Abstract
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.
Highlights
Alzheimer’s disease is a neurodegenerative disorder that affects the brain’s cognitive functioning and memory retention properties [1]
We previously found that activation of PKC by 25 nM phorbol myristate acetate (PMA) or by treatment with 250 nM BK prompted modulation of the BK B2 subtype receptor (BKB2R) in Alzheimer’s disease (AD) skin fibroblasts (Table 1), detected by monoclonal anti-BKB2R antibodies recognizing the modulated receptors that reflect enhanced activity of a Tyr phosphorylation pathway in the AD cells [8,12]
We subsequently have defined how persistent this modulated receptor signal is across AD skin fibroblast lines bearing mutations in different locations along the presenilin (PS) polypeptide chain
Summary
Alzheimer’s disease is a neurodegenerative disorder that affects the brain’s cognitive functioning and memory retention properties [1]. We have previously defined exaggerated signal transduction in AD patients’ skin fibroblasts in response to the inflammatory neuropeptide bradykinin (BK). Levels of this nonapeptide mediator generated via a proteolytic cascade increase under environmental insults such as stroke, head trauma injury, and pain [8,11], to initiate signaling pathways via G-protein-coupled receptors [12]. The modulated B2 receptors respond to BK at pathophysiologic levels of 25–250 nM characteristic of tissue injury, in skin fibroblasts from persons having familial AD presently but those at risk for future AD due to Trisomy 21 [8]. Neither the PKC-dependent BK B2R modulation nor the consequent tau Ser phosphorylation occurs in any normal skin fibroblasts from persons aged 17–82 [8]
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