Incipient Alzheimer's Disease: Microarray Correlation Analyses Reveal Major Transcriptional and Tumor Suppressor Responses

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 7; pp. 2173 - 2178
• Main Authors: Blalock, Eric M., Geddes, James W., Chen, Kuey Chu, Porter, Nada M., Markesbery, William R., Landfield, Philip W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.02.2004; National Acad Sciences
• Subjects: Aging; Algorithms; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Alzheimers disease; Axons; Biological Sciences; Calcium Signaling; Correlation analysis; Cyclic AMP-Dependent Protein Kinases - metabolism; Data interpretation; Disease Progression; DNA microarrays; Female; Gene Expression Profiling; Genes; Genes, Tumor Suppressor - physiology; Growth factors; Hippocampus - metabolism; Hippocampus - pathology; Hippocampus - physiopathology; Humans; Lipid metabolism; Male; Neurology; Neurons; Neuroscience; Oligonucleotide Array Sequence Analysis; P values; Pathology; Transcription Factors - metabolism; Transcription, Genetic - genetics; Tumors; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0308512100

The pathogenesis of incipient Alzheimer's disease (AD) has been resistant to analysis because of the complexity of AD and the overlap of its early-stage markers with normal aging. Gene microarrays provide new tools for addressing complexity because they allow overviews of the simultaneous activity of multiple cellular pathways. However, microarray data interpretation is often hindered by low statistical power, high false positives or false negatives, and by uncertain relevance to functional endpoints. Here, we analyzed hippocampal gene expression of nine control and 22 AD subjects of varying severity on 31 separate microarrays. We then tested the correlation of each gene's expression with MiniMental Status Examination (MMSE) and neurofibrillary tangle (NFT) scores across all 31 subjects regardless of diagnosis. These well powered tests revealed a major transcriptional response comprising thousands of genes significantly correlated with AD markers. Several hundred of these genes were also correlated with AD markers across only control and incipient AD subjects (MMSE > 20). Biological process categories associated with incipient AD-correlated genes were identified statistically (EASE program) and revealed up-regulation of many transcription factor/signaling genes regulating proliferation and differentiation, including tumor suppressors, oligodendrocyte growth factors, and protein kinase A modulators. In addition, up-regulation of adhesion, apoptosis, lipid metabolism, and initial inflammation processes occurred, and down-regulation of protein folding/metabolism/transport and some energy metabolism and signaling pathways took place. These findings suggest a new model of AD pathogenesis in which a genomically orchestrated up-regulation of tumor suppressor-mediated differentiation and involution processes induces the spread of pathology along myelinated axons.