ReviewAdvanced glycation end products as biomarkers and gerontotoxins – A basis to explore methylglyoxal-lowering agents for Alzheimer’s disease?
Section snippets
Alzheimer’s disease – epidemiology, histopathology and biochemistry
Alzheimer’s disease (AD) is the most common cause of dementia. One of the pathological features of AD is the presence of high densities of ‘neuritic plaques’ in the neuropil of the cerebral cortex and hippocampus. β-Amyloid (Aβ) peptide is one of the main components of neuritic plaques, and this 40–42 amino acid peptide is widely regarded as a major contributor to the neurodegeneration that occurs in AD brains. Other characteristics of AD are the intracellular accumulation of neurofibrillary
Chemistry of advanced glycation end products (AGEs)
Oxidative stress is defined as an imbalance of free radical production and detoxification, and this process has also been implicated in the pathogenesis of AD (Retz et al., 1998). DNA oxidation products such as 8-oxoguanosine or protein oxidation products such as dityrosine are characteristic markers of oxidative stress, which accumulates during aging and particularly in AD (Moreira et al., 2008, Münch et al., 1998a). By analogy, AGEs are markers of carbonyl stress, which accumulates due to an
Advanced glycation end products in aging and Alzheimer’s disease
In the 1970s and 1980s, Monnier and Cerami, the pioneers of the ‘non-enzymatic glycosylation theory of aging’ proposed that the AGE-mediated cross-linking of long-lived proteins contributes to the age-related decline in the function of cells and tissues in normal aging (Monnier et al., 1981). Recent progress in the understanding of this process has confirmed that AGEs play a significant role in the evolution of vascular complications in normal aging, especially in diabetes and renal failure (
The glyoxalase system – the key to the formation of advanced glycation end products and cross-linking in Alzheimer’s disease?
Methylglyoxal (MG) has been suggested to be one major source of intracellular reactive carbonyl compounds, and has been implicated in the increased AGE levels in age-related diseases including AD (Hipkiss, 2006). This hypothesis is supported by the presence of specific MG-derived AGEs including N(ɛ)-carboxyethyllysine (CEL) and methylglyoxal-lysine dimer (MOLD, derived from the reaction of MG with lysine) and methylglyoxal-derived hydroimidazolone, which have each been identified in
Increased risk of Alzheimer’s disease in patients with diabetes
Diabetes and dementia, including Alzheimer’s disease, are two major age-related diseases. Therefore, a possible correlation between these two diseases was analyzed in several population-based cohort studies. In the Rotterdam Study, the association of non-insulin-dependant diabetes mellitus (NIDDM) in people with different types of dementia was examined (Ott et al., 1996). Multiple logistic regression analyses, adjusting for age and sex differences, revealed a positive association between NIDDM
Carbonyl-based therapeutic approaches for Alzheimer’s disease
Currently, research for future treatments of AD focuses on finding agents which can modify the course of the disease or even stop it, and they are mostly focussed on the pathological features. As senile plaques and NFTs are the major hallmarks of AD, several approaches lean in this direction, such as the development of new drugs to reduce Aβ production and aggregation, to stimulate Aβ elimination, for example, via immunotherapy (Robinson et al., 2003), and to reduce the formation of NFTs (Gotz
Conclusions and outlook
In Alzheimer’s disease (AD), we suggest that age-related general cellular changes such as compromised energy production and increased mitochondrial radical formation are worsened by the influence of AGEs as additional, AD-specific burdens. AGEs act not only as biomarkers of the disease but contribute to disease-specific dysfunctions as neurotoxic and pro-inflammatory “gerontotoxins” (Sato et al., 2006, Takeuchi and Yamagishi, 2008). Intracellular AGEs (most likely derived from reactive
Acknowledgements
This work was financially supported by Alzheimer’s Australia, the Alzheimer Forschungs Initiative e.V. (AFI), the J.O. and J.R. Wicking Trust (to G.M.) and the NHMRC (Project Grants Nos. 436 797, 491 109) (to G.M.).
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