Abstract
Vasoactive intestinal peptide (VIP) is a multifunctional neuropeptide with demonstrated immunosuppressive and neuroprotective activities. It has been shown to inhibit Amyloid beta (Aβ)-induced neurodegeneration by indirectly suppressing the production and release of a variety of inflammatory and neurotoxic factors by activated microglia. We demonstrated that VIP markedly increased microglial phagocytosis of fibrillar Aβ42 and that this enhanced phagocytotic activity depended on activation of the Protein kinase C (PKC) signaling pathway. In addition, VIP suppressed the release of tumor necrosis factor alpha (TNF-α) and nitric oxide(NO) from microglia activated by combined treatment with fibrillar Aβ42 and low dose interferon-γ (IFN-γ). We utilized an adenovirus-mediated gene delivery method to overexpress VIP constitutively in the hippocampus of APPswPS1 transgenic mice. The Aβ load was significantly reduced in the hippocampus of this animal model of Alzheimer's disease, possibly due to the accumulation and activation of cd11b-immunoactive microglial cells. The modulation of microglial activation, phagocytosis, and secretion by VIP is a promising therapeutic option for the treatment of Alzheimer's disease(AD).
Highlights
Alzheimer’s disease is a progressive neurodegenerative disease characterized by senile plaques, intracellular neurofibrillary tangles, and reactive gliosis involving both microglia and astrocytes [1,2]
The present study investigated the effect of Vasoactive intestinal peptide (VIP) on the phagocytosis of Amyloid beta (Ab) by microglia and on the secretion of proinflammatory cytokines by microglia in response to Ab
To determine if VIP can modulate microglial uptake of Ab1–42, mouse primary microglial cells were incubated in 500 nM fibrilized-Cy3-Ab1–42 for 2 h in the presence or absence of VIP
Summary
Alzheimer’s disease is a progressive neurodegenerative disease characterized by senile plaques, intracellular neurofibrillary tangles, and reactive gliosis involving both microglia and astrocytes [1,2]. Microglia are derived from mononuclear phagocytes and function as the resident macrophage-like cells of the brain parenchyma. Microglia serve functions similar to other resident macrophages, including phagocytosis, antigen presentation and production of cytokines. Microglia-mediated immune responses play both protective and deleterious roles in the pathogenesis of AD. Microglia secrete neurotrophic agents and eliminating beta-amyloid through direct phagocytosis. Microglia release neurotoxic (pro-inflammatory) cytokinase and other factors that can cause neurodegeneration, including NO. Therapeutic strategies that inhibit the secretion of neurotoxins from microglia or enhance microglial phagocytic activity may reduce cerebral Ab load in mouse models of AD and limit neurodegeneration [3,4,5,6]
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