Uddin MS, Hasana S, Hossain MF, et al. Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease. Curr Gene Ther. 2021;21(1):43-52. doi:10.2174/1566523220666201123112822
7. Cacace R, Sleegers K, Van Broeckhoven C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement. 2016;12(6):733-748. doi:10.1016/j.jalz.2016.01.012
8. Lanoiselée HM, Nicolas G, Wallon D, et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017;14(3):e1002270. doi:10.1371/journal.pmed.1002270
9. Wang XF, Lin X, Li DY, et al. Linking Alzheimer’s disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach. J Neurol Sci. 2017;380:262-272. doi:10.1016/j.jns.2017.07.044
10. Li L, Cavuoto M, Biddiscombe K, Pike KE. Diabetes Mellitus Increases Risk of Incident Dementia in APOEɛ4 Carriers: A Meta-Analysis. J Alzheimers Dis JAD. 2020;74(4):1295-1308. doi:10.3233/JAD-191068
11. Li X, Song D, Leng SX. Link between type 2 diabetes and Alzheimer’s disease: from epidemiology to mechanism and treatment. Clin Interv Aging. 2015;10:549-560. doi:10.2147/CIA.S74042
12. Miao Y, Guo D, Li W, Zhong Y, Guo Y. Diabetes Promotes Development of Alzheimer’s Disease Through Suppression of Autophagy. J Alzheimer’s Dis. 2019;69(1):289-296. doi:10.3233/JAD-190156
13. Kellar D, Craft S. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 2020;19(9):758-766. doi:10.1016/S1474-4422(20)30231-3
14. Akhtar A, Sah SP. Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochem Int. 2020;135:104707. doi:10.1016/j.neuint.2020.104707
15. Nguyen TT, Ta QTH, Nguyen TKO, Nguyen TTD, Van Giau V. Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. Int J Mol Sci. 2020;21(9):3165. doi:10.3390/ijms21093165
16. Kevadiya BD, Ottemann BM, Thomas MB, et al. Neurotheranostics as Personalized Medicines. Adv Drug Deliv Rev. 2019;148:252-289. doi:10.1016/j.addr.2018.10.011
17. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168-181. doi:10.1038/nrneurol.2017.185
18. Altmann A, Ng B, Landau SM, Jagust WJ, Greicius MD. Regional brain hypometabolism is unrelated to regional amyloid plaque burden. Brain. 2015;138(12):3734-3746. doi:10.1093/brain/awv278
19. Baker LD, Cross D, Minoshima S, Belongia D, Watson GS, Craft S. INSULIN RESISTANCE IS ASSOCIATED WITH ALZHEIMER-LIKE REDUCTIONS IN REGIONAL CEREBRAL GLUCOSE METABOLISM FOR COGNITIVELY NORMAL ADULTS WITH PRE-DIABETES OR EARLY TYPE 2 DIABETES. Arch Neurol. 2011;68(1):51-57. doi:10.1001/archneurol.2010.225
20. Park SA. A Common Pathogenic Mechanism Linking Type-2 Diabetes and Alzheimer’s Disease: Evidence from Animal Models. J Clin Neurol Seoul Korea. 2011;7(1):10-18. doi:10.3988/jcn.2011.7.1.10
21. Chen C, Ahn EH, Kang SS, Liu X, Alam A, Ye K. Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer’s disease mouse model. Sci Adv. 2020;6(31):eaba0466. doi:10.1126/sciadv.aba0466
22. Strandwitz P, Kim KH, Terekhova D, et al. GABA Modulating Bacteria of the Human Gut Microbiota. Nat Microbiol. 2019;4(3):396-403. doi:10.1038/s41564-018-0307-3
23. Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer’s Disease. J Neurogastroenterol Motil. 2019;25(1):48-60. doi:10.5056/jnm18087
24. Oskarsson ME, Paulsson JF, Schultz SW, Ingelsson M, Westermark P, Westermark GT. In Vivo Seeding and Cross-Seeding of Localized Amyloidosis: A Molecular Link between Type 2 Diabetes and Alzheimer Disease. Am J Pathol. 2015;185(3):834-846. doi:10.1016/j.ajpath.2014.11.016
25. Amyloid‐β and islet amyloid pathologies link Alzheimer’s disease and type 2 diabetes in a transgenic model. doi:10.1096/fj.201700431R
26. Michailidis M, Moraitou D, Tata DA, Kalinderi K, Papamitsou T, Papaliagkas V. Alzheimer’s Disease as Type 3 Diabetes: Common Pathophysiological Mechanisms between Alzheimer’s Disease and Type 2 Diabetes. Int J Mol Sci. 2022;23(5):2687. doi:10.3390/ijms23052687
27. Terry AV, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003;306(3):821-827. doi:10.1124/jpet.102.041616
28. Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med. 2002;8(12):1390-1397. doi:10.1038/nm1202-793
29. Reed J, Bain SC, Kanamarlapudi V. Recent advances in understanding the role of glucagon-like peptide 1. F1000Research. 2020;9:F1000 Faculty Rev-239. doi:10.12688/f1000research.20602.1
30. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018;27(4):740-756. doi:10.1016/j.cmet.2018.03.001
31. Yildirim Simsir I, Soyaltin UE, Cetinkalp S. Glucagon like peptide-1 (GLP-1) likes Alzheimer’s disease. Diabetes Metab Syndr Clin Res Rev. 2018;12(3):469-475. doi:10.1016/j.dsx.2018.03.002
32. Baggio LL, Drucker DJ. Biology of Incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131-2157. doi:10.1053/j.gastro.2007.03.054
33. Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab. 2015;4(10):718-731. doi:10.1016/j.molmet.2015.07.008
34. Vrang N, Larsen PJ. Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: Role of peripherally secreted and centrally produced peptides. Prog Neurobiol. 2010;92(3):442-462. doi:10.1016/j.pneurobio.2010.07.003
35. Hunter K, Hölscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012;13:33. doi:10.1186/1471-2202-13-33
36. Złotek M, Kurowska A, Herbet M, Piątkowska-Chmiel I. GLP-1 Analogs, SGLT-2, and DPP-4 Inhibitors: A Triad of Hope for Alzheimer’s Disease Therapy. Biomedicines. 2023;11(11):3035. doi:10.3390/biomedicines11113035
37. Dong M, Wen S, Zhou L. The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors. Diabetes Metab Syndr Obes Targets Ther. 2022;15:2583-2597. doi:10.2147/DMSO.S375559
38. Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379(6560):69-72. doi:10.1038/379069a0
39. Hölscher C. Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer’s and Parkinson’s disease models. Neuropharmacology. 2018;136:251-259. doi:10.1016/j.neuropharm.2018.01.040
40. Monti G, Gomes Moreira D, Richner M, Mutsaers HAM, Ferreira N, Jan A. GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight. Cells. 2022;11(13):2023. doi:10.3390/cells11132023
41. Reich N, Hölscher C. The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review. Front Neurosci. 2022;16:970925. doi:10.3389/fnins.2022.970925
42. Lee CH, Jeon SJ, Cho KS, et al. Activation of Glucagon-Like Peptide-1 Receptor Promotes Neuroprotection in Experimental Autoimmune Encephalomyelitis by Reducing Neuroinflammatory Responses. Mol Neurobiol. 2018;55(4):3007-3020. doi:10.1007/s12035-017-0550-2
43. Bomba M, Granzotto A, Castelli V, et al. Exenatide Reverts the High-Fat-Diet-Induced Impairment of BDNF Signaling and Inflammatory Response in an Animal Model of Alzheimer’s Disease. J Alzheimers Dis JAD. 2019;70(3):793-810. doi:10.3233/JAD-190237
44. Parthsarathy V, Hölscher C. The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain. Eur J Pharmacol. 2013;700(1-3):42-50. doi:10.1016/j.ejphar.2012.12.012
45. McClean PL, Jalewa J, Hölscher C. Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res. 2015;293:96-106. doi:10.1016/j.bbr.2015.07.024
46. Perry T, Lahiri DK, Sambamurti K, et al. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res. 2003;72(5):603-612. doi:10.1002/jnr.10611
47. Cai HY, Yang JT, Wang ZJ, et al. Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer’s disease. Biochem Biophys Res Commun. 2018;495(1):1034-1040. doi:10.1016/j.bbrc.2017.11.114
48. McClean PL, Hölscher C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer’s disease. Neuropharmacology. 2014;86:241-258. doi:10.1016/j.neuropharm.2014.07.015
49. Zhang Y, Xie JZ, Xu XY, et al. Liraglutide Ameliorates Hyperhomocysteinemia-Induced Alzheimer-Like Pathology and Memory Deficits in Rats via Multi-molecular Targeting. Neurosci Bull. 2019;35(4):724-734. doi:10.1007/s12264-018-00336-7
50. Qi L, Ke L, Liu X, et al. Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3β pathway in an amyloid β protein induced alzheimer disease mouse model. Eur J Pharmacol. 2016;783:23-32. doi:10.1016/j.ejphar.2016.04.052
51. Chen S, An FM, Yin L, et al. Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation. Neuroscience. 2014;256:137-146. doi:10.1016/j.neuroscience.2013.10.038
52. Holst JJ, Burcelin R, Nathanson E. Neuroprotective properties of GLP-1: theoretical and practical applications. Curr Med Res Opin. 2011;27(3):547-558. doi:10.1185/03007995.2010.549466
53. McGovern SFJ, Hunter K, Hölscher C. Effects of the glucagon-like polypeptide-1 analogue (Val8)GLP-1 on learning, progenitor cell proliferation and neurogenesis in the C57B/16 mouse brain. Brain Res. 2012;1473:204-213. doi:10.1016/j.brainres.2012.07.029
54. Parthsarathy V, Hölscher C. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PloS One. 2013;8(3):e58784. doi:10.1371/journal.pone.0058784
55. McClean PL, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci Off J Soc Neurosci. 2011;31(17):6587-6594. doi:10.1523/JNEUROSCI.0529-11.2011
56. Batista AF, Forny-Germano L, Clarke JR, et al. The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer’s disease. J Pathol. 2018;245(1):85-100. doi:10.1002/path.5056
57. Spielman LJ, Gibson DL, Klegeris A. Incretin hormones regulate microglia oxidative stress, survival and expression of trophic factors. Eur J Cell Biol. 2017;96(3):240-253. doi:10.1016/j.ejcb.2017.03.004
58. Xie Y, Zheng J, Li S, et al. GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer’s disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway. Biochem Pharmacol. 2021;188:114578. doi:10.1016/j.bcp.2021.114578
59. Garabadu D, Verma J. Exendin-4 attenuates brain mitochondrial toxicity through PI3K/Akt-dependent pathway in amyloid beta (1-42)-induced cognitive deficit rats. Neurochem Int. 2019;128:39-49. doi:10.1016/j.neuint.2019.04.006
60. Kimura R, Okouchi M, Fujioka H, et al. Glucagon-like peptide-1 (GLP-1) protects against methylglyoxal-induced PC12 cell apoptosis through the PI3K/Akt/mTOR/GCLc/redox signaling pathway. Neuroscience. 2009;162(4):1212-1219. doi:10.1016/j.neuroscience.2009.05.025
61. Zhang H, Song B, Zhu W, et al. Glucagon-like peptide-1 attenuated carboxymethyl lysine induced neuronal apoptosis via peroxisome proliferation activated receptor-γ. Aging. 2021;13(14):19013-19027. doi:10.18632/aging.203351
62. Chen S, Yin L, Xu Z, et al. Inhibiting receptor for advanced glycation end product (AGE) and oxidative stress involved in the protective effect mediated by glucagon-like peptide-1 receptor on AGE induced neuronal apoptosis. Neurosci Lett. 2016;612:193-198. doi:10.1016/j.neulet.2015.12.007
63. Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002;302(3):881-888. doi:10.1124/jpet.102.037481
64. Qiu C, Wang YP, Pan XD, Liu XY, Chen Z, Liu LB. Exendin-4 protects Aβ(1-42) oligomer-induced PC12 cell apoptosis. Am J Transl Res. 2016;8(8):3540-3548.
65. Candeias E, Sebastião I, Cardoso S, et al. Brain GLP-1/IGF-1 Signaling and Autophagy Mediate Exendin-4 Protection Against Apoptosis in Type 2 Diabetic Rats. Mol Neurobiol. 2018;55(5):4030-4050. doi:10.1007/s12035-017-0622-3
66. Chang YF, Zhang D, Hu WM, Liu DX, Li L. Semaglutide-mediated protection against Aβ correlated with enhancement of autophagy and inhibition of apotosis. J Clin Neurosci Off J Neurosurg Soc Australas. 2020;81:234-239. doi:10.1016/j.jocn.2020.09.054
67. Panagaki T, Michael M, Hölscher C. Liraglutide restores chronic ER stress, autophagy impairments and apoptotic signalling in SH-SY5Y cells. Sci Rep. 2017;7(1):16158. doi:10.1038/s41598-017-16488-x
68. Jantrapirom S, Nimlamool W, Chattipakorn N, et al. Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity. Int J Mol Sci. 2020;21(5):1725. doi:10.3390/ijms21051725
69. Xiong H, Zheng C, Wang J, et al. The neuroprotection of liraglutide on Alzheimer-like learning and memory impairment by modulating the hyperphosphorylation of tau and neurofilament proteins and insulin signaling pathways in mice. J Alzheimers Dis JAD. 2013;37(3):623-635. doi:10.3233/JAD-130584
70. Yang Y, Ma D, Xu W, et al. Exendin-4 reduces tau hyperphosphorylation in type 2 diabetic rats via increasing brain insulin level. Mol Cell Neurosci. 2016;70:68-75. doi:10.1016/j.mcn.2015.10.005
71. Gejl M, Gjedde A, Egefjord L, et al. In Alzheimer’s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci. 2016;8:108. doi:10.3389/fnagi.2016.00108
72. Akimoto H, Negishi A, Oshima S, et al. Antidiabetic Drugs for the Risk of Alzheimer Disease in Patients With Type 2 DM Using FAERS. Am J Alzheimers Dis Other Demen. 2020;35:1533317519899546. doi:10.1177/1533317519899546
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Wiktoria Ulicka, Patryk Dudek, Klaudia Łuczak, Marcel Chudzikowski, Agnieszka Pawlik, Justyna Pięta, Adrianna Tabeau, Hanna Sitarek, Joanna Prus, Agata Prokopiuk
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 110
Number of citations: 0
