title: Paradoxical effect of TrkA inhibition in Alzheimer's disease models.
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.
authors: Buck Institute for Research on Aging, Novato, CA, USA.
authors: Qiang
authors: Q
authors: Zhang
authors: Buck Institute for Research on Aging, Novato, CA, USA.
authors: Olivier
authors: O
authors: Descamps
authors: Buck Institute for Research on Aging, Novato, CA, USA.
authors: Matthew J
authors: MJ
authors: Hart
authors: Buck Institute for Research on Aging, Novato, CA, USA.
authors: Karen S
authors: KS
authors: Poksay
authors: Buck Institute for Research on Aging, Novato, CA, USA.
authors: Patricia
authors: P
authors: Spilman
authors: Buck Institute for Research on Aging, Novato, CA, USA.
authors: Darci J
authors: DJ
authors: Kane
authors: Buck Institute for Research on Aging, Novato, CA, USA.
authors: Olivia
authors: O
authors: Gorostiza
authors: Buck Institute for Research on Aging, Novato, CA, USA.
authors: Varghese
authors: V
authors: John
authors: Buck Institute for Research on Aging, Novato, CA, USA.|Department of Neurology, University of California, San Francisco, CA, USA.
authors: Dale E
authors: DE
authors: Bredesen
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D020932:Nerve Growth Factor; D020917:Receptor, trkA; C523797:danusertib
keywords: Alzheimer's disease; AβPPneo; GW441756; TrkA receptor; amyloid-β protein precursor; nerve growth factor; transcriptional activation