Neurochemical Research

, Volume 42, Issue 8, pp 2326–2335 | Cite as

Liraglutide Improves Water Maze Learning and Memory Performance While Reduces Hyperphosphorylation of Tau and Neurofilaments in APP/PS1/Tau Triple Transgenic Mice

  • Shuyi Chen
  • Jie Sun
  • Gang Zhao
  • Ai Guo
  • Yanlin Chen
  • Rongxia Fu
  • Yanqiu DengEmail author
Original Paper


The purpose of this study was to explore how liraglutide affects AD-like pathology and cognitive function in APP/PS1/Tau triple transgenic (3 × Tg) Alzheimer disease (AD) model mice. Male 3 × Tg mice and C57BL/6 J mice were treated for 8 weeks with liraglutide (300 μg/kg/day, subcutaneous injection) or saline. Levels of phosphorylated tau, neurofilaments (NFs), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in brain tissues were assessed with western blots. Fluoro-Jade-B labeling were applied to detect pathological changes. The Morris water maze (MWM) was used to assess the spatial learning and memory. Liraglutide decreased levels of hyperphosphorylated tau and NFs in 3 × Tg liraglutide-treated (Tg + LIR) mice, increased ERK phosphorylation, and decreased JNK phosphorylation. Liraglutide also decreased the number of degenerative neurons in the hippocampus and cortex of Tg + LIR mice, and shortened their escape latencies and increased their hidden platform crossings in the MWM task. Liraglutide did not significantly affect the animals’ body weight (BW) or fasting blood glucose. Liraglutide can reduce hyperphosphorylation of tau and NFs and reduce neuronal degeneration, apparently through alterations in JNK and ERK signaling, which may be related to its positive effects on AD-like learning and memory impairment.


Alzheimer disease Liraglutide 3 × Tg mice Tau ERK JNK 



This work was supported by the National Natural Science Foundation of China (No. 81270422, 30973156) and the National Training Programs of Innovation and Entrepreneurship for Undergraduates (201610062013).


  1. 1.
    EsmaeiliTazangi P, Moosavi SM, Shabani M, Haghani M (2015) Erythropoietin improves synaptic plasticity and memory deficits by decrease of the neurotransmitter release probability in the rat model of Alzheimer’s disease. Pharmacol Biochem Behav 130:15–21CrossRefGoogle Scholar
  2. 2.
    Blennow K, Zetterberg H, Fagan AM (2012) Fluid biomarkers in Alzheimer disease. Cold Spring Harb Perspect Med 2:a006221CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Liu Q, Xie F, Alvarado-Diaz A, Smith MA, Moreira PI, Zhu X et al (2011) Neurofilamentopathy in neurodegenerative diseases. Open Neurol J 5:58–62CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Khan SS, Bloom GS (2016) Tau: the center of a signaling nexus in Alzheimer’s disease. Front Neurosci 10:31PubMedPubMedCentralGoogle Scholar
  5. 5.
    Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX (2009) Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: Implication for Alzheimer’s disease. Am J Pathol 175:2089–2098CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gerozissis K (2008) Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 585:38–49CrossRefPubMedGoogle Scholar
  7. 7.
    Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R et al (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimers Dis 7:63–80CrossRefPubMedGoogle Scholar
  8. 8.
    Egefjord L, Gejl M, Møller A, Brændgaard H, Gottrup H, Antropova O et al (2012) Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer s disease - protocol for a controlled, randomized double-blinded trial. Dan Med J 59:A4519PubMedGoogle Scholar
  9. 9.
    Hansen HH, Barkholt P, Fabricius K, Jelsing J, Terwel D, Pyke C 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 1634:158–170CrossRefPubMedGoogle Scholar
  10. 10.
    Sharma MK, Jalewa J, Hölscher C (2014) Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress. J Neurochem 128:459–471CrossRefPubMedGoogle Scholar
  11. 11.
    Candeias EM, Sebastião IC, Cardoso SM, Correia SC, Carvalho CI, Plácido AI et al (2015) Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide. World J Diabetes 6:807–827CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Xiong H, Zheng C, Wang J, Song J, Zhao G, Shen H et al (2013) 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 37:623–635PubMedGoogle Scholar
  13. 13.
    Gejl M, Gjedde A, Egefjord L, Møller A, Hansen SB, Vang K et al (2016) In Alzheimer’s disease, six-month treatment with GLP-1 analogue prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial. Front Aging Neurosci 8:108CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421CrossRefPubMedGoogle Scholar
  15. 15.
    Shishido H, Kishimoto Y, Kawai N, ToyotaY, Ueno M, Kubota T et al (2016) Traumatic brain injury accelerates amyloid-beta deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer’s disease. Neurosci Lett 629:62–67CrossRefPubMedGoogle Scholar
  16. 16.
    Femminella GD, Edison P (2014) Evaluation of neuroprotective effect of glucagon-like peptide 1 analogs using neuroimaging. Alzheimers Dement 10:S55–S61CrossRefPubMedGoogle Scholar
  17. 17.
    Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gadbury GL, Coffey CS, Allison DB (2003) Modern statistical methods for handling missing repeated measurements in obesity trial data: beyond LOCF. Obes Rev 4:175–184CrossRefPubMedGoogle Scholar
  19. 19.
    McClean PL, Parthsarathy V, Faivre E, Hölscher C (2011) The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 31:6587–6594CrossRefPubMedGoogle Scholar
  20. 20.
    Di J, Cohen LS, Corbo CP, Phillips GR, ElIdrissi A, Alonso AD (2016) Abnormal tau induces cognitive impairment through two different mechanisms: synaptic dysfunction and neuronal loss. Sci Rep 6:20833CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bertoni-Freddari C, Sensi SL, Giorgetti B, Balietti M, Di Stefano G, Canzoniero LM et al (2008) Decreased presence of perforated synapses in a triple-transgenic mouse model of Alzheimer’s disease. Rejuvenation Res 11:309–313CrossRefPubMedGoogle Scholar
  22. 22.
    LaFerla FM, Oddo S (2005) Alzheimer’s disease: a-beta, tau and synaptic dysfunction. Trends Mol Med 11:170–176CrossRefPubMedGoogle Scholar
  23. 23.
    Chen Y, Deng Y, Zhang B, Gong CX (2014) Deregulation of brain insulin signaling in Alzheimer’s disease. Neurosci Bull 30:282–294CrossRefPubMedGoogle Scholar
  24. 24.
    Qi L, Ke L, Liu X, Liao L, Ke S, Liu 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 783:23–32CrossRefPubMedGoogle Scholar
  25. 25.
    Hansen HH, Fabricius K, Barkholt P, Kongsbak-Wismann P, Schlumberger C, Jelsing J et al (2016) Long-term treatment with liraglutide, a glucagon-like peptide-1 (GLP-1) Receptor agonist, has no effect on β-amyloid plaque load in two transgenic APP/PS1 mouse models of Alzheimer’s disease. PLoS ONE 11(7):e0158205CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mansur RB, Ahmed J, Cha DS, Woldeyohannes HO, Subramaniapillai M, Lovshin J et al (2017) Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mooddisorders: a pilot, open-label study. J Affect Disord 207:114–120CrossRefPubMedGoogle Scholar
  27. 27.
    Yang Y, Zhang J, Ma D, Zhang M, Hu S, Shao S et al (2013) Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. J Alzheimers Dis 37:637–648PubMedGoogle Scholar
  28. 28.
    Li L, Zhang ZF, Hölscher C, Gao C, Jiang YH, Liu YZ (2012) (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 674(2–3):280–286CrossRefPubMedGoogle Scholar
  29. 29.
    Fernandez-Martos CM, King AE, Atkinson RA, Woodhouse A, Vickers JC (2015) Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer’s disease. Neurobiol Aging 36:2757–2767CrossRefPubMedGoogle Scholar
  30. 30.
    Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA et al (2008) Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer’s disease and correction by insulin. J Neurosci Res 86:3265–3274CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, Herman M et al (2007) Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci 27:13635–13648CrossRefPubMedGoogle Scholar
  32. 32.
    Kim EK, Choi EJ (2015) Compromised MAPK signaling in human diseases: an update. Arch Toxicol 89:867–882CrossRefPubMedGoogle Scholar
  33. 33.
    Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H et al (2012) An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Abeta oligomers. J Clin Invest 122(4):1339–1353CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Giovannini MG, Cerbai F, Bellucci A, Melani C, Grossi C, Bartolozzi C et al (2008) Differential activation of mitogen-activated protein kinase signaling pathways in the hippocampus of CRND8 transgenic mouse, a model of Alzheimer’s disease. Neuroscience 153:618–633CrossRefPubMedGoogle Scholar
  35. 35.
    Um HS, Kang EB, Koo JH, Kim HT, Jin-Lee, Kim EJ et al (2011) Treadmill exercise represses neuronal cell death in an aged transgenic mousemodel of Alzheimer’s disease. Neurosci Res 69:161–173CrossRefPubMedGoogle Scholar
  36. 36.
    Yarza R, Vela S, Solas M, Ramirez MJ (2015) c-Jun N-terminal Kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front Pharmacol 6:321PubMedGoogle Scholar
  37. 37.
    Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ et al (2008) A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322:1539–1543CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Arora K, Cheng J, Nichols RA (2015) Nicotinic acetylcholine receptors sensitize a MAPK-linked toxicity pathway on prolonged exposure to beta-amyloid. J Biol Chem 290:21409–21420CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ma QL, Harris-White ME, Ubeda OJ, Simmons M, Beech W, Lim GP et al (2007) Evidence of Abeta- and transgene-dependent defects in ERK-CREB signaling in Alzheimer’s models. J Neurochem 103:1594–1607CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Shuyi Chen
    • 1
  • Jie Sun
    • 1
  • Gang Zhao
    • 2
  • Ai Guo
    • 1
  • Yanlin Chen
    • 1
  • Rongxia Fu
    • 3
  • Yanqiu Deng
    • 1
    • 4
    Email author
  1. 1.Pathophysiology Department, School of Basic Medical SciencesTianjin Medical UniversityTianjinChina
  2. 2.Department of Pathology, Tianjin Cancer HospitalTianjin Medical UniversityTianjinChina
  3. 3.Food science and Biological Engineering DepartmentTianjin Agriculture UniversityTianjinChina
  4. 4.TianjinChina

Personalised recommendations