An important issue in neurodegenerative disorders is the issue of regional vulnerability. Why are specific cell types in specific brain regions targeted first, when most of the underlying disease-causing genes are expressed ubiquitously? In the case of Alzheimer's disease (AD), PSEN1, PSEN2, and APP mutations lead to a typical pattern of neurodegeneration in most cases, starting with degeneration of CA1 hippocampal pyramidal cells, followed later by degeneration of the structurally similar CAS pyramidal neurons, posterior, superior parietal lobe, and eventually by degeneration of most of the cerebral cortices, sparing cerebellum and primary sensory cortices. Sporadic AD, where specific Mendelian mutations have not been identified, leads to essentially the same disease progression. We hypothesize that regions relatively invulnerable to AD pathology express patterns of genes that provide relative protection, and that gene expression changes in more vulnerable regions reflect their vulnerability. Similarly, susceptibility to neurodegeneration does not occur on a whole tissue level, but rather in specific cell types. Therefore, by comparing gene expression in structurally similar neurons or regions of the hippocampus (CA1 and CAS) that are differentially vulnerable to AD pathology, targets for AD neuroprotection and susceptibility will be uncovered. Healthy pyramidal cells will be extracted from both CA1, which is vulnerable to AD pathology, and CAS, which is relatively less vulnerable, in both controls and individuals with advanced AD using laser capture microdissection. Amplified cRNA from pools of cells in these regions will then be hybridized to custom microarrays, and analyzed for differentially expressed genes using standard methods. Additionally, the transcriptional networks specific to each region will be identified using weighted gene co-expression network analysis (WGCNA), a powerful new method for uncovering transcriptomic organization. In all, expression data will be collected under six conditions: 1) Control CA1, 2) CAS, and 3) visual pole, as well as 4) diseased CA1, 5) CAS, and 6) visual pole, where visual pole is included as a control brain region that remains essentially unaffected by AD. These data will be used to determine the transcriptional network related to relative protection and susceptibility in AD through regional comparisons and control/disease comparisons. By designing our experiment around finding neuroprotective genes, this experimental plan will uncover novel target genes for AD, which may have the potential for early diagnoses and treatment of AD. ? ? ?
| Miller, Jeremy A; Cai, Chaochao; Langfelder, Peter et al. (2011) Strategies for aggregating gene expression data: the collapseRows R function. BMC Bioinformatics 12:322 |
| Miller, Jeremy A; Horvath, Steve; Geschwind, Daniel H (2010) Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proc Natl Acad Sci U S A 107:12698-703 |
| Miller, Jeremy A; Oldham, Michael C; Geschwind, Daniel H (2008) A systems level analysis of transcriptional changes in Alzheimer's disease and normal aging. J Neurosci 28:1410-20 |
