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    Familial Amyloid Polyneuropathy: Receptor for Advanced Glycation End Products-Dependent Triggering of Neuronal Inflammatory and Apoptotic Pathways

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    Issue Date
    2001-10-01
    Author
    Sousa, Mónica Mendes
    Yan, Shirley ShiDu
    Fernandes, Rui
    Guimarães, António
    Stern, David M.
    Saraiva, Maria João
    Publisher
    Society for Neuroscience
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Published Version
    http://www.jneurosci.org/content/21/19/7576.short?sid=590f7ac1-22ec-41bd-88e6-0995b772a4e0
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    Abstract
    Familial amyloid polyneuropathy (FAP) is a neurodegenerative disorder associated with extracellular deposition of mutant transthyretin (TTR) amyloid fibrils, particularly in the peripheral nervous system. We have hypothesized that binding of TTR fibrils to the receptor for advanced glycation end products (RAGE) on critical cellular targets is associated with a destructive stress response underlying peripheral nerve dysfunction. Analysis of nerve biopsy samples from patients with FAP (n = 16) at different stages of disease (0–3), compared with age-matched controls (n = 4), by semiquantitative immunohistology andin situ hybridization showed increased levels of RAGE, beginning at the earliest stages of the disease (FAP 0;p < 0.02) and especially localized in axons. Upregulation of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) (approximately threefold; p< 0.02) and the inducible form of nitric oxide synthase (iNOS) (∼2.5-fold; p < 0.04) was also observed in a distribution overlapping RAGE expression. Tyrosine nitration and increased activated caspase-3 in axons from FAP patients (p < 0.03) were apparent. Although these data suggest the presence of ongoing neuronal stress, there was no upregulation of neurotrophins (nerve growth factor and neurotrophin-3) in FAP nerves. Studies on cultured neuronal-like, Schwann, and endothelial cells incubated with TTR fibrils displayed RAGE-dependent expression of cytokines and iNOS at early times (6 and 12 hr, respectively), followed by later (24 hr) activation of caspase-3 and DNA fragmentation. We propose that the interaction of TTR fibrils with RAGE may contribute to cellular stress and toxicity in FAP. Furthermore, there is an apparent lack of responsiveness of Schwann cells in FAP nerve to provide neurotrophic factors.
    Description
    This is the publisher's version, also available electronically from http://www.jneurosci.org/content/21/19/7576.short?sid=590f7ac1-22ec-41bd-88e6-0995b772a4e0
    URI
    http://hdl.handle.net/1808/14817
    ISSN
    0270-6474
    Collections
    • Pharmacy Scholarly Works [286]
    Citation
    Sousa, Mónica Mendes et al. (2001). Familial Amyloid Polyneuropathy: Receptor for Advanced Glycation End Products-Dependent Triggering of Neuronal Inflammatory and Apoptotic Pathways. Journal of Neuroscience 21(19):7576-86.

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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