. 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 Genet. 2004 Jun 15;13(12):1225-40. PubMed.

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  1. In the provocative report by Chen et al., oligonucleotide array analysis was performed using whole brain from P301L-transgenic mice as an input source of RNA. P301L mice express the longest human brain tau isoform, i.e., "big tau," with a pathogenic mutation that in humans results in tauopathy associated with frontotemporal dementia (FTDP-17). Chen et al. use an extremely stringent analysis scheme to identify one gene that they report upon exclusively. The gene, glyoxalase I (GLO), encodes an enzyme that detoxifies carbonyls and reduces the formation of advanced glycation end products (AGEs), which are found in abundance in Alzheimer’s disease (AD) brains and related neurodegenerative disorders. An interesting facet of this study is that the group used microarray analysis to identify GLO as the sole target for their publication. Typically, microarray analysis is employed for high-throughput analysis to identify dozens to hundreds of transcripts. Instead, Chen et al. chose to whittle down potential targets from an original pool of 133 upregulated genes and 99 downregulated genes (relative to non-transgenic mice). When statistical analyses were combined with signal intensity filters, 34 upregulated and 12-down regulated genes remained. Stringent pair-wise analysis detected only GLO, which was determined to be significantly up regulated 1.6 fold in P301L mice versus controls. The report marks an interesting paradigm shift from conventional microarray analysis and provided a provocative target in a mouse model of tauopathy, which was further validated by a myriad of molecular and immunocytochemical based technologies.

    In a related paradigm, Reddy et al. used microarray analysis, in this case spotted cDNA microarrays, in a well-established mouse model of cerebral amyloidosis, the Tg2576 APP transgenic mouse, at three time points (two months, five months, both pre-amyloid deposition, and 18 months, when extensive amyloid has deposited). Employing a conventional array analysis scheme, 83 upregulated and 26 downregulated genes were observed relative to control mice at two months, 54 upregulated and 30 downregulated genes at five months, and 108 upregulated and 149 downregulated genes were observed at 18 months. Selected genes were validated using Northern blot analysis, in situ hybridization, and immunocytochemistry. Two classes of transcripts—mitochondrial genes and apoptotic genes—were consistently upregulated at all three time points, implicating these genes in the formation of cerebral amyloidosis and demonstrating their relevance towards understanding mechanisms of AD pathology.

    Taken together, these two reports illustrate the utility and flexibility of expression profiling paradigms in animal models of tauopathy and amyloid deposition, respectively. The statistical mode of detection and experimental analysis of genes can range from individual mRNAs to large classes of transcripts, depending upon the experimental design and biostatistical parameters. Notably, both studies used relatively large tissue dissections (e.g., whole brain and cortex) as input sources of RNA. It is interesting to speculate whether GLO and/or additional genes would be identified if the input sources were microdissected vulnerable regions (e.g., hippocampus) or individual cell types prone to neurodegeneration.

    View all comments by Stephen D. Ginsberg

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  1. GLOing Reports from Gene Profiling of Mouse Models