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