Carnosine Prevents A Beta-Induced Oxidative Stress And Inflammation In Microglial Cells: A Key Role Of Tgf-Beta 1

Carnosine (beta-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (A beta) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer's disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, the effects of carnosine on microglial cells and neuroinflammation are not well understood. In the present work, carnosine was tested for its ability to protect BV-2 microglial cells against oligomeric A beta 1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with A beta oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O-2(-center dot) intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1 beta, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-beta 1. Carnosine also prevented A beta-induced neurodegeneration in mixed neuronal cultures challenged with A beta oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-beta receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against A beta toxicity with a key role of TGF-beta 1 in mediating these protective effects.