Skip to main content
SpringerLink
Log in

Novel GLP-1 (Glucagon-Like Peptide-1) Analogues and Insulin in the Treatment for Alzheimer’s Disease and Other Neurodegenerative Diseases

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

The link between diabetes mellitus and Alzheimer’s disease (AD) has been known for the last few decades. Since insulin and insulin receptors are known to be present in the brain, the downstream signalling as well as the effect of hyperinsulinemia have been extensively studied in both AD and Parkinson’s disease. Glucagon-like peptide-1 (GLP-1) is a hormone belonging to the incretin family, and its receptors (GLP-1Rs) can be found in pancreatic cells and in vascular endothelium. Interestingly, GLP-1Rs are found in the neuronal cell body and dendrites in the central nervous system (CNS), in particular in the hypothalamus, hippocampus, cerebral cortex and olfactory bulb. Several studies have shown the importance of both insulin and GLP-1 signalling on cognitive function, and many preclinical studies have been performed to evaluate the potential protective role of GLP-1 on the brain. Here we review the underlying mechanism of insulin and GLP-1 signalling in the CNS, as well as the preclinical data for the use of GLP-1 analogues such as liraglutide, exenatide and lixisenatide in neurodegenerative diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63–75 (e2).

  2. Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol. 2011;7(3):137–52.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Alzheimer’s Association 2012. Alzheimer’s disease facts and figures. Alzheimers Dement. 2012;8(2):131–68.

    Article  Google Scholar 

  4. de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101–13.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Hoyer S, Nitsch R, Oesterreich K. Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type: a cross-sectional comparison against advanced late-onset and incipient early-onset cases. J Neural Transm Park Dis Dement Sect. 1991;3(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  6. Hoyer S, Oesterreich K, Wagner O. Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J Neurol. 1988;235(3):143–8.

    Article  CAS  PubMed  Google Scholar 

  7. Frolich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm. 1998;105(4–5):423–38.

    Article  CAS  PubMed  Google Scholar 

  8. Schwab RS. Progression and prognosis in Parkinson’s disease. J Nerv Ment Dis. 1960;130:556–66.

    Article  CAS  PubMed  Google Scholar 

  9. Boyd AE 3rd, Lebovitz HE, Feldman JM. Endocrine function and glucose metabolism in patients with Parkinson’s disease and their alternation by l-dopa. J Clin Endocrinol Metab. 1971;33(5):829–37.

    Article  PubMed  Google Scholar 

  10. Van Woert MW, Mueller PS. Glucose, insulin, and free fatty acid metabolism in Parkinson’s disease treated with levodopa. Clin Pharmacol Ther. 1971;12(2):360–7.

    PubMed  Google Scholar 

  11. Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad Sci USA. 1978;75(11):5737–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Hoyer S, Henneberg N, Knapp S, Lannert H, Martin E. Brain glucose metabolism is controlled by amplification and desensitization of the neuronal insulin receptor. Ann N Y Acad Sci. 1996;777:374–9.

    Article  CAS  PubMed  Google Scholar 

  13. Barone E, Butterfield AD. Insulin resistance in Alzheimer disease: Is heme oxygenase-1 an Achille’s heel? Neurobiol Dis. Epub. 2015. doi:10.1016/j.nbd.2015.02.013.

    Google Scholar 

  14. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology. 1999;53(9):1937–42.

    Article  CAS  PubMed  Google Scholar 

  15. De Felice FG, Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes. 2014;63(7):2262–72.

    Article  PubMed  Google Scholar 

  16. Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, et al. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology. 2011;77(12):1126–34.

  17. Yu LY, Pei Y. Insulin neuroprotection and the mechanisms. Chin Med J (Engl). 2015;128(7):976–81.

    Article  PubMed  Google Scholar 

  18. Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708–19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. De Felice FG, Lourenco MV, Ferreira ST. How does brain insulin resistance develop in Alzheimer’s disease? Alzheimers Dement. 2014;10(1 Suppl):S26–32.

    Article  PubMed  Google Scholar 

  20. Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31(2):224–43.

    Article  CAS  PubMed  Google Scholar 

  21. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta. 2009;1792(5):482–96.

    Article  CAS  PubMed  Google Scholar 

  22. Hoyer S, Lee SK, Loffler T, Schliebs R. Inhibition of the neuronal insulin receptor. An in vivo model for sporadic Alzheimer disease? Ann N Y Acad Sci. 2000;920:256–8.

    Article  CAS  PubMed  Google Scholar 

  23. Petrov D, Pedros I, Artiach G, Sureda FX, Barroso E, Pallas M, et al. High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents. Biochim Biophys Acta. 2015;1852(9):1687–99.

    Article  CAS  PubMed  Google Scholar 

  24. Reagan LP. Neuronal insulin signal transduction mechanisms in diabetes phenotypes. Neurobiol Aging. 2005;26(Suppl 1):56–9.

    Article  PubMed  Google Scholar 

  25. McNay EC, Recknagel AK. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes. Neurobiol Learn Mem. 2011;96(3):432–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010;93(4):546–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Crescenzo R, Bianco F, Mazzoli A, Giacco A, Liverini G, Iossa S. Mitochondrial efficiency and insulin resistance. Front Physiol. 2014;5:512.

    PubMed Central  PubMed  Google Scholar 

  28. Carvalho C, Santos MS, Oliveira CR, Moreira PI. Alzheimer’s disease and type 2 diabetes-related alterations in brain mitochondria, autophagy and synaptic markers. Biochim Biophys Acta. 2015;1852(8):1665–75.

    Article  CAS  PubMed  Google Scholar 

  29. Carvalho C, Cardoso S, Correia SC, Santos RX, Santos MS, Baldeiras I, et al. Metabolic alterations induced by sucrose intake and Alzheimer’s disease promote similar brain mitochondrial abnormalities. Diabetes. 2012;61(5):1234–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Dineley KT, Jahrling JB, Denner L. Insulin resistance in Alzheimer’s disease. Neurobiol Dis. 2014;72 (Pt A):92–103.

  31. Cabou C, Burcelin R. GLP-1, the gut-brain, and brain-periphery axes. Rev Diabet Stud. 2011;8(3):418–31.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Anagnostis P, Athyros VG, Adamidou F, Panagiotou A, Kita M, Karagiannis A, et al. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes Metab. 2011;13(4):302–12.

    Article  CAS  PubMed  Google Scholar 

  33. Wideman RD, Kieffer TJ. Mining incretin hormone pathways for novel therapies. Trends Endocrinol Metab. 2009;20(6):280–6.

    Article  CAS  PubMed  Google Scholar 

  34. Holscher C. The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer’s disease. Alzheimers Dement. 2014;10(1 Suppl):S47–54.

    Article  PubMed  Google Scholar 

  35. Gejl M, Rungby J, Brock B, Gjedde A. At the centennial of Michaelis and Menten, competing Michaelis-Menten steps explain effect of GLP-1 on blood-brain transfer and metabolism of glucose. Basic Clin Pharmacol. 2014;115(2):162–71.

    Article  CAS  Google Scholar 

  36. Gejl M, Egefjord L, Lerche S, Vang K, Bibby BM, Holst JJ, et al. Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia. J Cereb Blood Flow Metab. 2012;32(12):2146–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Pabreja K, Mohd MA, Koole C, Wootten D, Furness SG. Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation. Br J Pharmacol. 2014;171(5):1114–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Sonoda N, Imamura T, Yoshizaki T, Babendure JL, Lu JC, Olefsky JM. Beta-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic beta cells. Proc Natl Acad Sci USA. 2008;105(18):6614–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Holscher C, Li L. New roles for insulin-like hormones in neuronal signalling and protection: new hopes for novel treatments of Alzheimer’s disease? Neurobiol Aging. 2010;31(9):1495–502.

    Article  PubMed  Google Scholar 

  40. Lund A, Knop FK, Vilsboll T. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: differences and similarities. Eur J Intern Med. 2014;25(5):407–14.

    Article  CAS  PubMed  Google Scholar 

  41. Struble RG, Ala T, Patrylo PR, Brewer GJ, Yan XX. Is brain amyloid production a cause or a result of dementia of the Alzheimer’s type? J Alzheimers Dis. 2010;22(2):393–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Varnum MM, Ikezu T. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp (Warsz). 2012;60(4):251–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30(4):572–80.

    Article  CAS  PubMed  Google Scholar 

  44. Wilcox KC, Lacor PN, Pitt J, Klein WL. Abeta oligomer-induced synapse degeneration in Alzheimer’s disease. Cell Mol Neurobiol. 2011;31(6):939–48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Freude S, Plum L, Schnitker J, Leeser U, Udelhoven M, Krone W, et al. Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes. 2005;54(12):3343–8.

    Article  CAS  PubMed  Google Scholar 

  46. Moroo I, Yamada T, Makino H, Tooyama I, McGeer PL, McGeer EG, et al. Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson’s disease. Acta Neuropathol. 1994;87(4):343–8.

    Article  CAS  PubMed  Google Scholar 

  47. Takahashi M, Yamada T, Tooyama I, Moroo I, Kimura H, Yamamoto T, et al. Insulin receptor mRNA in the substantia nigra in Parkinson’s disease. Neurosci Lett. 1996;204(3):201–4.

    Article  CAS  PubMed  Google Scholar 

  48. Morris JK, Bomhoff GL, Gorres BK, Davis VA, Kim J, Lee PP, et al. Insulin resistance impairs nigrostriatal dopamine function. Exp Neurol. 2011;231(1):171–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014;8:112.

  50. Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P. Neuroinflammation and regeneration in the early stages of Alzheimer’s disease pathology. Int J Dev Neurosci. 2006;24(2–3):157–65.

    Article  CAS  PubMed  Google Scholar 

  51. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation. 2005;2:22.

    Article  PubMed Central  PubMed  Google Scholar 

  52. Sastre M, Klockgether T, Heneka MT. Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int J Dev Neurosci. 2006;24(2–3):167–76.

    Article  CAS  PubMed  Google Scholar 

  53. Misiak B, Leszek J, Kiejna A. Metabolic syndrome, mild cognitive impairment and Alzheimer’s disease–the emerging role of systemic low-grade inflammation and adiposity. Brain Res Bull. 2012;89(3–4):144–9.

    Article  CAS  PubMed  Google Scholar 

  54. Lee YH, Tharp WG, Maple RL, Nair S, Permana PA, Pratley RE. Amyloid precursor protein expression is upregulated in adipocytes in obesity. Obesity. 2008;16(7):1493–500.

    Article  CAS  PubMed  Google Scholar 

  55. Ho GJ, Drego R, Hakimian E, Masliah E. Mechanisms of cell signaling and inflammation in Alzheimer’s disease. Curr Drug Targets Inflamm Allergy. 2005;4(2):247–56.

    Article  CAS  PubMed  Google Scholar 

  56. Stojkovska I, Wagner BM, Morrison BE. Parkinson’s disease and enhanced inflammatory response. Exp Biol Med (Maywood). 2015;240(11):1387–95.

    Article  CAS  PubMed  Google Scholar 

  57. Iwai T, Ito S, Tanimitsu K, Udagawa S, Oka J. Glucagon-like peptide-1 inhibits LPS-induced IL-1beta production in cultured rat astrocytes. Neurosci Res. 2006;55(4):352–60.

    Article  CAS  PubMed  Google Scholar 

  58. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9(11):1118–27.

    Article  PubMed  Google Scholar 

  59. Femminella GD, Edison P. Evaluation of neuroprotective effect of glucagon-like peptide 1 analogs using neuroimaging. Alzheimers Dement. 2014;10(1 Suppl):S55–61.

    Article  PubMed  Google Scholar 

  60. Okello A, Koivunen J, Edison P, Archer HA, Turkheimer FE, Nagren K, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology. 2009;73(10):754–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, et al. Microglia, amyloid, and cognition in Alzheimer’s disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis. 2008;32(3):412–9.

    Article  CAS  PubMed  Google Scholar 

  62. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA. 1998;95(11):6448–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416(6880):535–9.

    Article  CAS  PubMed  Google Scholar 

  64. Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, et al. Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci. 2004;24(45):10191–200.

    Article  CAS  PubMed  Google Scholar 

  65. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA. 2009;106(6):1971–6.

    Article  PubMed Central  PubMed  Google Scholar 

  66. Pandini G, Pace V, Copani A, Squatrito S, Milardi D, Vigneri R. Insulin has multiple antiamyloidogenic effects on human neuronal cells. Endocrinology. 2013;154(1):375–87.

    Article  CAS  PubMed  Google Scholar 

  67. Perry T, Lahiri DK, Chen D, Zhou J, Shaw KT, Egan JM, et al. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther. 2002;300(3):958–66.

    Article  CAS  PubMed  Google Scholar 

  68. Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, 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):603–12.

    Article  CAS  PubMed  Google Scholar 

  69. Perry T, Holloway HW, Weerasuriya A, Mouton PR, Duffy K, Mattison JA, et al. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Exp Neurol. 2007;203(2):293–301.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003;9(9):1173–9.

    Article  CAS  PubMed  Google Scholar 

  71. Abbas T, Faivre E, Holscher C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: interaction between type 2 diabetes and Alzheimer’s disease. Behav Brain Res. 2009;205(1):265–71.

    Article  CAS  PubMed  Google Scholar 

  72. D’Amico M, Di Filippo C, Marfella R, Abbatecola AM, Ferraraccio F, Rossi F, et al. Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer’s prone mice. Exp Gerontol. 2010;45(3):202–7.

    Article  PubMed  Google Scholar 

  73. Kosaraju J, Gali CC, Khatwal RB, Dubala A, Chinni S, Holsinger RM, et al. Saxagliptin: a dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer’s disease. Neuropharmacology. 2013;72:291–300.

    Article  CAS  PubMed  Google Scholar 

  74. Kosaraju J, Murthy V, Khatwal RB, Dubala A, Chinni S, Muthureddy Nataraj SK, et al. Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer’s disease. J Pharm Pharmacol. 2013;65(12):1773–84.

    Article  CAS  PubMed  Google Scholar 

  75. Kornelius E, Lin CL, Chang HH, Li HH, Huang WN, Yang YS, et al. DPP-4 inhibitor linagliptin attenuates Abeta-induced cytotoxicity through activation of AMPK in neuronal cells. CNS Neurosci Ther. 2015;21(7):549–57.

    Article  CAS  PubMed  Google Scholar 

  76. Jaturapatporn D, Isaac MG, McCleery J, Tabet N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev. 2012;2:CD006378.

  77. Shie FS, Nivison M, Hsu PC, Montine TJ. Modulation of microglial innate immunity in Alzheimer’s disease by activation of peroxisome proliferator-activated receptor gamma. Curr Med Chem. 2009;16(6):643–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Heneka MT, Landreth GE. PPARs in the brain. Biochim Biophys Acta. 2007;1771(8):1031–45.

    Article  CAS  PubMed  Google Scholar 

  79. Risner ME, Saunders AM, Altman JFB, Ormandy GC, Craft S, Foley IM, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J. 2006;6(4):246–54.

    CAS  PubMed  Google Scholar 

  80. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone—a preliminary study. Am J Geriat Psychiatry. 2005;13(11):950–8.

    Google Scholar 

  81. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011;32(9):1626–33.

    Article  CAS  PubMed  Google Scholar 

  82. Shiraishi D, Fujiwara Y, Komohara Y, Mizuta H, Takeya M. Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation. Biochem Biophys Res Commun. 2012;425(2):304–8.

    Article  CAS  PubMed  Google Scholar 

  83. Foltynie T, Aviles-Olmos I. Exenatide as a potential treatment for patients with Parkinson’s disease: first steps into the clinic. Alzheimers Dement. 2014;10(1 Suppl):S38–46.

    Article  PubMed  Google Scholar 

  84. Rampersaud N, Harkavyi A, Giordano G, Lever R, Whitton J, Whitton PS. Exendin-4 reverses biochemical and behavioral deficits in a pre-motor rodent model of Parkinson’s disease with combined noradrenergic and serotonergic lesions. Neuropeptides. 2012;46(5):183–93.

    Article  CAS  PubMed  Google Scholar 

  85. Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res. 2008;86(2):326–38.

    Article  CAS  PubMed  Google Scholar 

  86. Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci USA. 2009;106(4):1285–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Kahan J, Ell P, et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis. 2014;4(3):337–44.

    Article  CAS  PubMed  Google Scholar 

  88. Liu W, Jalewa J, Sharma M, Li G, Li L, Holscher C. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience. 2015;303:42–50.

    Article  CAS  PubMed  Google Scholar 

  89. Holscher C. First clinical data of the neuroprotective effects of nasal insulin application in patients with Alzheimer’s disease. Alzheimers Dement. 2014;10(1 Suppl):S33–7.

    Article  PubMed  Google Scholar 

  90. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69(1):29–38.

    Article  PubMed Central  PubMed  Google Scholar 

  91. Yang Y, Ma D, Wang Y, Jiang T, Hu S, Zhang M, et al. Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. J Alzheimers Dis. 2013;33(2):329–38.

    CAS  PubMed  Google Scholar 

  92. Yang Y, Zhang J, Ma D, Zhang M, Hu S, Shao S, et al. Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. J Alzheimers Dis. 2013;37(3):637–48.

    PubMed  Google Scholar 

  93. Gengler S, McClean PL, McCurtin R, Gault VA, Holscher C. Val(8)GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/PS1 mice. Neurobiol Aging. 2012;33(2):265–76.

    Article  CAS  PubMed  Google Scholar 

  94. Bomba M, Ciavardelli D, Silvestri E, Canzoniero LM, Lattanzio R, Chiappini P, et al. Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals. Cell Death Dis. 2013;4:e612.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Hunter K, Holscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012;13:33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci. 2011;31(17):6587–94.

    Article  CAS  PubMed  Google Scholar 

  97. McClean PL, Holscher C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer’s disease. Neuropharmacology. 2014;76(Pt A):57–67.

  98. McClean PL, Holscher C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer’s disease. Neuropharmacology. 2014;86:241–58.

    Article  CAS  PubMed  Google Scholar 

  99. Li L, Zhang ZF, Holscher C, Gao C, Jiang YH, Liu YZ. (Val(8)) glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains. Eur J Pharmacol. 2012;674(2–3):280–6.

    Article  CAS  PubMed  Google Scholar 

  100. Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, 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’s disease. J Alzheimers Dis. 2015;46(4):877–88.

    Article  CAS  PubMed  Google Scholar 

  101. Kelly P, McClean PL, Ackermann M, Konerding MA, Holscher C, Mitchell CA. Restoration of cerebral and systemic microvascular architecture in APP/PS1 transgenic mice following treatment with Liraglutide. Microcirculation. 2015;22(2):133–45.

    Article  CAS  PubMed  Google Scholar 

  102. Ma DL, Chen FQ, Xu WJ, Yue WZ, Yuan G, Yang Y. Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice. J Neurochem. 2015;135(2):301–8.

    Article  CAS  PubMed  Google Scholar 

  103. Barkholt P, Fabricius K, Jelsing J, Terwel D, Hansen HH, Pyke C, et al. The GLP-1 analog liraglutide improves motor function, survival rate and reduces neurofibrillary tangle load in a transgenic hTauP301L tauopathy mouse model of Alzheimer’s disease [poster no. 691.02]. Neuroscience 2014. 2014 (Washington, DC). http://www.abstractsonline.com/plan/start.aspx?mkey=%7B8334BE29-8911-4991-8C31-32B32DD5E6C8%7D. Accessed 10 Dec 2015.

  104. Imperial College London. Evaluating Liraglutide in Alzheimer’s Disease (ELAD) [ClinicalTrials.gov identifier NCT01843075]. 2013. US National Institutes of Health, ClinicalTrials.gov. http://clinicaltrials.gov. Accessed 27 Nov 2015.

  105. Talbot K, Wang HY. The nature, significance, and glucagon-like peptide-1 analog treatment of brain insulin resistance in Alzheimer’s disease. Alzheimers Dement. 2014;10(1 Suppl):S12–25.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neurology Imaging Unit, Imperial College London, 1st Floor B Block, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Valeria Calsolaro

  2. Division of Brain Sciences, Department of Medicine, Neurology Imaging Unit, Imperial College London, 1st Floor B Block, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Paul Edison

Authors
  1. Valeria Calsolaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul Edison
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul Edison.

Ethics declarations

Conflicts of interest

Dr. Calsolaro has nothing to disclose. Dr. Edison received funding from Novo Nordisk Pharmaceuticals and from GE Healthcare. Dr. Edison was funded by the Medical Research Council and is currently funded by the Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer’s Research UK, Alzheimer’s Drug Discovery Foundation, the UK Alzheimer’s Society, Novo Nordisk and GE Healthcare. Dr Calsolaro received funding from Alzheimer Research, UK.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Calsolaro, V., Edison, P. Novel GLP-1 (Glucagon-Like Peptide-1) Analogues and Insulin in the Treatment for Alzheimer’s Disease and Other Neurodegenerative Diseases. CNS Drugs 29, 1023–1039 (2015). https://doi.org/10.1007/s40263-015-0301-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-015-0301-8

Keywords

Search

Navigation