title: 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 Hardy-Weinberg 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.
authors.affiliation: Division of Psychiatry Research, University of Zürich, August Forel Strasse 1, 8008 Zurich, Switzerland.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: M Axel
authors.initials: MA
authors.lastname: Wollmer
authors.forename: Frederic
authors.initials: F
authors.lastname: Hoerndli
authors.forename: Gerald
authors.initials: G
authors.lastname: Münch
authors.forename: Björn
authors.initials: B
authors.lastname: Kuhla
authors.forename: Evgeny I
authors.initials: EI
authors.lastname: Rogaev
authors.forename: Magdalini
authors.initials: M
authors.lastname: Tsolaki
authors.forename: Andreas
authors.initials: A
authors.lastname: Papassotiropoulos
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D007791:Lactoylglutathione Lyase