In:
Journal of Neuroscience Research, Wiley, Vol. 78, No. 2 ( 2004-10-15), p. 193-199
Kurzfassung:
Neurotrophin level imbalances and altered p75 neurotrophin receptor (p75 NTR ) expression are implicated in spinal motor neuron degeneration in human and mouse models of amyotrophic lateral sclerosis (ALS). Recently, elevated reactive astrocyte‐derived nerve growth factor (NGF) was linked to p75 NTR ‐expressing motor neuron death in adult transgenic ALS mice. To test the role of NGF‐dependent p75 NTR ‐mediated signalling in ALS, we examined the effects of a cyclic decapeptide antagonist of p75 NTR ligand binding by using neurotrophin‐stimulated cell death assays and transgenic ALS mice. Murine motor neuron‐like (NSC‐34) cell cultures expressed full‐length and truncated p75 NTR , tyrosine receptor kinase B (TrkB), and the novel neurotrophin receptor homolog‐2 (NHR2) but were TrkA deficient. Accordingly, treatment of cells with NGF induced dose‐dependent cell death, which was significantly blocked by the cyclic decapeptide p75 NTR antagonist. Application of brain‐derived neurotrophic factor, neurotrophin‐3, or neurotrophin‐4 to cultures increased cell proliferation, and such trophic effects were abolished by pretreatment with the tyrosine kinase inhibitor K‐252a. Systemic administration of a modified cyclic decapeptide p75 NTR antagonist conjugated to the TAT4 cell permeabilization sequence to presymptomatic transgenic SOD1 G93A mice affected neither disease onset nor disease progression, as determined by hindlimb locomotor, grip strength, and survival analyses. These studies suggest that disrupting NGF‐p75 NTR interactions by using this approach is insufficient to alter the disease course in transgenic ALS mice. Thus, alternate ligand‐independent pathways of p75 NTR activation or additional NGF receptor targets may contribute to motor neuron degeneration in ALS mice. © 2004 Wiley‐Liss, Inc.
Materialart:
Online-Ressource
ISSN:
0360-4012
,
1097-4547
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2004
ZDB Id:
1474904-X
SSG:
12
