Study Title
Anti-AGEing defences against Alzheimer’s disease
Biochemical Society Transactions

G.Muench, B.Kuhla, H.-J. Lueth, T. Arendt and S.R. Robinson


Accumulation of insoluble protein deposits and their cross-linking by AGEs (advanced glycation end products) in the brain is a feature of aging and neurodegeneration, especially in AD (Alzheimer’s disease). In AD, two types of fibrillar protein aggregates are present: extracellular deposits (plaques) consisting mainly of Aβ (β- amyloid peptide), and intracellular deposits (tangles) composed predominantly of microtubule-associated protein tau. Both plaques and tangles are modified by AGEs, which occurs particularly at lysine and arginine residues. Interaction of a synthetic amyloid plaque (fibrillar Aβ) with microglia leads to a strong pro- inflammatory response, indicating that priming of immune cells with β-amyloid potentiates their response to secondary stimuli such as AGE and cytokines such as interferon-γ. Formation of hyperphosphorylated and cross-linked microtubule-associated protein tau aggregates, especially tau dimers as the first step in tangle formation, can be induced in vitro by the combination of okadaic acid, a PP2A phosphatase inhibitor, and methylglyoxal. These results suggest that excess production of reactive carbonyl compound (‘carbonyl stress’) and subsequent AGE formation can contribute to cross-linking of protein fibrils and to pathological pro-inflammatory signalling, which all contribute to pathological changes and dementia progression in AD. However, the human brain has developed the glyoxalase system, a most effective defence system to scavenge small dicarbonyl compounds such as glyoxal and methylglyoxal. Very importantly, this system needs GSH as a rate-limiting cofactor. Since GSH is limited under conditions of oxidative stress and inflammation, supplementation with antioxidants such as lipoic acid, vitamin E or flavonoids could indirectly strengthen the anti-glycation defence system in AD. In addition, synthetic carbonyl scavengers and anti-inflammatory drugs could also be valuable drugs for the ‘anti-glycation’ treatment of AD.

December 1, 2003
View study

Share This

Related Topics

AntioxidantOxidative StressInflammationAlzheimer’sAdvanced Glycation End Products (AGEs)

Dr. Perlmutter is one of the leading lights in medicine today, illuminating the path for solving chronic illness

Mark Hyman, MD