Protein Modification by Dicarbonyl Molecular Species in Neurodegenerative Diseases

Neurodegeneration results from abnormalities in cerebral metabolism and energy balance within neurons, astrocytes, microglia, or microvascular endothelial cells of the blood-brain barrier. In Alzheimer's disease, -amyloid is considered the primary contributor to neuropathology and neurodegeneration. It now is believed that certain systemic diseases, such as diabetes mellitus, can contribute to neurodegeneration through the effects of chronic hyperglycemia/insulin resistance resulting in protein glycation, oxidative stress and inflammation within susceptible brain regions. Here, we present an overview of research focusing on the role of protein glycation, oxidative stress, and inflammation in the neurodegenerative process. Of special interest in this paper is the effect of methylglyoxal (MGO), a cytotoxic byproduct of glucose metabolism, elevated in neurodegenerative disease, and diabetes mellitus, on cerebral protein function and oxidative stress. How MGO interacts with amino acid residues within -amyloid, and small peptides within the brain, is also discussed in terms of the affect on protein function. 1. Introduction Approximately 24 million people worldwide suffer the effects of some form of dementia, with numbers expected to increase substantially over the next several decades [1]. Neurodegenerative diseases are highly dynamic, multifactorial pathological conditions the causes of which remain poorly understood. The chronic nature of their development and progression suggests an insidious etiology that may involve multiple synergistic interactions among biochemically unrelated molecular species, and perhaps dysfunctional or overcompensatory metabolic, and immunologic pathways. Numerous studies have contributed to our improved, yet far from complete understanding of the etiological causes of Alzheimer’s disease (AD), multiple sclerosis, Pick’s disease, Creutzfeldt-Jakob disease (CJD), and Parkinson’s disease (PD). Many of these studies suggest several mechanistic similarities among these clinically disparate diseases, including abnormalities in protein folding and aggregation, elevated release of intracellular reactive oxygen species (ROS) leading to development of oxidative stress and inflammation, and increased glycation of key cellular proteins [2]. In this paper we will address key elements of our current level of understanding as they relate to the effects of oxidative stress and inflammation on neuronal degeneration. We will then focus on the abnormal glycation of proteins and small peptides relevant to specific neurodegenerative diseases and