LAUSR

Advanced glycation endproducts (AGEs) are toxic metabolites deriving from reactions between dicarbonyl compounds, such as methylglyoxal, and proteins, which compromise protein function. AGEs effects are counteracted by an enzymatic cycle where glyoxalase (Glo)-1, the limiting enzyme of AGEs detoxification, catalyses the glutathione (GSH)-dependent conversion of methylgyoxal into S-D-lactoylglutathione, which is further metabolised to D-lactate by Glo-2. A pathogenic role for AGEs in neurodegeneration has been evidenced by several studies showing that the abnormal proteins accumulating in brain in the typical lesions of different diseases are glycated. In addition to physiological ageing, the cerebral accumulation of AGEs can be enhanced by the consumption of saturated fat-rich, sugar-added or high temperature-processed foods contributing to the precocious onset or accelerated progression of neurodegenerative diseases [1,2]. In particular, we recently documented that a high fructose intake evokes AGEs accumulation in hippocampal neurons related to impaired activity of Glo-1, and this was associated to mitochondrial dysfunction and oxidative stress due to inhibition of nuclear factor-erythroid 2 p45 subunit-related factor 2 (Nrf2). Nrf2 is an essential transcription factor regulating the expression of genes containing an antioxidant-response element (ARE) responsible for protection against oxidative stress and GSH-recycling. Interestingly, in the hippocampus of fructose-fed mice, the inhibition of AGEs production by the administration of pyridoxamine, able to trap the dicarbonyl precursors, also led to restoration of both Glo-1 and Nrf2 activities, limiting the extension of inflammation and oxidative stress [1]. In addition to a healthy diet, low in fat, sugar, and exogenous AGEs, the possibility to enhance Glo-1 and Nfr2 activities may slow the progression of neurodegeneration. Indeed, studies reporting the positive effects of Nrf2 stimulation on mitochondrial dysfunction and neurodegeneration have been recently reviewed by Esteras and colleagues [3], while the beneficial impact of Glo-1 restoration on specific indicators of Alzheimer's disease has been evidenced in a transgenic mouse model [4]. In this latter study, the administration of ψ-GSH, a synthetic cofactor of Glo-1 resistant to hydrolysis by intestinal and hepatic γ-GGTs and able to pass the blood brain barrier, reduced cognitive decline, Aβ plaque deposition, protein carbonyl content, and reactive oxygen species. However, these effects were presumably due in part to a general antioxidant effect of GSH replenishing, in addition to specific Glo-1 restoration [4]. Intriguingly, there are increasing indications of a reciprocal influence between Glo-1 and Nrf2: Nrf2 target genes are involved in GSH recycling providing the essential co-factor for Glo-1 enzymatic activity, and vice …