Molecular Profiling Reveals Diversity of Stress Signal Transduction Cascades in Highly Penetrant Alzheimer's Disease Human Skin Fibroblasts

Department of Anatomy and Neurobiology, Program in Molecular Cell Biology, Division of Biology and Biomedical Sciences, Washington University, St.Louis, Missouri, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(2):e4655. DOI: 10.1371/journal.pone.0004655
Source: PubMed


The serious and growing impact of the neurodegenerative disorder Alzheimer's disease (AD) as an individual and societal burden raises a number of key questions: Can a blanket test for Alzheimer's disease be devised forecasting long-term risk for acquiring this disorder? Can a unified therapy be devised to forestall the development of AD as well as improve the lot of present sufferers? Inflammatory and oxidative stresses are associated with enhanced risk for AD. Can an AD molecular signature be identified in signaling pathways for communication within and among cells during inflammatory and oxidative stress, suggesting possible biomarkers and therapeutic avenues? We postulated a unique molecular signature of dysfunctional activity profiles in AD-relevant signaling pathways in peripheral tissues, based on a gain of function in G-protein-coupled bradykinin B2 receptor (BKB2R) inflammatory stress signaling in skin fibroblasts from AD patients that results in tau protein Ser hyperphosphorylation. Such a signaling profile, routed through both phosphorylation and proteolytic cascades activated by inflammatory and oxidative stresses in highly penetrant familial monogenic forms of AD, could be informative for pathogenesis of the complex multigenic sporadic form of AD. Comparing stimulus-specific cascades of signal transduction revealed a striking diversity of molecular signaling profiles in AD human skin fibroblasts that express endogenous levels of mutant presenilins PS-1 or PS-2 or the Trisomy 21 proteome. AD fibroblasts bearing the PS-1 M146L mutation associated with highly aggressive AD displayed persistent BKB2R signaling plus decreased ERK activation by BK, correctible by gamma-secretase inhibitor Compound E. Lack of these effects in the homologous PS-2 mutant cells indicates specificity of presenilin gamma-secretase catalytic components in BK signaling biology directed toward MAPK activation. Oxidative stress revealed a JNK-dependent survival pathway in normal fibroblasts lost in PS-1 M146L fibroblasts. Complex molecular profiles of signaling dysfunction in the most putatively straightforward human cellular models of AD suggest that risk ascertainment and therapeutic interventions in AD as a whole will likely demand complex solutions.

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Available from: Justyna A Dobrowolska Zakaria
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    • "Since many oxidative stress-related progressive or non-progressive chronic diseases are referred to as degenerative diseases we investigated the possibility that vitiligo melanocytes express common features with cells of neurodegenerative disorders. For most of these pathologies it has been demonstrated that sublethal oxidative stress and subsequent cellular alterations, including modification of lipid metabolism [20], impairment of the mitochondrial respiratory chain [21], dysfunction of intracellular signaling, and enhanced sensibility to pro-apoptotic stimuli [22], culminate in aging and cell degeneration [23]. Moreover, a premature senescent-like cell phenotype in vivo and in vitro has been linked to the degenerative diseases [24]. "
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    Full-text · Article · Mar 2013 · PLoS ONE
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    • "Interestingly, multiple proteins interact with S100A10 [40] and many of them have been previously reported to be associated to AD, such as transglutaminase [41], cytosolic phospholipase A2 [42] [43], and cathepsin B [44]. It is noteworthy that TPM4 and CapG are calcium binding proteins, as many studies have previously shown that calcium metabolism is altered in AD fibroblasts [45] [46] [47]. Moreover, altered calcium homeostasis at CNS level has been proposed as a pathogenic mechanism for AD, either concomitant or alternative to the amyloid cascade hypothesis [48] [49]. "
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