Similar to other organs, brain function declines with age. Indeed, a decline in both cognitive and motor functions is one of the characteristics of normal aging, resulting in changes in learning and memory as well as deficits in balance and coordination. Age is also the single greatest risk factor for a variety of neurological disorders including Alzheimer's disease (AD). Since the average age in many Western countries is increasing, identifying approaches for reducing the effects of aging on brain function is taking on a new urgency. Among the factors that have been proposed to contribute to the decrease in brain function with age are alterations in protein processing. How and why this occurs is unclear but we hypothesize that it is tightly linked to increases in methylglyoxal (MG) and, in consequence, protein glycation. The non-enzymatic addition of sugars to proteins results in the formation of advanced glycation end- products (AGEs). Although the enhanced formation of glycated proteins was initially associated with diabetes, it is now recognized that this protein modification is also increased during normal aging and is exacerbated in age-dependent neurodegenerative diseases such as Alzheimer's disease (AD). MG is one of the major reactive aldehydes responsible for AGE formation. It is a by-product of glycolysis but can also be obtained both directly and indirectly from dietary sources. Multiple factors have been proposed to contribute to the aging process including alterations in redox homeostasis, protein processing, mitochondrial function and the immune response. Although these alterations appear to be quite diverse, it is hypothesized that they are linked by a common factor, MG. In support of this idea, a reduction in the glycolytic rate has been shown to increase longevity while impairments in protein processing and especially proteasome function have negative effects on aging both in cultured cells and in animal models. Recent evidence suggests that MG can both directly and indirectly inhibit proteasome activity via modification of specific proteasome subunits. Furthermore, both MG and ubiquitin covalently modify proteins on lysine residues. Since ubiquitin-dependent pathways are required for the removal of many aggregated, misfolded, or oxidized proteins, it is possible that the glycation of proteins can hinder ubiquitin dependent degradation. Thus, it is further hypothesized that age-dependent increases in MG-protein glycation and age-dependent decreases in proteasome function are directly linked and contribute to cognitive dysfunction. The proposed research is designed to test this hypothesis using both cell culture studies and an animal model of AD.
Aging is associated with both an increase in the addition of sugars to proteins and the accumulation of damaged proteins. We propose to test the hypothesis that these two changes are directly linked and contribute to decreases in brain function. Since there are still no good treatments for age-related neurodegenerative diseases, the characterization of novel pathways that impact brain function could underlie a new approach to therapy.
|Dafre, Alcir Luiz; Schmitz, Ariana Ern; Maher, Pamela (2017) Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells. Free Radic Biol Med 108:270-279|
|Dafre, A L; Goldberg, J; Wang, T et al. (2015) Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells. Free Radic Biol Med 89:8-19|