Gnerer and colleagues present evidence to suggest that accumulation of dihydroxyacetone phosphate (DHAP), by virtue of the wasted away mutation of triosephosphate isomerase in Drosophila, may be a mechanism linked to neuronal toxicity. Increased accumulation of DHAP results in generation of methylglyoxal (MG), a highly reactive α-oxoaldehyde that is a precursor to generation of advanced glycation end-products (AGEs). Experimental evidence suggests that AGEs accumulate in human neurodegenerative disorders such as Alzheimer disease, amyotrophic lateral sclerosis (ALS), and Parkinson disease. The possibility that increased accumulation of AGEs is linked to neurodegeneration—especially given biochemical data in human neurodegenerative disease—is compelling.

Experimental evidence suggests that AGEs may not solely be “biomarkers” of diseases such as diabetes and renal failure. Rather, by their ability to interact with and activate signal transduction receptors, chief among them being receptor for AGE (RAGE), AGEs may impart toxic effects to neurons, including,...  Read more

Gnerer and colleagues present evidence to suggest that accumulation of dihydroxyacetone phosphate (DHAP), by virtue of the wasted away mutation of triosephosphate isomerase in Drosophila, may be a mechanism linked to neuronal toxicity. Increased accumulation of DHAP results in generation of methylglyoxal (MG), a highly reactive α-oxoaldehyde that is a precursor to generation of advanced glycation end-products (AGEs). Experimental evidence suggests that AGEs accumulate in human neurodegenerative disorders such as Alzheimer disease, amyotrophic lateral sclerosis (ALS), and Parkinson disease. The possibility that increased accumulation of AGEs is linked to neurodegeneration—especially given biochemical data in human neurodegenerative disease—is compelling.

Experimental evidence suggests that AGEs may not solely be “biomarkers” of diseases such as diabetes and renal failure. Rather, by their ability to interact with and activate signal transduction receptors, chief among them being receptor for AGE (RAGE), AGEs may impart toxic effects to neurons, including, ultimately, cell death. Although Gnerer and colleagues suggest that aberrant protein misfolding may not be a key mechanism driving neurological phenotypes, it is important to note that among the properties of AGEs are their ability to cross-link and significantly modify protein structure and conformation. Thus, the findings of Gnerer and colleagues may place AGEs at the fore of pivotal mechanisms that trigger a cascade of receptor-dependent and perhaps receptor-independent pathways that may lead to advanced neural toxicity. Does such neural toxicity yield or contribute to frank neurodegeneration? Studies testing the role of RAGE in neurodegeneration in mammalian models suggest that this receptor is part of the problem. In a murine model of accumulation of mutant amyloid precursor protein (mAPP), our laboratory group has shown that transgene-driven expression of neuronal RAGE exacerbated neuronal dysfunction in the mutant mice; in contrast, introduction of a signal transduction deficient RAGE mutant, selectively in neurons in the mAPP background, attenuated neuronal stress.

The previously held narrow view that AGE biology is restricted to hyperglycemia is now greatly expanding. Does accumulation of AGEs in chronic neurodegeneration focus neuronal and inflammatory stress, in part via RAGE, in the injured brain? These considerations suggest that probing the role of AGEs and their signaling receptors in neurodegeneration may uncover novel targets for therapeutic intervention in these highly refractory disorders. Indeed, simple lessons from simpler organisms such as Drosophila may uncover universal roles for AGEs in mediating toxicity in cells such as neurons of the central nervous system.

View all comments by Ravichandran Ramasamy
View all comments by Anne Marie Schmidt
View all comments by Shi Fang Yan
View all comments by Shirley ShiDu Yan

Enzymes involved in glucose metabolism emerge as key players in the pathogenesis of a range of neurodegenerative disorders. Gnerer and coworkers identify a role for triosephosphate isomerase in age-related neurodegeneration in Drosophila, possibly due to a build-up of methylglyoxal. Interestingly enough, we have shown by using Affymetrix chips that glyoxalase I, a detoxifying enzyme preventing the formation of advanced glycation end-products (AGEs) is increased in mice with an Alzheimer-related tau pathology (Chen et al., 2004).

Extending these studies, we were able to show by proteomics that other enzymes involved in glucose metabolism such as pyruvate kinase isozymes M1/M2 or phosphoglycerate mutase 1 are differentially regulated in Aβ-treated tau-transgenic mouse and tissue culture models (David et al., 2005; David et al., 2006, in press).

View all comments by Jurgen Goetz