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J Alzheimers Dis. 2014;40(3):605-617. doi: 10.3233/JAD-130017.

Paradoxical effect of TrkA inhibition in Alzheimer's disease models.

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Buck Institute for Research on Aging, Novato, CA, USA.
Department of Neurology, University of California, San Francisco, CA, USA.
Contributed equally


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.


Alzheimer's disease; AβPPneo; GW441756; TrkA receptor; amyloid-β protein precursor; nerve growth factor; transcriptional activation

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