Advanced Glycation End-Products in Neurodegenerative Disease
Advanced glycation end-products (AGEs) of various types are both generated in the body and arrive via the diet. Some are short-lived and easily broken down, but still a problem in people with abnormal metabolisms, such as diabetics, as well as through promotion of chronic inflammation for the rest of us via their interaction with RAGE, the receptor for AGEs. Some forms of AGE, most notably glucosepane in humans, are hard or impossible for our biochemistry to deal with, however, and they linger to form cross-links that glue together important proteins in tissues. These unwanted additions progressively degrade structural properties such as elasticity of blood vessels and strength of bone, and are a contributing factor in many of the aspects of degenerative aging.
When it comes to the contribution of AGEs to the progression of neurodegenerative conditions such as Alzheimer's disease the focus is on inflammation and RAGE. Here the most studied AGE is N(6)-Carboxymethyllysine (CML), as the relevant mechanisms are very different from those involving glucosepane and cross-linking. This open access paper provides a tour of the biochemistry, but note that the full thing is only available in PDF format (link above the title):
Protein glycation occurs through a complex series of very slow reactions in the body, including the Amadori reaction, Schiff base formation, and the Maillard reaction. These give rise to the formation of advanced glycation end products (AGEs). Since these glycation reactions were slow, it was believed that this process predominantly affected long-lived proteins. However, it was later found that even short-lived compounds such as lipids, nucleic acids, and intracellular growth factors are glycated. N(6)-carboxymethyllysine (CML) is thus far the most important AGE that occurs in vivo. It has been extensively studied and implicated in neurodegenerative disorders.Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. A recent report suggests that glycation plays a key role in the formation of amyloid protein. AGEs are also formed from the reaction of reactive carbonyl or dicarbonyl compounds with lysine or arginine groups on proteins, and are present in beta-amyloid plaques and neurofibillary tangles (NFTs). The plaque fractions of AD brains contain higher levels of AGEs than samples from age-matched controls. Furthermore, immunohistochemical methods have convincingly demonstrated that AGEs are present in NFTs and senile plaques. Although some authors suggested that AGEs are very late markers of the disease, it is now widely accepted that they are active participants in the progression of the disease.
A link between diabetes mellitus and AD was recently postulated because humans with diabetes show a greater deposition of brain AGEs and RAGE, which may mediate a common pro-inflammatory pathway in neurodegenerative disorders. Immunohistochemical studies of human postmortem samples showed that patients with the combination of AD and diabetes had higher AGE levels, increased numbers of beta-amyloid dense plaques, higher RAGE- and tau-positive cells, and major microglial activation in their brains when compared to the brains of patients with AD alone.
The AGE-RAGE damaging axis is now considered to be a promising drug target. The main molecular approaches used to inhibit RAGE activation are inactivation of the ligand, inactivation of RAGE and downregulation of RAGE expression. Additionally, there are defense enzymes and protein present in the body that protect the neuronal cell from glycation and carbonyl stress. The formation of toxic oligomeric species could be controlled by using novel inhibitors. Using combination therapies, novel drugs could be designed that simultaneously target multiple pathways and may obviously be more efficient than those drugs that modify a single pathway and thereby decrease the risk of side effects.