10 May 2004. Despite the vastly heterogeneous nature of mammalian brains, researchers are pressing on with gene profiling experiments aimed at identifying potential risk factors for neurodegenerative diseases, including Alzheimer’s disease (AD). Two such studies appeared in last week’s Proceedings of the National Academy of Sciences and Human Molecular Genetics. In PNAS, an international collaboration led by Juergen Goetz from the University of Zurich, reports gene profiling of transgenic mice that express mutated tau (P301L). These animals develop a murine equivalent of frontotemporal dementia with neurofibrillary tangles.
First author Feng Chen and colleagues used Affymetrix DNA chips to compare expression patterns of 6,000 genes in wild-type and tau-mutant animals. Remarkably, statistical analysis of the data revealed that just one gene was differentially expressed, namely that for the enzyme glyoxalase I (GLO). Together with a second enzyme, glyoxalase II, and the cofactor glutathione, glyoxalase I detoxifies α-ketoaldehydes.
To test whether this finding is relevant, the authors used in-situ hybridization to examine expression of GLO directly. They found that the enzyme is expressed throughout the brain, and not just in neurons. Moreover, the enzyme is more highly expressed in tau-mutant mice than in wild-type, the scientists report. Next, the authors turned to samples of postmortem human brain tissue to test if glyoxalase expression is altered in human AD brain, and indeed they found the enzyme to be more highly expressed in people who had had AD than in controls.
As always, when studying postmortem samples, it remains uncertain what the cause-and-effect relationship between GLO and AD might be. The authors did find that, in human neurons, there is an inverse relationship between the GLO enzyme and phosphorylated tau expression, as judged by immunostaining. As GLO is involved in preventing the formation of advanced glycation end products, which can render tau resistant to proteolysis, it may be required for regulation of tau metabolism.
In the second paper, Hemachandra Reddy and colleagues performed a microarray-based gene expression analysis of the Tg2576 strain, a widely used mouse model that overexpresses human mutant AβPP. These scientists, from Oregon Health Sciences University, compared expression of 11,000 genes in wild-type and transgenic animals at two months, five months, and 18 months of age. They found that gene expression differences grew as the animals aged. At two months there were 83 upregulated and 26 downregulated genes in the transgenic animals; by 18 months there were 108 and 149, respectively.
Reddy et al. write that most of these genes were related to mitochondrial energy metabolism. They validated their data by measuring expression changes of select genes with Northern blots. Focusing on three of the genes, ATPase-6, heat shock protein 86, and programmed cell death gene 8, the authors found that in transgenic animals these were overexpressed in pyramidal neurons of the hippocampus and cortex. Dual detection of ATPase-6 and 8-hydroxyguanosine, a marker for oxidative damage, suggested a link between overexpression of the mitochondrial protein and damage due to oxidation.
Evidence is growing for a link between mitochondrial damage, reactive oxygen species, and neurodegeneration. To quote but one recent example, work from Jie Shen’s lab has shown that mutations that cause a rare form of Parkinsonism also result in changes in mitochondrial gene expression. But interestingly, much like Goetz’s group, Shen and colleagues found far fewer genes to be affected, and theirs were mostly downregulated (see ARF related news story).
At this point, a mechanistic interpretation of changes in global brain gene expression patterns remains challenging (see ARF related news story).—Tom Fagan.
Chen F, Wollmer MA, Hoerndli F, Munch G, Kuhla B, Rogaev EI, Tsolaki M, Papassotiropoulos A, Goetz J. Role for glyoxylase I in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7687-92. Epub 2004 May 05. Abstract
Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Partovi D, Jung J, Yau V, Searles R, Mori M, Quinn J. Gene Expression Profiles of Transcripts in Amyloid Precursor Protein Transgenic Mice: Up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer’s disease. Hum. Mol. Genetics. Abstract