Paradoxical effect of TrkA inhibition in Alzheimer's disease models

Qiang Zhang; Olivier Descamps; Matthew J Hart; Karen S Poksay; Patricia Spilman; Darci J Kane; Olivia Gorostiza; Varghese John; Dale E Bredesen

doi:10.3233/JAD-130017

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Paradoxical effect of TrkA inhibition in Alzheimer's disease models

Journal article

Peer reviewed

Paradoxical effect of TrkA inhibition in Alzheimer's disease models

Qiang Zhang, Olivier Descamps, Matthew J Hart, Karen S Poksay, Patricia Spilman, Darci J Kane, Olivia Gorostiza, Varghese John and Dale E Bredesen

Journal of Alzheimer's disease, Vol.40(3), pp.605-617

2014

DOI: 10.3233/JAD-130017

PMCID: PMC4091737

PMID: 24531152

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https://www.ncbi.nlm.nih.gov/pmc/articles/4091737View

Open Access

Abstract

An unbiased screen for compounds that block amyloid-β protein precursor (AβPP) caspase cleavage identified ADDN-1351, which reduced AβPP-C31 by 90%. Target identification studies showed that ADDN-1351 is a TrkA inhibitor, and, in complementary studies, TrkA overexpression increased AβPP-C31 and cell death. TrkA was shown to interact with AβPP and suppress AβPP-mediated transcriptional activation. Moreover, treatment of PDAPP transgenic mice with the known TrkA inhibitor GW441756 increased sAβPPα and the sAβPPα to Aβ 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.

Cricetulus

Humans

Receptor, trkA - antagonists & inhibitors

Dose-Response Relationship, Drug

Protein Kinase Inhibitors - chemistry

Transfection

Amyloid beta-Protein Precursor - metabolism

HEK293 Cells

Benzamides - pharmacology

Cell Death - drug effects

CHO Cells

Disease Models, Animal

Pyrazoles - pharmacology

Nerve Growth Factor - metabolism

Gene Expression Regulation - genetics

Alzheimer Disease - drug therapy

Nerve Growth Factor - pharmacology

Mice, Transgenic

Mutation - genetics

Gene Expression Regulation - drug effects

Amyloid beta-Protein Precursor - genetics

Animals

Receptor, trkA - metabolism

Protein Kinase Inhibitors - therapeutic use

Alzheimer Disease - metabolism

Receptor, trkA - genetics

Mice

Details

Title: Subtitle: Paradoxical effect of TrkA inhibition in Alzheimer's disease models
Creators: Qiang Zhang - Buck Institute for Research on Aging, Novato, CA, USA
Olivier Descamps - Buck Institute for Research on Aging, Novato, CA, USA
Matthew J Hart - Buck Institute for Research on Aging, Novato, CA, USA
Karen S Poksay - Buck Institute for Research on Aging, Novato, CA, USA
Patricia Spilman - Buck Institute for Research on Aging, Novato, CA, USA
Darci J Kane - Buck Institute for Research on Aging, Novato, CA, USA
Olivia Gorostiza - Buck Institute for Research on Aging, Novato, CA, USA
Varghese John - Buck Institute for Research on Aging, Novato, CA, USA
Dale E Bredesen - Department of Neurology, University of California, San Francisco, CA, USA
Resource Type: Journal article
Publication Details: Journal of Alzheimer's disease, Vol.40(3), pp.605-617
DOI: 10.3233/JAD-130017
PMID: 24531152
PMCID: PMC4091737
NLM abbreviation: J Alzheimers Dis
ISSN: 1387-2877
eISSN: 1875-8908
Publisher: Netherlands
Grant note: AG034427 / NIA NIH HHS AG036975 / NIA NIH HHS R21 AG041456 / NIA NIH HHS R01 AG034427 / NIA NIH HHS AG041456 / NIA NIH HHS R21 AG036975 / NIA NIH HHS
Language: English
Date published: 2014
Academic Unit: Neurology
Record Identifier: 9984020793002771

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