Abstract
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.
Highlights
Amyloid beta (Aβ) is a peptide composed of 42 amino acids, often indicated asAβ1-42, normally present in both the brain and cerebrospinal fluid of humans [1]
Despite the significant protection exerted by carnosine, its presence did not completely abolish the ability of Aβ1-42 oligomers to kill macrophage cells, showing cell death percentage values higher than those observed in resting cells (p < 0.05)
After demonstrating the ability of carnosine to counteract the death of macrophages induced by Aβ1-42 oligomers, we evaluated whether the protective effect of this dipeptide was related, at least in part, to its ability to modulate the percentage of cell population undergoing apoptosis
Summary
Amyloid beta (Aβ) is a peptide composed of 42 amino acids, often indicated asAβ1-42, normally present in both the brain and cerebrospinal fluid of humans [1]. This peptide is implicated in the neuropathological hallmarks of Alzheimer’s disease (AD), which include enhanced oxidative stress [2], pronounced inflammation [3], deposition in the brain of Aβ-insoluble aggregates [4,5], and the formation of neurofibrillary tangles due to the aggregation of hyperphosphorylated tau [6] It is well-known that Aβ peptide can undergo aggregation through a cascade process, starting with soluble monomers and going through the formation of soluble oligomer intermediates, high molecular weight protofibrils, and mature and insoluble fibrils [7]. A defective capacity of peripheral monocytes/macrophages to engulf Aβ has been reported in AD patients [22]
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