Abstract
Carnosine (β-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 (Aβ) 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 Aβ1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with Aβ oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O2−• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1β, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1. Carnosine also prevented Aβ-induced neurodegeneration in mixed neuronal cultures challenged with Aβ oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-β receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against Aβ toxicity with a key role of TGF-β1 in mediating these protective effects.
Highlights
Carnosine (β-alanyl-L-histidine) is a natural dipeptide widely distributed in mammalian tissues [1,2]and exists at high concentrations in the brain as well as in skeletal and cardiac muscles
In order to understand the molecular mechanisms underlying the ability of carnosine in decreasing the production of molecules related to oxidative and nitrosative stresses, we studied the expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase (Nox) enzymes along with the expression and secretion of pro- and anti-inflammatory cytokines in BV-2 cells challenged with Aβ1-42 oligomers
The rescue of TGF-β1 signaling represents a new pharmacological strategy to yield neuroprotection in Alzheimer’s disease (AD) and second-generation antidepressants such as fluoxetine increase the release of TGF-β1 from astrocytes and exert relevant neuroprotective effects in experimental models of Starting from this evidence, we examined the neuroprotective effects of carnosine in mixed neuronal cultures challenged with Aβ oligomers, an established an experimental model of Aβ-induced neurodegeneration [46,47]
Summary
Carnosine (β-alanyl-L-histidine) is a natural dipeptide widely distributed in mammalian tissues [1,2]and exists at high concentrations (millimolar order) in the brain as well as in skeletal and cardiac muscles (up to 20 mM). Carnosine has been shown to be neuroprotective through different mechanisms: the prevention of oxidative stress [3], reduction of intraneuronal amyloid-βeta (Aβ) accumulation, mitochondrial dysfunctions and cognitive deficits in 3xTg-AD mice [4], as well as the inhibition of Aβ aggregation [5], modulation of macrophage nitric oxide (NO) production and pro-/anti-inflammatory (M1/M2) ratio [6]. Together with marked inflammation [10], both the extracellular deposition of insoluble aggregates of this peptide in the brain and its blood vessels [11,12] and the formation of neurofibrillary tangles composed by the highly phosphorylated form of tau protein [13]. Aβ peptide can undergo aggregation through a step-by-step process, starting with soluble monomers and evolving to the formation of oligomers, protofibrils, and mature fibrils [14], with the oligomeric structures representing the more toxic species [15]
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