Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer’s disease — a target for neuroprotective treatment strategies?

Münch, Gerald; Deuther‐Conrad, Winnie; Gasic-Milenkovic, Jovana

doi:10.1007/978-3-7091-6139-5_28

Cited by 41 publications

(24 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since no particular substance has been found in association with DAT and VD diseases, as it was the case with glucose in DIAB, causal mechanisms explaining the association found between oxidative stress and dementia are rather speculative and involve ROS [39], elevation of hydrogen peroxide synthesis [40], and advanced glycation end-products [41].…”

Section: Discussionmentioning

confidence: 98%

Oxidative stress in Alzheimer's and vascular dementias: masking of the antioxidant profiles by a concomitant Type II diabetes mellitus condition

Serra

Marschoff

Domínguez³

et al. 2004

Journal of the Neurological Sciences

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 98%

Oxidative stress in Alzheimer's and vascular dementias: masking of the antioxidant profiles by a concomitant Type II diabetes mellitus condition

Serra

Marschoff

Domínguez³

et al. 2004

Journal of the Neurological Sciences

View full text Add to dashboard Cite

“…Their formation is thought to contribute to several pathophysiological conditions, including tissue damage after ischemia, aging, and the development of blindness and vascular diseases in diabetic patients (34,35). In AD, cross-linking by AGEs of lysine residues in the microtubule binding domain of tau results in the formation of detergent-insoluble and proteaseresistant aggregates such as NFT (2,3,36,37). In these, AGE determinants were localized in their fibrillar protein component, the tau filaments, by electron microscopy (38).…”

Section: Discussionmentioning

confidence: 99%

Role for glyoxalase I in Alzheimer's disease

Chen

Wollmer

Hoerndli

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

146

101

View full text Add to dashboard Cite

P301L mutant tau transgenic mice develop neurofibrillary tangles, a histopathologic hallmark of Alzheimer's disease and frontotemporal dementia (FTDP-17). To identify differentially expressed genes and to gain insight into pathogenic mechanisms, we performed a stringent analysis of the microarray dataset obtained with RNA from whole brains of P301L mutant mice and identified a single up-regulated gene, glyoxalase I. This enzyme plays a critical role in the detoxification of dicarbonyl compounds and thereby reduces the formation of advanced glycation end products. In situ hybridization analysis revealed expression of glyoxalase I in all brain areas analyzed, both in transgenic and control mice. However, levels of glyoxalase I protein were significantly elevated in P301L brains, as shown by Western blot analysis and immunohistochemistry. Moreover, a glyoxalase I-specific antiserum revealed many intensely stained flame-shaped neurons in Alzheimer's disease brain compared with brains from nondemented controls. In addition, we examined a single nucleotide polymorphism predicting a nonconservative amino acid substitution at position 111 (E111A) in ethnically independent populations. We identified significant and consistent deviations from HardyWeinberg equilibrium, which points to the presence of selection forces. The E111A single nucleotide polymorphism was not associated with the risk for Alzheimer's disease in the overall population. Together, our data demonstrate the potential of transcriptomics applied to animal models of human diseases. They suggest a previously unidentified role for glyoxalase I in neurodegenerative disease. A lzheimer's disease (AD) and frontotemporal dementia are common forms of age-related dementing diseases. They are characterized by proteinaceous aggregates, which are resistant to proteolysis due to conformational changes and posttranslational modifications such as hyperphosphorylation and glycation (1-4). In AD, these aggregates are ␤-amyloid plaques and neurofibrillary tangles (NFT). NFT formation, in the absence of overt amyloid plaques, is found in a group of neurodegenerative diseases, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) (5, 6). In affected cells, the microtubule-associated protein tau is abnormally phosphorylated and relocalized from axonal to somatodendritic compartments, where it accumulates in aggregates that eventually assemble into NFT (7). The identification of mutations in the tau gene in FTDP-17 established that dysfunction of tau in itself can lead to dementia (6).NFT formation has been reproduced in transgenic mice by expression of FTDP-17 mutant tau, both in neurons (8-12) and in glial cells (13)(14)(15). Moreover, intracerebral injection of ␤-amyloid fibrils caused significant increases of NFT in the amygdala of P301L (FTDP-17) mutant mice (16). A similar increase was achieved by crossing ␤-amyloid-producing amyloid precursor protein mutant mice with P301L mice (17).The pathologic similarities between the P301L transgenic ...

show abstract

“…During the aging process, AGEs have been shown to accumulate in several forms and diverse cell types such as neurons, vascular and bone cells. Sites of AGE accumulation on a cellular level are associated with pathologic lesions in age-related diseases, such as diabetes, Alzheimer's disease, atherosclerosis, and others (Munch et al ., 2002;Ahmed, 2005). Tolmasoff et al .…”

Section: Introductionmentioning

confidence: 99%

Glyoxalase‐1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans

et al. 2008

View full text Add to dashboard Cite

SummaryStudies of mutations affecting lifespan in Caenorhabditis elegans show that mitochondrial generation of reactive oxygen species (ROS) plays a major causative role in organismal aging. Here, we describe a novel mechanism for regulating mitochondrial ROS production and lifespan in C . elegans : progressive mitochondrial protein modification by the glycolysis-derived dicarbonyl metabolite methylglyoxal (MG). We demonstrate that the activity of glyoxalase-1, an enzyme detoxifying MG, is markedly reduced with age despite unchanged levels of glyoxalase-1 mRNA. The decrease in enzymatic activity promotes accumulation of MG-derived adducts and oxidative stress markers, which cause further inhibition of glyoxalase-1 expression. Over-expression of the C . elegans glyoxalase-1 orthologue CeGly decreases MG modifications of mitochondrial proteins and mitochondrial ROS production, and prolongs C . elegans lifespan. In contrast, knock-down of CeGly increases MG modifications of mitochondrial proteins and mitochondrial ROS production, and decreases C . elegans lifespan.

show abstract

Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer’s disease — a target for neuroprotective treatment strategies?

Cited by 41 publications

References 11 publications

Oxidative stress in Alzheimer's and vascular dementias: masking of the antioxidant profiles by a concomitant Type II diabetes mellitus condition

Oxidative stress in Alzheimer's and vascular dementias: masking of the antioxidant profiles by a concomitant Type II diabetes mellitus condition

Role for glyoxalase I in Alzheimer's disease

Glyoxalase‐1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans

Contact Info

Product

Resources

About