Paradoxical effect of TrkA inhibition in Alzheimer's disease models.
J Alzheimers Dis
; 40(3): 605-617, 2014.
Article
en En
| MEDLINE
| ID: mdl-24531152
ABSTRACT
An unbiased screen for compounds that block amyloid-ß protein precursor (AßPP) caspase cleavage identified ADDN-1351, which reduced AßPP-C31 by 90%. Target identification studies showed that ADDN-1351 is a TrkA inhibitor, and, in complementary studies, TrkA overexpression increased AßPP-C31 and cell death. TrkA was shown to interact with AßPP and suppress AßPP-mediated transcriptional activation. Moreover, treatment of PDAPP transgenic mice with the known TrkA inhibitor GW441756 increased sAßPPα and the sAßPPα to Aß ratio. These results suggest TrkA inhibition-rather than NGF activation-as a novel therapeutic approach, and raise the possibility that such an approach may counteract the hyperactive signaling resulting from the accumulation of active NGF-TrkA complexes due to reduced retrograde transport. The results also suggest that one component of an optimal therapy for Alzheimer's disease may be a TrkA inhibitor.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptor trkA
/
Inhibidores de Proteínas Quinasas
/
Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Alzheimers Dis
Asunto de la revista:
GERIATRIA
/
NEUROLOGIA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos