Carnosine (β-alanyl-
L-histidine) is a naturally occurring endogenous
peptide widely distributed in excitable tissues such as the brain. This
dipeptide has well-known
antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of
neurodegenerative disorders such as
Alzheimer's disease (AD). In this disease, peripheral infiltrating macrophages play a substantial role in the clearance of
amyloid beta (Aβ)
peptides from the brain. Correspondingly, in patients suffering from AD, defects in the capacity of peripheral macrophages to engulf Aβ have been reported. The effects of
carnosine on macrophages and oxidative stress associated with AD are consequently of substantial interest for drug discovery in this field. In the present work, a model of stress induced by Aβ1-42 oligomers was investigated using a combination of methods including
trypan blue exclusion, microchip electrophoresis with
laser-induced fluorescence, flow cytometry, fluorescence microscopy, and high-throughput quantitative real-time PCR. These assays were used to assess the ability of
carnosine to protect macrophage cells, modulate oxidative stress, and profile the expression of genes related to
inflammation and pro- and
antioxidant systems. We found that pre-treatment of RAW 264.7 macrophages with
carnosine counteracted cell death and apoptosis induced by Aβ1-42 oligomers by decreasing oxidative stress as measured by levels of intracellular
nitric oxide (NO)/
reactive oxygen species (ROS) and production of
peroxynitrite. This protective activity of
carnosine was not mediated by modulation of the canonical inflammatory pathway but instead can be explained by the well-known
antioxidant and
free-radical scavenging activities of
carnosine, enhanced macrophage phagocytic activity, and the rescue of
fractalkine receptor CX3CR1. These new findings obtained with macrophages challenged with Aβ1-42 oligomers, along with the well-known multimodal mechanism of action of
carnosine in vitro and in vivo, substantiate the therapeutic potential of this
dipeptide in the context of AD pathology.