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The Journal of Neuroscience, October 1, 2001, 21(19):7576-7586
Familial Amyloid Polyneuropathy: Receptor for Advanced Glycation
End Products-Dependent Triggering of Neuronal Inflammatory and
Apoptotic Pathways
Mónica Mendes
Sousa1,
Shi
Du Yan2,
Rui
Fernandes1,
António
Guimarães3,
David
Stern2, and
Maria João
Saraiva1, 4
1 Institute for Cellular and Molecular Biology,
2 Departments of Pathology, Surgery, and Physiology and
Cellular Biophysics, Columbia University, New York, New York 10032, 3 Hospital Geral de Santo António, Porto 4150-180, Portugal, and 4 Instituto de Ciências
Biomédicas Abel Salazar, Porto 4099-003, Portugal
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 and
in 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- and interleukin-1 ) (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.
Key words:
familial amyloidotic polyneuropathy; amyloid; transthyretin; RAGE; caspase-3; inducible nitric oxide synthase; inflammatory cytokine
Copyright © 2001 Society for Neuroscience 0270-6474/01/21197576-11$05.00/0
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