Role for glyoxalase I in Alzheimer's disease

Abstract

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 ...

Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation

“…These data fit with increased carbonyl reductase, alcohol dehydrogenase (31), and pentose-phosphate pathway activities (32) in brains from AD patients. In addition, recent data stress the potential importance of glyoxalase I, an enzyme against reactive dicarbonyls, as a risk factor in AD pathogenesis (33). Coexistence of the RAGE overexpression with AGE may be a more pathogenically relevant finding than AGE alone.…”

Ageing and the brain

“…There are enzymes (glyoxalases) that provide protection against glycation. These have been found to be up-regulated in the brain in a transgenic model of AD [53,54].…”

Glyoxalase II, a Detoxifying Enzyme of Glycolysis Byproduct Methylglyoxal and a Target of p63 and p73, Is a Pro-survival Factor of the p53 Family

“…In fact, MG is considered as a marker for glycemic fluctuation (41), and increased formation of MG-induced AGEs is one of the major mechanisms underlying the microvascular complications of diabetes (39). Alzheimer disease is characterized by formation of neurofibrillary tangles assembled from microtubule-associated protein Tau, aggregation of which is facilitated by AGEs modification (13). Therefore, based on the essential role of GLX2 in MG detoxification, modulation of GLX2 through p63 and p73 to inhibit AGEs formation deserves further exploration, which could lead to novel therapeutic strategies for managing diabetes and Alzheimer disease.…”

“…Overexpression of GLX1 is capable of inhibiting the formation of hyperglycemia-induced advanced glycation end products (AGEs) in bovine endothelial cells, indicating that GLX1 has a protective role in diabetic microangiopathy (12). Recent studies revealed that GLX1 has additional roles in the pathogenesis of Alzheimer disease and anxiety (13,14). All these studies indicate that the glyoxalase system plays an important role in the pathogenesis of various human diseases.…”