Vasoactive Intestinal Peptide Decreases β-Amyloid Accumulation and Prevents Brain Atrophy in the 5xFAD Mouse Model of Alzheimer’s Disease

  • Orhan Tansel KorkmazEmail author
  • Hakan Ay
  • Nurgul Aytan
  • Isabel Carreras
  • Neil W. Kowall
  • Alpaslan Dedeoglu
  • Nese Tuncel


Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by extracellular deposits of fibrillary β-amyloid (Aβ) plaques in the brain that initiate an inflammatory process resulting in neurodegeneration. The neuronal loss associated with AD results in gross atrophy of affected regions causing a progressive loss of cognitive ability and memory function, ultimately leading to dementia. Growing evidence suggests that vasoactive intestinal peptide (VIP) could be beneficial for various neurodegenerative diseases, including AD. The study investigated the effects of VIP on 5xFAD, a transgenic mouse model of AD. Toward this aim, we used 20 5xFAD mice in two groups (n = 10 each), VIP-treated (25 ng/kg i.p. injection, three times per week) and saline-treated (the drug’s vehicle) following the same administration regimen. Treatment started at 1 month of age and ended 2 months later. After 2 months of treatment, the mice were euthanized, their brains dissected out, and immunohistochemically stained for Aβ40 and Aβ42 on serial sections. Then, plaque analysis and stereological morphometric analysis were performed in different brain regions. Chronic VIP administration in 5xFAD mice significantly decreased the levels of Aβ40 and Aβ42 plaques in the subiculum compared to the saline treated 5xFAD mice. VIP treatment also significantly decreased Aβ40 and Aβ42 plaques in cortical areas and significantly increased the hippocampus/cerebrum and corpus callosum/cerebrum ratio but not the cerebral cortex/cerebrum ratio. In summary, we found that chronic administration of VIP significantly decreased Aβ plaques and preserved against atrophy for related brain regions in 5xFAD AD mice.


Alzheimer’s disease Vasoactive intestinal peptide β-Amyloid plaques Brain atrophy Neuroinflammation 5xFAD 



The authors thank to Lokman Hossain for animal husbandry.


This research is supported by grants from NIA (R01AG031896, RF1AG056032) and the Department of Veteran Affairs (Merit Award; 5I01BX001875-03) to A. Dedeoglu and P30AG013846 to NW Kowall, and Scientific and Technical Research Council of Turkey (TUBITAK, 1059B190900502) to O.T. Korkmaz.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.


  1. Aytan N, Choi JK, Carreras I, Crabtree L, Nguyen B, Lehar M, Blusztajn JK, Jenkins BG, Dedeoglu A (2018) Protective effects of 7,8-dihydroxyflavone on neuropathological and neurochemical changes in a mouse model of Alzheimer's disease. Eur J Pharmacol 3 828:9–17CrossRefGoogle Scholar
  2. Bayer TA, Wirths O, Majtényi K, Hartmann T, Multhaup G, Beyreuther K, Czech C (2001) Key factors in Alzheimer's disease: beta-amyloid precursor protein processing, metabolism and intraneuronal transport. Brain Pathol 11(1):1–11, 1CrossRefGoogle Scholar
  3. Bertram L, Lill CM, Tanzi RE (2010) The genetics of Alzheimer disease: back to the future. Neuron 68(2):270–281CrossRefGoogle Scholar
  4. Brenneman DE (1988) Regulation of activity-linked neuronal survival by vasoactive intestinal peptide. Ann NYAcad Sci 527:595–597CrossRefGoogle Scholar
  5. Brenneman DE, Gozes I (1996) A femtomolar-acting neuroprotective peptide. J Clin Invest 97(10):2299–2307CrossRefGoogle Scholar
  6. Carreras I, McKee AC, Choi JK, Aytan N, Kowall NW, Jenkins BG, Dedeoglu A (2013) R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer’s disease. Brain Res 1541:115–127CrossRefGoogle Scholar
  7. Choi JK, Carreras I, Aytan N, Jenkins-Sahlin E, Dedeoglu A, Jenkins BG (2014) The effects of aging, housing and ibuprofen treatment on brain neurochemistry in a triple transgene Alzheimer’s disease mouse model using magnetic resonance spectroscopy and imaging. Brain Res 1590:85–96CrossRefGoogle Scholar
  8. Delgado M, Varela N, Gonzalez-Rey E (2008) Vasoactive intestinal peptide protects against beta-amyloid-induced neurodegeneration by inhibiting microglia activation at multiple levels. Glia 56(10):1091–1103CrossRefGoogle Scholar
  9. Deng G, Jin L (2017) The effects of vasoactive intestinal peptide in neurodegenerative disorders. Neurol Res 39(1):65–72CrossRefGoogle Scholar
  10. Dogrukol-Ak D, Banks WA, Tuncel N, Tuncel M (2003) Passage of vasoactive intestinal peptide across the blood-brain barrier. Peptides 24(3):437–444CrossRefGoogle Scholar
  11. Ge S, Sailor KA, Ming GL, Song H (2008) Synaptic integration and plasticity of new neurons in the adult hippocampus. J Physiol 586(16):3759–3765CrossRefGoogle Scholar
  12. Gonzales-Reyes R, Nava-Mesa MO, Vargas-Sanches K, Ariza-Salamanca D, Mora-Munoz L (2017) Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective.
  13. Gouras GK1, Olsson TT, Hansson O (2015) β-Amyloid peptides and amyloid plaques in Alzheimer’s disease. Neurotherapeutics 12(1):3–11CrossRefGoogle Scholar
  14. Gozes I, Bardea A, Reshef A, Zamostiano R, Zhukovsky S, Rubinraut S, Fridkin M, Brenneman DE (1996) Neurobiology neuroprotective strategy for Alzheimer disease: intranasal administration of a fatty neuropeptide. Proc Natl Acad Sci U S A 93:427–432CrossRefGoogle Scholar
  15. Han P, Caselli RJ, Baxter L, Serrano G, Yin J, Beach TG, Reiman EM, Shi J (2015) Association of pituitary adenylate cyclase-activating polypeptide with cognitive decline in mild cognitive impairment due to Alzheimer disease. JAMA Neurol 72(3):333–339CrossRefGoogle Scholar
  16. Han P, Tang Z2, Yin J et al. (2014) Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity. Neurobiol Aging ;35(9):2064–2071CrossRefGoogle Scholar
  17. Hardy J (2002) Testing times for the “amyloid cascade hypothesis”. Neurobiol Aging 23(6):1073–1074CrossRefGoogle Scholar
  18. Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR, Rawlings SR, Robberecht P, Said SI, Sreedharan SP, Wank SA, Waschek JA (1998) International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev 50(2):265–270PubMedGoogle Scholar
  19. Hill JM, Hauser JM, Sheppard LM, Abebe D, Spivak-Pohis I, Kushnir M, Deitch I, Gozes I (2007) Blockage of VIP during mouse embryogenesis modifies adult behaviour and results in permanent changes in brain chemistry. J Mol Neurosci 31(3):183–200PubMedGoogle Scholar
  20. Hill JM, Mervis RF, Politi J, McCune SK, Gozes I, Fridkin M, Brenneman DE (1994) Blockade of VIP during neonatal development induces neuronal damage and increases VIP and VIP receptors in brain. Ann N Y Acad Sci 739:211–225CrossRefGoogle Scholar
  21. Incerti M, Vink J, Roberson R, Benassou I, Abebe D, Spong CY (2010) Prevention of the alcohol-induced changes in brainderived neurotrophic factor expression using neuroprotective peptides in a model of fetal alcohol syndrome. Am J Obstet Gynecol 202(5):457 e1–4CrossRefGoogle Scholar
  22. Jan YN, Jan LY (2003) The control of dendrite development. Neuron 40(2):229–242CrossRefGoogle Scholar
  23. Kalaria RN (1999) Microglia and Alzheimer’s disease. Curr Opin Hematol 6(1):15–24CrossRefGoogle Scholar
  24. Korkmaz O, Ay H, Ulupinar E, Tunçel N (2012) Vasoactive intestinal peptide enhances striatal plasticity and prevents dopaminergic cell loss in Parkinsonian rats. J Mol Neurosci 48(3):565–573CrossRefGoogle Scholar
  25. Kowall NW, Hantraye P, Brouillet E, Beal MF, McKee AC, Ferrante RJ (2000) MPTP induces alpha-synuclein aggregation in the substantia nigra of baboons. Neuroreport 11(1):211–213CrossRefGoogle Scholar
  26. Lindberg O, Mårtensson G, Stomrud E, Palmqvist S, Wahlund LO, Westman E, Hansson O (2017) Atrophy of the posterior subiculum is associated with memory impairment, tau- and Aβ pathology in non-demented individuals. Front Aging Neurosci 9:306CrossRefGoogle Scholar
  27. Magarinos AM, Li CJ, Gal TJ et al (2011) Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodelling of hippocampal neurons. Hippocampus 21(3):253–264CrossRefGoogle Scholar
  28. McDonald DR, Bamberger ME, Combs CK, Landreth GE (1998) Beta-amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci 18(12):4451–4460CrossRefGoogle Scholar
  29. McGeer EG, McGeer PL (1998) The importance of inflammatory mechanisms in Alzheimer disease. Exp Gerontol 33(5):371–378CrossRefGoogle Scholar
  30. McGeer EG, McGeer PL (1999) Brain inflammation in Alzheimer disease and the therapeutic implications. Curr Pharm Des 5(10):821–836PubMedGoogle Scholar
  31. Meraz-Ríosv MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernández J, Campos-Peña V (2013) Inflammatory process in Alzheimer’s disease. Front Integr Neurosci 7:59Google Scholar
  32. Nunan R, Sivasathiaseelan H, Khan D, Zaben M, Gray W (2014) Microglial VPAC1R mediates a novel mechanism of neuroimmune-modulation of hippocampal precursor cells via IL-4 release. Glia 62(8):1313–1327CrossRefGoogle Scholar
  33. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26(40):10129–10140CrossRefGoogle Scholar
  34. Onoue S, Endo K, Ohshima K, Yajima T, Kashimoto K (2002) The neuropeptide PACAP attenuates beta-amyloid (1-42)-induced toxicity in PC12 cells. Peptides 23(8):1471–1478CrossRefGoogle Scholar
  35. Onoue S, Waki Y, Nagano Y, Satoh S, Kashimoto K (2001) The neuromodulatory effects of VIP/PACAP on PC-12 cells are associated with their N-terminal structures. Peptides 22(6):867–872CrossRefGoogle Scholar
  36. Pellegri G, Magistretti PJ, Martin JL (1998) VIP and PACAP potentiate the action of glutamate on BDNF expression in mouse cortical neurones. Eur J Neurosci 10(1):272–280CrossRefGoogle Scholar
  37. Philipson O, Lord A, Gumucio A, O'Callaghan P, Lannfelt L, Nilsson LN (2010) Animal models of amyloid-beta-related pathologies in Alzheimer’s disease. FEBS J 277(6):1389–1409CrossRefGoogle Scholar
  38. Rangon CM, Dicou E, Goursaud S et al (2006) Mechanisms of VIP induced neuroprotection against neonatal excitotoxicity. Ann N Y Acad Sci 1070:512–517CrossRefGoogle Scholar
  39. Rat D1, Schmitt U, Tippmann F et al. (2012) Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer’s disease-like pathology in amyloid precursor protein-transgenic mice. FASEB J 25(9):3208–3218CrossRefGoogle Scholar
  40. Redwine JM, Kosofsky B, Jacobs RE, Games D, Reilly JF, Morrison JH, Young WG, Bloom FE (2003) Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: a magnetic resonance microscopy and stereologic analysis. Proc Natl Acad Sci U S A 100(3):1381–1386CrossRefGoogle Scholar
  41. Smith-Swintosky VL, Gozes I, Brenneman DE, D'Andrea MR, PlataSalaman CR (2005) Activity-dependent neurotrophic factor-9 and NAP promote neurite outgrowth in rat hippocampal and cortical cultures. J Mol Neurosci 25(3):225–238CrossRefGoogle Scholar
  42. Solito E, Sastre M (2012) Microglia function in Alzheimer’s disease. Front Pharmacol 3:14CrossRefGoogle Scholar
  43. Song M, Xiong JX, Wang YY, Tang J, Zhang B, Bai Y (2012) VIP enhances phagocytosis of fibrillar beta-amyloid by microglia and attenuates amyloid deposition in the brain of APP/PS1 mice. PLoS One 7(2):e29790CrossRefGoogle Scholar
  44. Stranahan AM (2011) Physiological variability in brain-derived neurotrophic factor expression predicts dendritic spine density in the mouse dentate gyrus. Neurosci Lett 9;495(1):60-62CrossRefGoogle Scholar
  45. Villoslada P, Moreno B, Melero I et al (2008) Immunotherapy for neurological diseases. Clin Immunol 128(3):294–305CrossRefGoogle Scholar
  46. Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, O'Hare E, Esler WP, Maggio JE, Mantyh PW (1998) Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 18(6):2161–2173CrossRefGoogle Scholar
  47. Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD (2002) Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia. J Neurosci 22(9):3484–3492CrossRefGoogle Scholar
  48. Yelkenli IH, Ulupinar E, Korkmaz OT, Şener E, Kuş G, Filiz Z, Tunçel N (2016) Modulation of corpus striatal neurochemistry by astrocytes and vasoactive intestinal peptide (VIP) in parkinsonian rats. J Mol Neurosci 59(2):280–289CrossRefGoogle Scholar
  49. Zaben M, Sheward WJ, Shtaya A, Abbosh C, Harmar AJ, Pringle AK, Gray WP (2009) The neurotransmitter VIP expands the pool of symmetrically dividing postnatal dentate gyrusprecursors via VPAC2 receptors or directs them toward a neuronal fate via VPAC1 receptors. Stem Cells 27(10):2539–2551CrossRefGoogle Scholar
  50. Zhang QL, Liu J, Lin PX, Webster HD (2002) Local administration of vasoactive intestinal peptide after nerve transection accelerates early myelination and growth of regenerating axons. J Peripher Nerv Syst 7:118–127CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Research and DevelopmentVA Boston Healthcare SystemBostonUSA
  2. 2.Department of NeurologyBoston University School of MedicineBostonUSA
  3. 3.Department of Physiology, Faculty of MedicineEskisehir Osmangazi UniversityEskisehirTurkey
  4. 4.Faculty of Medicine, Department of PhysiologyEskisehir Osmangazi UniversityEskisehirTurkey
  5. 5.Department of Anatomy, Faculty of MedicineEskisehir Osmangazi UniversityEskisehirTurkey
  6. 6.Department of BiochemistryBoston University School of MedicineBostonUSA
  7. 7.Department of RadiologyMGH and Harvard Medical SchoolBostonUSA

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