P2‐390: Emerging relationship between development and degeneration: TrkA‐APP interaction as a therapeutic target in Alzheimer's disease

Abstract

It has been proposed that disrupted retrograde transport of NGF-TrkA complexes underlies basal forebrain cholinergic neuron (BFCN) degeneration in Alzheimer's disease (AD). Indeed, targeted BFCN delivery of NGF has been found promising in AD treatment and is currently in a phase II clinical trial. The prevailing view of Alzheimer's disease (AD) is that amyloid-beta (Abeta) causes toxicity through chemical and physical mechanisms. Our data suggest that Abeta functions physiologically as an anti-trophin, and Abeta binding to APP induces APP processing to multiple peptides that mediate physiological neurite retraction and synaptic reorganization (Nat Med 6:397; PNAS 103:7130). An unbiased screen for compounds that block APP caspase cleavage identified ADDN1351, which reduced APP-C31 by 90%. Surprisingly, ADDN1351 proved to be a TrkA inhibitor. We then evaluated the effect of TrkA over-expression on APP-C31 production and cell death induction through transfection, Western blots and MTT assays. We also studied the interaction between APP and TrkA through co-immunoprecipitation and APP-Gal4 transactivation. Furthermore, we treated PDAPP transgenic mice with TrkA inhibitor GW441756 (10mg/kg, 5 days) and assayed the levels of Abeta and sAPPalpha through ELISA and AlphaLISA. TrkA over-expression increased APP-C31 and cell death. APP-C31 cleavage did not occur with the kinase-dead TrkA mutant or in the presence of TrkA inhibitor GW441756, whereas induction was enhanced by NGF. TrkA was shown to interact with APP in co-immunoprecipitation. In APP-Gal4 transactivation assays, TrkA inhibited the transactivation directed by Fe65 or Mint3/YAP by over 90%. Moreover, treatment of PDAPP transgenic mice with GW441756 not only decreased Abeta, but also increased sAPPalpha. 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 the optimal therapy for AD may involve both the delivery of NGF or NGF mimetics to basal forebrain cholinergic neuron somata and a TrkA inhibitor that is active more distally.