Check out the newest gene microarray results in the Alzheimer's brain, and see if they give a lift to some of your favorite hypotheses and molecular suspects. The study, by Eric Blalock, Philip Landfield, and colleagues at the University of Kentucky, Lexington, appeared in this week's early online PNAS.
Blalock and colleagues were following up on last year's similar study looking at changes in gene expression in normal aging (Blalock, et al., 2003). Hoping to obtain sufficient statistical power to avoid both high false-positive and high false-negative errors, the scientists gathered a sizable sample of hippocampal tissue from AD patients with "incipient" (MMSE 20 - 26; n = 7), moderate (MMSE 14 - 19; n = 8), and severe disease (MMSE < 14; n = 7), along with nine elderly controls. In all, the authors found that the expression of 3,413 genes was significantly correlated with MMSE score and/or the neurofibrillary tangle (NFT) index across all subjects. With regard to early events in AD pathogenesis, the authors found that 609 of these genes correlated with incipient AD versus controls, and of these, changes in 89 genes correlated with both MMSE score and NFT index.
Last year, researchers led by Paul Coleman at the University of Rochester, New York, reported a microarray analysis of five AD brains which indicated that genes involved in trafficking synaptic vesicles were selectively decreased in AD (Yao et al., 2003). The year before, Walter Lukiw and colleagues at Louisiana State University in New Orleans reported microarray data of hippocampal CA1 from AD patients (Colangelo et al., 2002). These scientists found transcription and neurotrophic factors to be downregulated and apoptotic and proinflammatory signaling molecules to be upregulated in AD patients versus controls. Other studies have found evidence for gene expression changes in genes related to synaptic function and remodeling (see ARF related news story).
In an attempt to cull biological meaning from their new wealth of data, Blalock et al. have used software called the Expression Analysis Systematic Explorer (EASE), which was developed by researchers at the National Institute of Allergy and Infectious Disease (Hosack et al., 2003). They found "widespread and apparently orchestrated" changes in transcription factors/signaling genes regulating proliferation and differentiation, particularly upregulation of tumor suppressors, oligodendrocyte growth factors, and protein kinase A pathway molecules. They also point to upregulation of genes involved in cell adhesion, apoptosis, lipid metabolism, and initial inflammation processes, and downregulation of genes involved in protein folding/metabolism/transport, as well as some energy metabolism and signaling pathways, roughly mirroring and expanding the data of Colangelo et al.
This kind of unbiased data is frequently used to generate new hypotheses, and the scientists present a model for incipient AD pathology that starts in the white matter. "Alterations in axons or myelin sheaths initially stimulate growth/remyelination responses in localized oligodendrocytes, which in turn secrete growth factors which activate adjacent neurons and glial cells. This triggers compensatory tumor suppressor responses specific to cell type which induce protein aggregation, affect axonal-myelin interactions, and result in NFTs. As NFT density increases, wider extracellular matrix, amyloid precursor protein, and inflammatory changes may be triggered which impact cognition," the authors write. In particular, the authors suggest that this model could help explain the apparent progression of AD pathology along efferents from entorhinal cortex to hippocampus and neocortex, "leaving NFTs and plaques in its wake."—Hakon Heimer
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- Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW. Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2173-8. PubMed.