Nϵ-Carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease

Gironès, Xavier; Guimerà, Arantxa; Cruz-Sánchez, Celia-Z; Ortega, Arantxa; Sasaki, Nobuyuki; Makita, Zenji; Lafuente, José Vicente; Kalaria, Raj N.; Cruz-Sánchez, F. F.

doi:10.1016/j.freeradbiomed.2004.02.006

Cited by 92 publications

(50 citation statements)

References 23 publications

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“…CML, the predominant AGE that accumulates in vivo [18,60] along with its glycation-specific precursor hexitol-lysine are increased in neurons, especially those containing intracellular neurofibrillary pathology in cases of AD [11]. Using immunocytochemical methods, Girones et al [24] examined the distribution of CML in brain tissue from AD and diabetes mellitus subjects and aging controls. They observed that CML reactivity was more evident in brains from patients suffering from both AD and diabetes mellitus, followed by AD, diabetes mellitus, and aging controls.…”

Section: Discussionmentioning

confidence: 99%

Lipoic Acid and N-acetyl Cysteine Decrease Mitochondrial-Related Oxidative Stress in Alzheimer Disease Patient Fibroblasts

Moreira

Harris

Zhu

et al. 2007

JAD

173

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Abstract. In this study, we evaluated the effect of lipoic acid (LA) and N -acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal, N ε -(carboxymethyl)lysine and heme oxygenase-1] and apoptotic (caspase 9 and Bax) markers in fibroblasts from patients with Alzheimer disease (AD) and age-matched and young controls. AD fibroblasts showed the highest levels of oxidative stress, and the antioxidants, lipoic acid (1 mM) and/or N -acetyl cysteine (100 µM) exerted a protective effect as evidenced by decreases in oxidative stress and apoptotic markers. Furthermore, we observed that the protective effect of LA and NAC was more pronounced when both agents were present simultaneously. AD-type changes could be generated in control fibroblasts using N -methylprotoporphyrin to inhibit cytochrome oxidase assembly indicating that the the oxidative damage observed was associated with mitochondrial dysfunction. The effects of N -methylprotoporphyrine were reversed or attenuated by both lipoic acid and N -acetyl cysteine. These data suggest mitochondria are important in oxidative damage that occurs in AD. As such, antioxidant therapies based on lipoic acid and N -acetyl cysteine supplementation may be promising.

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Section: Discussionmentioning

confidence: 99%

Lipoic Acid and N-acetyl Cysteine Decrease Mitochondrial-Related Oxidative Stress in Alzheimer Disease Patient Fibroblasts

Moreira

Harris

Zhu

et al. 2007

JAD

173

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“…Hyperglycemia causes oxidative stress via the polyol pathway, enhances advanced glycation end products (AGE), and increases lipid peroxidation and imbalances in the generation of reactive oxygen species and their scavengers [53,54]. N ε -Carboxymethyllysine (CML), the most prominent AGE product, is crucially involved in the development of diabetic microangiopathy [55], and the level of CML expression is high in the blood vessels and brain of diabetic patients, but low in aging controls [56]. Oxidative stress has also been implicated in the pathophysiology of Alzheimer's disease and hypoxic brain insults [57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese elderly diabetes intervention trial (J‐EDIT)

Akisaki

Sakurai

Takata

et al. 2006

Diabetes Metabolism Res

138

109

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“…1), as described previously (12). We now focused on and quantified the intensity of the CML staining in the cerebral vessels in DM and non-DM brain tissues.…”

Section: Human Tissuementioning

confidence: 99%

“…AGE distribution in the vasculature of the kidney, retina and peripheral nerves has extensively been investigated. In addition, Gironès et al (12) have examined the topographical distribution of CML reactivity in the brain of patients with Alzheimer's disease and diabetes, but they did not quantify this. In our study, we have focused on and quantified the AGE accumulation in the vasculature of the diabetic brain, both in humans and rats.…”

Section: Controls Nz13mentioning

confidence: 99%

Increased Nε-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus

Deutekom

Niessen²,

Schalkwijk³

et al. 2008

European Journal of Endocrinology

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Objective: Non-enzymatic glycation of proteins and their end products (advanced glycation end products, AGE) have been implicated in the pathogenesis of diabetic complications. Our aim was to evaluate the association between diabetes mellitus (DM) and the accumulation of one of the most abundant AGEs, N3-(carboxymethyl)-lysine (CML), in cerebral vessels. Research design and methods: Brain tissue samples were obtained by autopsy from 20 DM patients and 13 age-matched controls. In addition, we investigated brain tissue samples of seven rats after induction of diabetes with streptozotocin (STZ) and six non-diabetic control rats. We used an immunohistochemical staining method to examine the CML immunoreactivity in the cerebral vessels. Results: Staining intensity of CML was significantly higher in cerebral vessels of diabetic patients than in non-diabetic subjects (median of the immunohistochemical intensity score/cm 2 in the diabetic group of 0.85 (interquartile range (IQR) 0.66-1.52) vs 0.63 in the control group (IQR 0.44-0.70); PZ0.002). Furthermore, there was a similar significant difference in CML staining intensity of cerebral vessels between STZ diabetic rats and non-diabetic control rats (median of the immunohistochemical intensity score/cm 2 in the diabetic group of 1.08 (IQR 0.73-1.43) vs 0.23 in the control group (IQR 0.12-0.43); PZ0.003). Conclusions: Accumulation of CML-modified proteins is significantly greater in the cerebral vessels of the diabetic patients than their age-matched controls. This association has been confirmed in the insulin-deficient diabetic rat model. It may be possible that the excessive accumulation of AGE-modified proteins in the cerebral vasculature alters the local environment and microcirculation and thereby contributes to the development of cognitive impairments in diabetes. Therefore, additional study on the causal link between AGE accumulation and cognitive dysfunction and the potential benefits of AGEblocking and/or breaking compounds is indicated.European Journal of Endocrinology 158 655-660

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Nϵ-Carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease

Cited by 92 publications

References 23 publications

Lipoic Acid and N-acetyl Cysteine Decrease Mitochondrial-Related Oxidative Stress in Alzheimer Disease Patient Fibroblasts

Lipoic Acid and N-acetyl Cysteine Decrease Mitochondrial-Related Oxidative Stress in Alzheimer Disease Patient Fibroblasts

Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese elderly diabetes intervention trial (J‐EDIT)

Increased Nε-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus

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