Vasoactive Intestinal Peptide Decreases β-Amyloid Accumulation and Prevents Brain Atrophy in the 5xFAD Mouse Model of Alzheimer’s Disease
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.
KeywordsAlzheimer’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.
- 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
- 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. https://doi.org/10.3389/fnmol.2017.00427
- 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
- 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
- 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
- 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
- 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