Advertisement

Molecular Neurobiology

, Volume 54, Issue 8, pp 6074–6084 | Cite as

Linagliptin, a Dipeptidyl Peptidase-4 Inhibitor, Mitigates Cognitive Deficits and Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

  • Jayasankar Kosaraju
  • R. M. Damian Holsinger
  • Lixia Guo
  • Kin Yip Tam
Article

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone shown to be active in the treatment of type-2 diabetes (T2D) and has also been shown as efficacious in Alzheimer’s disease (AD). Dipeptidyl peptidase-4 (DPP-4), an enzyme that is expressed in numerous cells, rapidly inactivates endogenous GLP-1. Therefore, DPP-4 inhibition is employed as a therapeutic avenue to increase GLP-1 levels in the management of T2D. The effectiveness of DPP-4 inhibitors in the treatment of AD has been reported in various animal models of AD. With this background, the present study was designed to examine the effectiveness of linagliptin, a DPP-4 inhibitor in the 3xTg-AD mouse model of Alzheimer’s disease. Nine-month-old 3xTg-AD mice were administered linagliptin orally (5, 10, and 20 mg/kg) for 8 weeks. At the end of the linagliptin treatment, mice were evaluated for cognitive ability on the Morris Water Maze and Y-maze. Following cognitive evaluation, mice were sacrificed to determine the effect of the linagliptin on brain incretin levels, amyloid burden, tau phosphorylation, and neuroinflammation. We confirm that linagliptin treatment for 8 weeks mitigates the cognitive deficits present in 3xTg-AD mice. Moreover, linagliptin also improves brain incretin levels and attenuates amyloid beta, tau phosphorylation as well as neuroinflammation. In conclusion, linagliptin possesses neuroprotective properties that may be attributed to the improvement of incretin levels in the brain.

Keywords

Glucagon-like peptide-1 Glucose-dependent insulinotropic polypeptide Amyloid beta Tau phosphorylation Neuroinflammation 

Notes

Acknowledgments

We thank Shun Ming Yuen from Histopathology Core (Faculty of Health Sciences, University of Macau) for assistance in histological analysis and Shaolin Zhang for verifying the purity of linagliptin. We thank the Science and Technology Development Fund, Macao S.A. R (FDCT) (project reference no.: 118/2013/A3) for the financial support.

Authors’ Contribution

JK executed most of the study including dosing, behavioral studies, immunoblotting, histology, data interpretation, and manuscript writing. RMDH supported in analyzing the results and manuscript editing. LG involved in data interpretation. KYT supervised and guided all phases of the project, including the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2016_125_MOESM1_ESM.tif (70 mb)
Fig S1 Cognitive assessment in 10 month old control (C57BL/6) and 3xTg-AD female mice in the Morris Water Maze test. (A) Latency to reach the escape platform and (B) path length taken to reach the platform during acquisition trials. (C) Percentage of time spent in the platform quadrant and (D) number of platform crossings during the probe trial. (E) Tracking details on day 4 trial 2 of corresponding groups. Significance was analyzed by unpaired t test (n = 6, mean ± SEM) using Graphpad Prism. **p < 0.01 and ***p < 0.001, compared to control mice (C57BL/6). (TIFF 71729 kb)
12035_2016_125_Fig10_ESM.gif (91 kb)

High resolution image (GIF 90 kb)

12035_2016_125_MOESM2_ESM.tif (39.1 mb)
Fig S2 Cognitive assessment in 10 month old control (C57BL/6) and 3xTg-AD female mice in the Y-maze test. (A) Time spent in the novel arm and (B) percentage of alterations. Significance was analyzed by unpaired t test (n = 6, mean ± SEM) using Graphpad Prism. ***p < 0.001, compared with control mice (C57BL/6). (TIFF 39998 kb)
12035_2016_125_Fig11_ESM.gif (52 kb)

High resolution image (GIF 51 kb)

References

  1. 1.
    Kumar A, Singh A, Ekavali (2015) A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Reports 67:195–203. doi: 10.1016/j.pharep.2014.09.004 CrossRefGoogle Scholar
  2. 2.
    Auld DS, Kornecook TJ, Bastianetto S, Quirion R (2002) Alzheimer’s disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol 68:209–245. doi: 10.1016/s0301-0082(02)00079-5 CrossRefPubMedGoogle Scholar
  3. 3.
    Kazim SF, Blanchard J, Dai C-L, Tung Y-C, LaFerla FM, Iqbal I-G, Iqbal K et al (2014) Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 71:110–130. doi: 10.1016/j.nbd.2014.07.001 CrossRefPubMedGoogle Scholar
  4. 4.
    Calsolaro V, Edison P (2015) 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. doi: 10.1007/s40263-015-0301-8 CrossRefPubMedGoogle Scholar
  5. 5.
    Holscher C (2010) Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer’s disease. Recent Pat CNS Drug Discov 5:109–117CrossRefPubMedGoogle Scholar
  6. 6.
    McClean PL, Jalewa J, Hölscher C (2015) Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res 293:96–106. doi: 10.1016/j.bbr.2015.07.024 CrossRefPubMedGoogle Scholar
  7. 7.
    Qi L, Ke L, Liu X, Liao L, Ke S, Liu X, Wang Y, Lin X et al (2016) 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 783:23–32. doi: 10.1016/j.ejphar.2016.04.052 CrossRefPubMedGoogle Scholar
  8. 8.
    Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, Pyke C, Knudsen LB et al (2015) 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 Alzheimer’s Dis 46:877–888. doi: 10.3233/JAD-143090 CrossRefGoogle Scholar
  9. 9.
    Duffy AM, Holscher C (2013) The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer’s disease. Neuroscience 228:294–300. doi: 10.1016/j.neuroscience.2012.10.045 CrossRefPubMedGoogle Scholar
  10. 10.
    McClean PL, Hölscher C (2014) Lixisenatide, a drug developed to treat type 2 diabetes, 15 shows neuroprotective effects in a mouse model of Alzheimer’s disease. Neuropharmacology 86:241–258. doi: 10.1016/j.neuropharm.2014.07.015 CrossRefPubMedGoogle Scholar
  11. 11.
    Jia X, Ye-Tian Y-L, Zhang GJ, Liu ZD, Di ZL, Ying XP, Fang Y et al (2016) Exendin-4, a glucagon-like peptide 1 receptor agonist, protects against amyloid-β peptide-induced impairment of spatial learning and memory in rats. Physiol Behav 159:72–79. doi: 10.1016/j.physbeh.2016.03.016 CrossRefPubMedGoogle Scholar
  12. 12.
    Katsurada K, Yada T (2016) Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist. J Diabetes Investig 7:64–69. doi: 10.1111/jdi.12464 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Shannon RP (2013) DPP-4 inhibition and neuroprotection: do mechanisms matter? Diabetes 62:1029–1031. doi: 10.2337/db12-1794 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Metcalfe MJ, Figueiredo-Pereira ME (2010) Relationship between tau pathology and neuroinflammation in Alzheimer’s disease. Mt Sinai J Med 77:50–58. doi: 10.1002/msj.20163 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ji C, Xue G-F, Lijun C, Feng P, Li D, Li L, Li G, Holscher C et al (2016) A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson’s disease by increasing expression of BNDF. Brain Res 11:326–331. doi: 10.1016/j.brainres.2015.09.035 Google Scholar
  16. 16.
    Angelucci F, Gelfo F, Fiore M, Croce N, Mathe AA, Bernardini S, Caltagirone C et al (2014) The effect of neuropeptide Y on cell survival and neurotrophin expression in in-vitro models of Alzheimer’s disease. Can J Physiol Pharmacol 92:621–630. doi: 10.1139/cjpp-2014-0099 CrossRefPubMedGoogle Scholar
  17. 17.
    Spencer B, Potkar R, Metcalf J, Thrin I, Adame A, Rockenstein E, Masliah E et al (2016) Systemic central nervous system (CNS)-targeted delivery of neuropeptide y (NPY) reduces neurodegeneration and increases neural precursor cell proliferation in a mouse model of Alzheimer disease. J Biol Chem 291:1905–1920. doi: 10.1074/jbc.M115.678185 CrossRefPubMedGoogle Scholar
  18. 18.
    Wang Q, Xu Y, Chen J-C, Qin YY, Liu M, Liu Y, Xie MJ, Yu ZY et al (2012) Stromal cell-derived factor 1α decreases β-amyloid deposition in Alzheimer’s disease mouse model. Brain Res 1459:15–26. doi: 10.1016/j.brainres.2012.04.011 CrossRefPubMedGoogle Scholar
  19. 19.
    D’Amico M, Di Filippo C, Marfella R, Abbatecola AM, Ferraraccio F, Rossi F, Paolisso G et al (2010) Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer’s prone mice. Exp Gerontol 45:202–207. doi: 10.1016/j.exger.2009.12.004 CrossRefPubMedGoogle Scholar
  20. 20.
    Kosaraju J, Murthy V, Khatwal RB, Dubala A, Chinni S, Muthureddy Nataraj SK, Basavan D et al (2013) Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer’s disease. J Pharm Pharmacol 65:1773–1784. doi: 10.1111/jphp.1214816 CrossRefPubMedGoogle Scholar
  21. 21.
    Kosaraju J, Gali CC, Khatwal RB, Dubala A, Chinni S, Holsinger RM, Madhunapantula VS, Muthureddy Nataraj SK et al (2013) Saxagliptin: a dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer’s disease. Neuropharmacology 72:291–300. doi: 10.1016/j.neuropharm.2013.04.008 CrossRefPubMedGoogle Scholar
  22. 22.
    Deacon CF (2011) Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes, Obes Metab 13:7–18. doi: 10.1111/j.1463-1326.2010.01306.x CrossRefGoogle Scholar
  23. 23.
    Kornelius E, Lin C-L, Chang H-H, Li HH, Huang WN, Yang WS, Lu YL, Peng CH et al (2015) DPP-4 inhibitor Linagliptin attenuates Aβ-induced cytotoxicity through activation of AMPK in neuronal cells. CNS Neurosci Ther 21:549–557. doi: 10.1111/cns.12404 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Darsalia V, Ortsäter H, Olverling A, Darlof E, Wolbert P, Nystrom T, Klein T, Sjoholm A et al (2013) The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: A comparison with glimepiride. Diabetes 62:1289–1296. doi: 10.2337/db12-0988 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ma M, Hasegawa Y, Koibuchi N, Toyama K, Uekawa K, Nakagawa T, Lin B, Kim- Mitsuyama S et al (2015) DPP-4 inhibition with linagliptin ameliorates cognitive impairment and brain atrophy induced by transient cerebral ischemia in type 2 diabetic mice. Cardiovasc Diabetol 14:54. doi: 10.1186/s12933-015-0218-z CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wongchai K, Schlotterer A, Lin J, Humpert PM, Klein T, Hammes H-P, Morcos M et al (2015) Protective Effects of Liraglutide and Linagliptin in C. elegans as a New Model for Glucose-Induced Neurodegeneration. Horm Metab Res 48:70–75. doi: 10.1055/s-0035-1549876 CrossRefPubMedGoogle Scholar
  27. 27.
    Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F et al (2008) Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res 1216:92–103. doi: 10.1016/j.brainres.2008.03.079 CrossRefPubMedGoogle Scholar
  28. 28.
    Clinton LK, Billings LM, Green KN, Caccamo A, Nqot J, Oddo S, McGauqh JL, LaFerla FM et al (2007) Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol Dis 28:76–82. doi: 10.1016/j.nbd.2007.06.013 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Branca C, Wisely EV, Hartman LK, Caccamo A, Oddo S et al (2014) Administration of a selective β2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer’s disease. Neurobiol Aging 35:2726–2735. doi: 10.1016/j.neurobiolaging.2014.06.011 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sarnyai Z, Sibille EL, Pavlides C, Fenster RJ, McEwen BS, Toth M et al (2000) Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin(1A) receptors. Proc Natl Acad Sci U S A 97:14731–14736. doi: 10.1073/pnas.97.26.1473117 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yousefi BH, von Reutern B, Scherübl D, Manook A, Schwaiger M, Grimmer T, Henriksen G, Förster S et al (2015) FIBT versus florbetaben and PiB: a preclinical comparison study with amyloid-PET in transgenic mice. EJNMMI Res 5:20. doi: 10.1186/s13550-015-0090-6 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Puzzo D, Lee L, Palmeri A, Calabrese G, Arancio O et al (2014) Behavioral assays with mouse models of Alzheimer’s disease: Practical considerations and guidelines. Biochem Pharmacol 88:450–467. doi: 10.1016/j.bcp.2014.01.011 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mittal K, Mani RJ, Katare DP (2016) Type 3 Diabetes: Cross Talk between Differentially Regulated Proteins of Type 2 Diabetes Mellitus and Alzheimer’s Disease. Sci Rep 6:25589. doi: 10.1038/srep25589 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yu Y-W, Hsieh T-H, Chen K-Y, Wu JC, Hoffer BJ, Greig NH, Li Y, Lai JH et al (2016) Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats. J Neurotrauma. doi: 10.1089/neu.2015.4229 Google Scholar
  35. 35.
    Asadbegi M, Yaghmaei P, Salehi I, Ebrahim-Habibi A, Komaki A et al (2016) Neuroprotective effects of metformin against Aβ-mediated inhibition of long-term potentiation in rats fed a high-fat diet. Brain Res Bull 121:178–185. doi: 10.1016/j.brainresbull.2016.02.005 CrossRefPubMedGoogle Scholar
  36. 36.
    Toba J, Nikkuni M, Ishizeki M, Yoshii A, Watamura N, Inoue T, Ohshima T et al (2016) PPARγ agonist pioglitazone improves cerebellar dysfunction at pre-Aβ deposition stage in APPswe/PS1dE9 Alzheimer’s disease model mice. Biochem Biophys Res Commun 473:1039–1044. doi: 10.1016/j.bbrc.2016.04.012 CrossRefPubMedGoogle Scholar
  37. 37.
    Stevens LM, Brown RE (2015) Reference and working memory deficits in the 3xTg-AD mouse between 2 and 15-months of age: A cross-sectional study. Behav Brain Res 278:496–505. doi: 10.1016/j.bbr.2014.10.033 CrossRefPubMedGoogle Scholar
  38. 38.
    Baeta-Corral R, Giménez-Llort L (2015) Persistent hyperactivity and distinctive strategy features in the Morris water maze in 3xTg-AD mice at advanced stages of disease. Behav Neurosci 129:129–137. doi: 10.1037/bne0000027 CrossRefPubMedGoogle Scholar
  39. 39.
    Stover KR, Campbell MA, Van Winssen CM, Brown RE (2015) Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer’s disease. Behav Brain Res 289:29–38. doi: 10.1016/j.bbr.2015.04.012 CrossRefPubMedGoogle Scholar
  40. 40.
    Matteucci E, Giampietro O (2015) Mechanisms of neurodegeration in type 2 diabetes and the neuroprotective potential of dipeptidyl peptidase 4 inhibitor. Curr Med Chem 22:1573–1581CrossRefPubMedGoogle Scholar
  41. 41.
    Jain S, Sharma B (2015) Neuroprotective effect of selective DPP-4 inhibitor in experimental vascular dementia. Physiol Behav 152:182–193. doi: 10.1016/j.physbeh.2015.09.007 CrossRefPubMedGoogle Scholar
  42. 42.
    Pintana H, Apaijai N, Chattipakorn N, Chattipakorn SC (2013) DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats. J Endocrinol 218:1–11. doi: 10.1530/JOE-12-0521 CrossRefPubMedGoogle Scholar
  43. 43.
    Sakr HF (2013) Effect of sitagliptin on the working memory and reference memory in type 2 diabetic Sprague-Dawley rats: possible role of adiponectin receptors 1. J Physiol Pharmacol 64:613–623PubMedGoogle Scholar
  44. 44.
    Abbas T, Faivre E, Hölscher C (2009) 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 205:265–271. doi: 10.1016/j.bbr.2009.06.035 CrossRefPubMedGoogle Scholar
  45. 45.
    Faivre E, Gault VA, Thorens B, Hölscher C (2011) Glucose-dependent insulinotropic polypeptide receptor knockout mice are impaired in learning, synaptic plasticity, and neurogenesis. J Neurophysiol 105:1574–1580. doi: 10.1152/jn.00866.2010 CrossRefPubMedGoogle Scholar
  46. 46.
    Faivre E, Hamilton A, Hölscher C (2012) Effects of acute and chronic administration of GIP analogues on cognition, synaptic plasticity and neurogenesis in mice. Eur J Pharmacol 674:294–306. doi: 10.1016/j.ejphar.2011.11.007 CrossRefPubMedGoogle Scholar
  47. 47.
    Nyberg J (2005) Glucose-Dependent Insulinotropic Polypeptide Is Expressed in Adult Hippocampus and Induces Progenitor Cell Proliferation. J Neurosci 25:1816–1825. doi: 10.1523/JNEUROSCI.4920-04.2005 CrossRefPubMedGoogle Scholar
  48. 48.
    Qin Z, Sun Z, Huang J, Hu Y, Wu Z, Mei B et al (2008) Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid-beta peptide (1-42). Neurosci Lett 444:217–221. doi: 10.1016/j.neulet.2008.08.047 CrossRefPubMedGoogle Scholar
  49. 49.
    Perry T, Greig NH (2002) The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer’s disease. J Alzheimers Dis 4:487–496CrossRefPubMedGoogle Scholar
  50. 50.
    Chen S, Liu AR, An FM, Yao WB, Gao XD et al (2012) Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer’s disease by exendin-4. Age (Omaha) 34:1211–1224. doi: 10.1007/s11357-011-9303-8 CrossRefGoogle Scholar
  51. 51.
    Gault VA, Hölscher C (2008) GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. Eur J Pharmacol 587:112–117. doi: 10.1016/j.ejphar.2008.03.02519 CrossRefPubMedGoogle Scholar
  52. 52.
    McClean PL, Gault VA, Harriott P, Hölscher C (2010) Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: A link between diabetes and Alzheimer’s disease. Eur J Pharmacol 630:158–162. doi: 10.1016/j.ejphar.2009.12.023 CrossRefPubMedGoogle Scholar
  53. 53.
    Hansen HH, Barkholt P, Fabricius K, Jelsing J, Terwel D, Pyke C, Knudsen LB, Vrang N et al (2016) 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 1634:158–170. doi: 10.1016/j.brainres.2015.12.052 CrossRefPubMedGoogle Scholar
  54. 54.
    McClean PL, Hölscher C (2014) Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer’s disease. Neuropharmacology 76:57–67. doi: 10.1016/j.neuropharm.2013.08.005 CrossRefPubMedGoogle Scholar
  55. 55.
    Calsolaro V, Edison P (2016) Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement 12:719–732. doi: 10.1016/j.jalz.2016.02.010 CrossRefPubMedGoogle Scholar
  56. 56.
    Hirakawa H, Zempo H, Ogawa M, Watanabe R, Suzuki J, Akazawa H, Komuro I, Isobe M et al (2015) A DPP-4 inhibitor suppresses fibrosis and inflammation on experimental autoimmune myocarditis in mice. PLoS One 10, e0119360. doi: 10.1371/journal.pone.0119360 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Shah Z, Kampfrath T, Deiuliis JA, Zhong J, Pineda C, Ying Z, Xu X, Lu B et al (2011) Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 124:2338–2349. doi: 10.1161/CIRCULATIONAHA.111.041418 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Song X, Jia H, Jiang Y, Wang L, Zhang Y, Mu Y, Liu Y et al (2015) Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 Diabetes Mellitus: A meta-analysis. Sci Rep 5:10202. doi: 10.1038/srep10202 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Long-Smith CM, Manning S, McClean PL, Coakley MF, O’Halloran DJ, Holscher C, O’Neill C et al (2013) The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-β plaque and glial pathology in a mouse model of Alzheimer’s disease. Neuro Mol Med 15:102–114. doi: 10.1007/s12017-012-8199-5 CrossRefGoogle Scholar
  60. 60.
    McClean PL, Parthsarathy V, Faivre E, Holscher C (2011) The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer’s Disease. J Neurosci 31:6587–6594. doi: 10.1523/JNEUROSCI.0529 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jayasankar Kosaraju
    • 1
  • R. M. Damian Holsinger
    • 2
    • 3
  • Lixia Guo
    • 4
  • Kin Yip Tam
    • 1
  1. 1.Drug Development Core, Faculty of Health SciencesUniversity of MacauTaipaChina
  2. 2.Laboratory of Molecular Neuroscience and Dementia, The Brain and Mind CentreThe University of SydneyCamperdownAustralia
  3. 3.The Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical SchoolThe University of SydneyLidcombeAustralia
  4. 4.Chongqing Key Lab of Natural Medicine ResearchChongqing Technology and Business UniversityChongqingChina

Personalised recommendations