Anti-AGEing defences against Alzheimer's disease.
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 Abeta (beta-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 Abeta) with microglia leads to a strong pro-inflammatory response, indicating that priming of immune cells with beta-amyloid potentiates their response to secondary stimuli such as AGE and cytokines such as interferon-gamma. 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.
Münch
G
G
Neuroimmunological Cell Biology Unit, Interdisciplinary Center for Clinical Research (IZKF) Leipzig, Inselstrasse 22, 04103 Leipzig, Germany. Gerald.Munch@jcu.edu.au
Kuhla
B
B
Lüth
H-J
HJ
Arendt
T
T
Robinson
S R
SR
D000544:Alzheimer Disease / Q000378:metabolism / Q000628:therapy*; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000378:metabolism*; D006801:Humans
D017127:Glycation End Products, Advanced