Vasoactive intestinal peptide protects against beta-amyloid-induced neurodegeneration by inhibiting microglia activation at multiple levels.

Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar beta-amyloid (Abeta) in the brain, increased microglial-mediated inflammatory reactions in senile plaques, selective neuronal death, and cognitive deficits. The use of agents that limit microglial activation and inflammation in AD has recently emerged as an attractive therapeutic strategy for this disease. The vasoactive intestinal peptide (VIP), a widely distributed neuropeptide, has shown neuroprotective effects in acute brain damage in vivo and potent anti-inflammatory actions in central nervous system. Here, we report that VIP inhibits Abeta-induced neurodegeneration by indirectly inhibiting the production of a wide panel of inflammatory and neurotoxic agents by activated microglia cells. The inhibitory effect of VIP is mediated by blocking signaling through the p38 MAPK, p42/p44 MAPK, and NFkB cascades, the three major transduction pathways involved in the transcription of inflammatory mediators and the production of free radicals by Abeta-activated microglia cells. Based on its neuroprotective action and its efficacy in inhibiting a broad range of inflammatory responses, VIP may provide a novel therapeutic approach to AD.