Pentosidine and Nε-(carboxymethyl)-lysine in Alzheimer’s disease and vascular dementia
Introduction
Advanced glycation end products (AGE) are formed by a complex cascade of non-enzymatic reactions of sugars with amino groups of proteins [18], [22], [35], [44]. Originally implicated in several different pathological processes such as diabetic nephropathy or rheumatoid arthritis [8], [32], [39], [40] a number of studies have also linked them to brain pathology [19], [20], [25], [26]. Oxidative stress has been implicated as an important mechanism in neurological disorders including stroke, vascular dementia (VD), Alzheimer’s disease (AD), Parkinson’s disease and head trauma [4], [15], [30], [31]. Particularly in Alzheimer’s disease, lipid peroxidation, protein and DNA oxidation [5], [17], as well as the formation of AGEs are thought to be of major relevance to the disease process [6], [19], [21], [45]. Several studies point to a role of AGEs in AD pathology suggesting involvement in early pathogenesis and demonstrating accumulation of the two AGE molecules Nε-(carboxymethyl)-lysine (CML) and pentosidine with age [12], [22], [32]. These AGE products are co-localized with neurofibrillary tangles (NFT) and senile plaques, structures characteristic for AD [3], [13], [36], [41]. For instance pentosidine has been shown in NFTs of AD brains but not in apparently healthy neurons [36]. Another study did not find any difference of CML or pentosidine concentrations in the frontal cortex of Alzheimer’s disease patients when compared to controls [33]. The definite role of AGEs in the neuropathology of AD, therefore, needs further elucidation. AGEs are known to interact with the receptor for AGE (RAGE), thereby activating key cell signalling pathways such as NF-κB and modulating proinflammatory gene expression [14], [42]. This interaction and its biochemical sequel might be a future therapeutic target.
Previous studies investigated changes of AGE levels in various neurodenegenerative disorders [25], [26], [31]. However, this has not included vascular dementia (VD). Like AD, VD is also associated with apoptosis [24], but its pathophysiology is primarily linked to vascular changes. Consequences of AGE deposition on the vascular wall, such as narrowing and occlusion as well as monocyte activation and cytokine release, have been described [2], [10], [23]. In this study, we assessed levels of CML and pentosidine in paired samples of both blood and CSF from patients with Alzheimer’s dementia, vascular dementia and controls. The aim of our study was (a) to assess the feasibility of measuring AGE concentrations in CSF, (b) to study CML and pentosidine in two different types of dementia (i.e. AD and VD), (c) to examine the influence of subject age on AGE levels in the control group, and (d) to evaluate possible difference of blood versus CSF sampling for the determination of these metabolites.
Section snippets
Methods
Samples of blood and cerebrospinal fluid (CSF) were obtained during routine clinical procedures from patients with probable AD, VD and control subjects free of neurological disease (for demographic and psychometric data see Table 1). All participants were screened for medical conditions, in particular subjects had to be free of diabetes mellitus and any renal disease. All participants gave written informed consent to a study protocol approved by the Ethics Committee of the Friedrich-Schiller
Results
A significant difference (P<0.033) between young (mean±S.D.: 1.4±0.15 pmol/mg; age: 32.3±8.2 years) and aged controls (2.04±0.23 pmol/mg; age: 66.8±8.7 years) was found for serum levels of pentosidine. Concentrations of pentosidine in CSF, however, were not significantly different (P<0.38) between young (13.5±2.2 pmol/mg) and aged controls (11.17±1.28 pmol/mg).
Concentrations of CML did not differ significantly in serum (young: 25.67±2.01 pmol/mg, aged controls: 27.74±1.44 pmol/mg, P<0.42) nor in CSF
Discussion
In this study, we demonstrated differential increases of AGE products CML and pentosidine in CSF samples of patients with Alzheimer’s dementia and vascular dementia. Before discussing the implications of these findings, we shall briefly focus on some methodological issues.
As mentioned, studies of AGE products in ageing or neurodegenerative disorders have mostly relied on either post-mortem brain tissue or blood samples [3], [13], [22], [32], [33]. Although the latter is a simple way to obtain
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