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.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Protein Kinase Inhibitors/therapeutic use , Receptor, trkA/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Benzamides/pharmacology , CHO Cells , Cell Death/drug effects , Cricetulus , Disease Models, Animal , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , HEK293 Cells , Humans , Mice , Mice, Transgenic , Mutation/genetics , Nerve Growth Factor/metabolism , Nerve Growth Factor/pharmacology , Protein Kinase Inhibitors/chemistry , Pyrazoles/pharmacology , Receptor, trkA/antagonists & inhibitors , Receptor, trkA/genetics , TransfectionABSTRACT
Programmed cell death signaling is a critical feature of development, cellular turnover, oncogenesis, and neurodegeneration, among other processes. Such signaling may be transduced via specific receptors, either following ligand binding-to death receptors-or following the withdrawal of trophic ligands-from dependence receptors. Although dependence receptors display functional similarities, no common structural domains have been identified. Therefore, we employed the Multiple Expectation Maximization for Motif Elicitation and the Motif Alignment and Search Tool software programs to identify a novel transmembrane motif, dubbed dependence-associated receptor transmembrane (DART) motif, that is common to all described dependence receptors. Of 3,465 human transmembrane proteins, 25 (0.7%) display the DART motif. The predicted secondary structure features an alpha helical structure, with an unusually high percentage of valine residues. At least four of the proteins undergo regulated intramembrane proteolysis. To date, we have not identified a function for this putative domain. We speculate that the DART motif may be involved in protein processing, interaction with other proteins or lipids, or homomultimerization.
