AVP(4-8) Improves Cognitive Behaviors and Hippocampal Synaptic Plasticity in the APP/PS1 Mouse Model of Alzheimer’s Disease

  • Xiumin Zhang
  • Fang Zhao
  • Chenfang Wang
  • Jun Zhang
  • Yu Bai
  • Fang Zhou
  • Zhaojun Wang
  • Meina Wu
  • Wei Yang
  • Junhong GuoEmail author
  • Jinshun Qi
Original Article


Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin (AVP) in the brain of patients with Alzheimer’s disease (AD). AVP(4-8), different from its precursor AVP, plays memory enhancement roles in the CNS without peripheral side-effects. However, it is not clear whether AVP(4-8) can improve cognitive behaviors and synaptic plasticity in the APP/PS1 mouse model of AD. Here, we investigated for the first time the neuroprotective effects of AVP(4-8) on memory behaviors and in vivo long-term potentiation (LTP) in APP/PS1-AD mice. The results showed that: (1) APP/PS1-AD mice had lower spontaneous alternation in the Y-maze than wild-type (WT) mice, and this was significantly reversed by AVP(4-8); (2) the prolonged escape latency of APP/PS1-AD mice in the Morris water maze was significantly decreased by AVP(4-8), and the decreased swimming time in target quadrant recovered significantly after AVP(4-8) treatment; (3) in vivo hippocampal LTP induced by high-frequency stimulation had a significant deficit in the AD mice, and this was partly rescued by AVP(4-8); (4) AVP(4-8) significantly up-regulated the expression levels of postsynaptic density 95 (PSD95) and nerve growth factor (NGF) in the hippocampus of AD mice. These results reveal the beneficial effects of AVP(4-8) in APP/PS1-AD mice, showing that the intranasal administration of AVP(4-8) effectively improved the working memory and long-term spatial memory of APP/PS1-AD mice, which may be associated with the elevation of PSD95 and NGF levels in the brain and the maintenance of hippocampal synaptic plasticity.


AVP(4-8) APP/PS1 transgenic mice Cognitive behavior Synaptic plasticity In vivo hippocampal LTP 



This work was supported by the National Natural Science Foundation of China (31471080), the Scientific Program for “Sanjin Scholars” of Shanxi Province, Shanxi “1331 Project” Key Subjects Construction (1331KSC), and Science Foundation for Excellent Young Scholars of Shanxi Province, China (201801D211005).

Conflict of interest

The authors claim no conflict of interest.


  1. 1.
    Wuwongse S, Chang RC, Law AC. The putative neurodegenerative links between depression and Alzheimer’s disease. Prog Neurobiol 2010, 91: 362–375.PubMedCrossRefGoogle Scholar
  2. 2.
    Varga J, Klausz B, Kálmán ÁD, Pákáski M, Szucs S, Garab D, et al. Increase in Alzheimer’s related markers preceeds memory disturbances: Studies in vasopressin-deficient Brattleboro rat. Brain Res Bull 2014, 100: 6–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Strac DS, Muck-Seler D, Pivac N. Neurotransmitter measures in the cerebrospinal fluid of patients with Alzheimer’s disease: a review. Psychiatr Danub 2015, 27: 14–24.PubMedGoogle Scholar
  4. 4.
    Sun BL, Li WW, Zhu C, Jin WS, Zeng F, Liu YH, et al. Clinical research on Alzheimer’s disease: progress and perspectives. Neurosci Bull 2018, 34: 1111–1118.PubMedCrossRefGoogle Scholar
  5. 5.
    Raskind MA, Peskind ER, Lampe TH, Risse SC, Taborsky GJ, Dorsa D. Cerebrospinal fluid vasopressin, oxytocin, somatostatin, and beta-endorphin in Alzheimer’s disease. Arch Gen Psychiatry 1986, 43: 382–388.PubMedCrossRefGoogle Scholar
  6. 6.
    Mazurek MF, Bed MF, Bird ED, Martin JB. Vasopressin in Alzheimer’s disease: a study of postmortem brain concentrations. Ann Neurol 1986, 20: 665–670.PubMedCrossRefGoogle Scholar
  7. 7.
    Rotondo F, Butz H, Syro LV, Yousef GM, Di Ieva A, Restrepo LM. Arginine vasopressin (AVP): a review of its historical perspectives, current research and multifunctional role in the hypothalamohypophysial system. Pituitary 2016, 19: 345–355.PubMedCrossRefGoogle Scholar
  8. 8.
    van Wimersma Greidanus TB, Bohus B, de Wied D. The role of vasopressin in memory processes. Prog Brain Res 1975, 42: 135–141.PubMedCrossRefGoogle Scholar
  9. 9.
    Engelmann M, Landgraf R. Microdialysis administration of vasopressin into the septum improves social recognition in Brattleboro rats. Physiol Behav1994, 55: 145–149.PubMedCrossRefGoogle Scholar
  10. 10.
    Egashira N, Tanoue A, Higashihara F, Mishima K, Fukue Y, Takano Y, et al. V1a receptor knockout mice exhibit impairment of spatial memory in an eight-arm radial maze. Neurosci Lett 2004, 356: 195–198.PubMedCrossRefGoogle Scholar
  11. 11.
    DeVito LM, Konigsberg R, Lykken C, Sauvage M, Young WS, 3rd, Eichenbaum H. Vasopressin 1b receptor knock-out impairs memory for temporal order. J Neurosci 2009, 29: 2676–2683.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 2004, 29: 483–493.PubMedCrossRefGoogle Scholar
  13. 13.
    Nephew BC, Bridges RS. Arginine vasopressin V1a receptor antagonist impairs maternal memory in rats. Physiol Behav 2008, 95: 182–186.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Weingartner H, Gold P, Ballenger JC, Smallberg SA, Summers R, Rubinow DR, et al. Effects of vasopressin on human memory functions. Science 1981, 211: 601–603.PubMedCrossRefGoogle Scholar
  15. 15.
    Yang C, Zhang X, Gao J, Wang M, Yang Z. Arginine vasopressin ameliorates spatial learning impairments in chronic cerebral hypoperfusion via V1a receptor and autophagy signaling partially. Transl Psychiatry 2017, 7: e1174.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    de Wied D, Gaffori O, van Ree JM, de Jong W. Central target for the behavioural effects of vasopressin neuropeptides. Nature 1984, 308: 276–278.PubMedCrossRefGoogle Scholar
  17. 17.
    Pan YF, Jia XT, Wang XH, Chen XR, Li QS, Gao XP, et al. Arginine vasopressin remolds the spontaneous discharges disturbed by amyloid beta protein in hippocampal CA1 region of rats. Regul Pept 2013, 183: 7–12.PubMedCrossRefGoogle Scholar
  18. 18.
    Jing W, Guo F, Cheng L, Zhang JF, Qi JS. Arginine vasopressin prevents amyloid beta protein-induced impairment of long-term potentiation in rat hippocampus in vivo. Neurosci Lett 2009, 450: 306–310.PubMedCrossRefGoogle Scholar
  19. 19.
    Hicks C, Ramos L, Reekie T, Misagh GH, Narlawar R, Kassiou M, et al. Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats. Br J Pharmacol 2014, 171: 2868–2887.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Song Z, Albers HE. Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery. Front Neuroendocrinol 2018, 51: 14–24.PubMedCrossRefGoogle Scholar
  21. 21.
    Alescio-Lautier B, Soumireu-Mourat B. Effects of peripherally administered arginine-vasopressin on learning, retention and forgetting in mice. Behav Brain Res 1990, 41: 117–128.PubMedCrossRefGoogle Scholar
  22. 22.
    Wu JH, Du YC. Binding sites of ZNC(C)PR, a pentapeptide fragment of argipressin, in rat brain. Acta Pharmacol Sin 1995, 16: 141–144.Google Scholar
  23. 23.
    Du YC, Wu JH, Jiang XM, Gu YJ. Characterization of binding sites of a memoryenhancing peptide AVP(4-8) in rat cortical synaptosomal membranes. Peptides 1994, 15: 1273–1279.PubMedCrossRefGoogle Scholar
  24. 24.
    Reijmers LGJE, van Ree JM, Spraijt BM, Burbach JP, De Wied D. Vasopressin metabolites: A link between vasopressin and memory? Prog Brain Res 1999, 119: 523–535.CrossRefGoogle Scholar
  25. 25.
    Burbach JP, Kovacs GL, de Wied D, van Nispen JW, Greven HM. A major metabolite of arginine vasopressin in the brain is a highly potent neuropeptide. Science 1983, 221: 1310–1312.PubMedCrossRefGoogle Scholar
  26. 26.
    De Wied D, Gaffori O, Van Ree JM, De Jong W. Vasopressin antagonists block peripheral as well as central vasopressin receptors. Pharmacol Biochem Behav 1984, 21: 393–400.PubMedCrossRefGoogle Scholar
  27. 27.
    Peineau S, Rabiant K, Pierrefiche O, Potier B. Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer’s disease. Pharmacol Res 2018, 130: 385–401.PubMedCrossRefGoogle Scholar
  28. 28.
    Ni B, Wu R, Yu T, Zhu H, Li Y, Liu Z. Role of the hippocampus in distinct memory traces: timing of match and mismatch enhancement revealed by intracranial recording. Neurosci Bull 2017, 33: 664–674.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Gelman S, Palma J, Tombaugh G, Ghavami A. Differences in synaptic dysfunction between rTg4510 and APP/PS1 mouse models of Alzheimer’s disease. J Alzheimers Dis 2018, 61: 195–208.PubMedCrossRefGoogle Scholar
  30. 30.
    Chepkova AN, French P, De Wied D, Ontskul AH, Ramakers GM, Skrebitski VG, et al. Long-lasting enhancement of synaptic excitability of CA1/subiculum neurons of the rat ventral hippocampus by vasopressin and vasopressin(4-8). Brain Res 1995, 701: 255–266.PubMedCrossRefGoogle Scholar
  31. 31.
    Dubrovsky B, Tatarinov A, Gijsbers K, Harris J, Tsiodras A. Effects of arginine-vasopressin (AVP) on long-term potentiation in intact anesthetized rats. Brain Res Bull 2003, 59: 467–472.PubMedCrossRefGoogle Scholar
  32. 32.
    Wang M, Chen JT, Ruan DY, Xu YZ. Vasopressin reverses aluminum-induced impairment of synaptic plasticity in the rat dentate gyrus in vivo. Brain Res 2001, 899: 193–200.PubMedCrossRefGoogle Scholar
  33. 33.
    Reddy PH, Yin X, Manczak M, Kumar S, Pradeepkiran JA, Vijayan M, et al. Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s disease. Hum Mol Genet 2018, 27: 2502–2516.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Mirza FJ, Zahid S. The role of synapsins in neurological disorders. Neurosci Bull 2018, 34: 349–358.PubMedCrossRefGoogle Scholar
  35. 35.
    Pham E, Crews L, Ubhi K, Hansen L, Adame A, Cartier A, et al. Progressive accumulation of amyloid-beta oligomers in Alzheimer’s disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins. FEBS J 2010, 277: 3051–3067.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Shinohara Y. Quantification of postsynaptic density proteins: glutamate receptor subunits and scaffolding proteins. Hippocampus 2012, 22: 942–953.PubMedCrossRefGoogle Scholar
  37. 37.
    Du YC, Yan QW, Qiao LY. Function and molecular basis of action of vasopressin 4-8 and its analogues in rat brain. Prog Brain Res 1998, 119: 163–175.PubMedCrossRefGoogle Scholar
  38. 38.
    Qiao LY, Du YC. Involvement of a putative G-protein-coupled receptor and a branching pathway in argipressin (4-8) signal transduction in rat hippocampus. Acta Pharmacol Sin 1998, 19: 15–20.Google Scholar
  39. 39.
    Yan QW, Du YC. AVP(4-8) may stimulate a G protein-coupled receptor in rat hippocampal synaptosomal membranes. Acta Biochim Biophys Sin 1998, 30: 505–509.PubMedGoogle Scholar
  40. 40.
    Qiao LY, Chen XF, Gu BX, Wang TX, Du YC. Effect of AVP(4-8) administration on Ca2+/CaM-dependent protein kinase II autophosphorylation in rat brain. Acta Physiol Sin 1998, 50: 132–138.Google Scholar
  41. 41.
    Zhen X, Dong M, Du YC. Effect of arginine-vasopressin(4-8) on PKC and PKA activities in rat brain. Chin J Biochem Mol Biol 2000, 16: 529–532.Google Scholar
  42. 42.
    Zhen XG, Du YC. AVP(4-8) enhances PKC and MAPK activities in SK-N-SH cells. Acta Biochim Biophys Sin 2000, 32: 105–108.PubMedGoogle Scholar
  43. 43.
    Guo J, Zhou AW, Du YC, Chen XF. AVP(4-8) increases NGF mRNA and protein content in rat hippocampus. Chin J Neurosci 1996, 3: 23–27.Google Scholar
  44. 44.
    Zhou AW, Guo J, Wang HY, Gu BX, Du YC. Enhancement of NGF gene expression in rat brain by the memory-enhancing peptide AVP(4-8). Peptides 1995, 16: 581–586.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhou AW, Li WX, Guo J, Du YC. Facilitation of AVP(4-8) on gene expression of BDNF and NGF in rat brain. Peptides 1997, 18: 1179–1187.PubMedCrossRefGoogle Scholar
  46. 46.
    Chen XF, Tang T, Zhang JW, Miao HH, Wang TX, Du YC. ZNC(C)PR affects developmental changes of P46 phosphorylation in rat hippocampus. Mol Reprod Dev 1993, 35: 251–256.PubMedCrossRefGoogle Scholar
  47. 47.
    Isaev NK, Stelmashook EV, Genrikhs EE. Role of nerve growth factor in plasticity of forebrain cholinergic neurons. Biochemistry (Mosc) 2017, 82: 291–300.CrossRefGoogle Scholar
  48. 48.
    Tiernan CT, Ginsberg SD, He B, Ward SM, Guillozet-Bongaarts AL, Kanaan NM, et al. Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer’s disease. Neurobiol Dis 2018, 117: 125–136.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Yamada K, Nitta A, Hasegawa T, Fuji K, Hiramatsu M, Kameyama T, et al. Orally active NGF synthesis stimulators: potential therapeutic agents in Alzheimer’s disease. Behav Brain Res 1997, 83: 117–122.PubMedCrossRefGoogle Scholar
  50. 50.
    Berardi N, Braschi C, Capsoni S, Cattaneo A, Maffei L. Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration. J Alzheimers Dis 2007, 11: 359–370.PubMedCrossRefGoogle Scholar
  51. 51.
    De Rosa R, Garcia AA, Braschi C, Capsoni S, Maffei L, Berardi N, et al. Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc Natl Acad Sci U S A 2005, 102: 3811–3816.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Tarumi T, Sugimoto Y, Chen Z, Zhao Q, Kamei C. Effects of metabolic fragments of [Arg(8)]-vasopressin on nerve growth in cultured hippocampal neurons. Brain Res Bull 2000, 51: 407–411.PubMedCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  1. 1.Department of Physiology, Key laboratory of Cellular Physiology, Ministry of EducationShanxi Medical UniversityTaiyuanChina
  2. 2.Department of Physiology, Key Laboratory of Cellular PhysiologyMinistry of Education, Shanxi Medical UniversityTaiyuanChina

Personalised recommendations