OBJECTIVE: Selective neuronal vulnerability in neurodegenerative diseases is poorly understood. In Alzheimer's disease, the basal forebrain cholinergic neurons are selectively vulnerable, putatively because of their expression of the cell death mediator p75(NTR) (the common neurotrophin receptor), and its interaction with proapoptotic ligands pro-nerve growth factor and amyloid-beta peptide. However, the relation between amyloid precursor protein (APP) and p75(NTR) has not been described previously. METHODS: APP and p75(NTR) were assayed for interaction by coimmunoprecipitation in vitro and in vivo, yeast two-hybrid assay, bioluminescence resonance energy transfer, and confocal microscopy. Effects on APP processing and signaling were studied using immunoblotting, enzyme-linked immunosorbent assays, and luciferase reporter assays. RESULTS: The results of this study are as follows: (1) p75(NTR) and APP interact directly; (2) this interaction is modified by ligands nerve growth factor and beta-amyloid; (3) APP and p75(NTR) colocalization in vivo is modified in Alzheimer's model transgenic mice; (4) APP processing is altered by p75(NTR), and to a lesser extent, p75(NTR) processing is altered by the presence of APP; (5) APP-dependent transcription mediated by Fe65 is blocked by p75(NTR); and (6) coexpression of APP and p75(NTR) triggers cell death. INTERPRETATION: These results provide new insight into the emerging signaling network that mediates the Alzheimer's phenotype and into the mechanism of basal forebrain cholinergic neuronal selective vulnerability. In addition, the results argue that the interaction between APP and p75(NTR) may represent a therapeutic target in Alzheimer's disease.
OBJECTIVE: Selective neuronal vulnerability in neurodegenerative diseases is poorly understood. In Alzheimer's disease, the basal forebrain cholinergic neurons are selectively vulnerable, putatively because of their expression of the cell death mediator p75(NTR) (the common neurotrophin receptor), and its interaction with proapoptotic ligands pro-nerve growth factor and amyloid-beta peptide. However, the relation between amyloid precursor protein (APP) and p75(NTR) has not been described previously. METHODS: APP and p75(NTR) were assayed for interaction by coimmunoprecipitation in vitro and in vivo, yeast two-hybrid assay, bioluminescence resonance energy transfer, and confocal microscopy. Effects on APP processing and signaling were studied using immunoblotting, enzyme-linked immunosorbent assays, and luciferase reporter assays. RESULTS: The results of this study are as follows: (1) p75(NTR) and APP interact directly; (2) this interaction is modified by ligands nerve growth factor and beta-amyloid; (3) APP and p75(NTR) colocalization in vivo is modified in Alzheimer's model transgenic mice; (4) APP processing is altered by p75(NTR), and to a lesser extent, p75(NTR) processing is altered by the presence of APP; (5) APP-dependent transcription mediated by Fe65 is blocked by p75(NTR); and (6) coexpression of APP and p75(NTR) triggers cell death. INTERPRETATION: These results provide new insight into the emerging signaling network that mediates the Alzheimer's phenotype and into the mechanism of basal forebrain cholinergic neuronal selective vulnerability. In addition, the results argue that the interaction between APP and p75(NTR) may represent a therapeutic target in Alzheimer's disease.
Authors: D C Lu; S Rabizadeh; S Chandra; R F Shayya; L M Ellerby; X Ye; G S Salvesen; E H Koo; D E Bredesen Journal: Nat Med Date: 2000-04 Impact factor: 53.440
Authors: Michael J Saganich; Brock E Schroeder; Veronica Galvan; Dale E Bredesen; Edward H Koo; Stephen F Heinemann Journal: J Neurosci Date: 2006-12-27 Impact factor: 6.167
Authors: Carlos E Pedraza; Petar Podlesniy; Noemí Vidal; Juan Carlos Arévalo; Ramee Lee; Barbara Hempstead; Isidre Ferrer; Montse Iglesias; Carme Espinet Journal: Am J Pathol Date: 2005-02 Impact factor: 4.307
Authors: M Yaar; S Zhai; I Panova; R E Fine; P B Eisenhauer; J K Blusztajn; I Lopez-Coviella; B A Gilchrest Journal: Neuropathol Appl Neurobiol Date: 2007-06-27 Impact factor: 8.090
Authors: Gregory D Van Vickle; Chera L Esh; Walter M Kalback; R Lyle Patton; Dean C Luehrs; Tyler A Kokjohn; Frederick G Fifield; Paul E Fraser; David Westaway; Joanne McLaurin; John Lopez; Daniel Brune; Amanda J Newel; Marissa Poston; Thomas G Beach; Alex E Roher Journal: Biochemistry Date: 2007-08-18 Impact factor: 3.162
Authors: Melissa J Alldred; Helen M Chao; Sang Han Lee; Judah Beilin; Brian E Powers; Eva Petkova; Barbara J Strupp; Stephen D Ginsberg Journal: Hippocampus Date: 2018-02-12 Impact factor: 3.899
Authors: Sylvia E Perez; Bin He; Muhammad Nadeem; Joanne Wuu; Stephen W Scheff; Eric E Abrahamson; Milos D Ikonomovic; Elliott J Mufson Journal: Biol Psychiatry Date: 2014-01-11 Impact factor: 13.382
Authors: Alex M Sykes; Nickless Palstra; Daniel Abankwa; Justine M Hill; Sune Skeldal; Dusan Matusica; Prahatha Venkatraman; John F Hancock; Elizabeth J Coulson Journal: J Biol Chem Date: 2012-10-26 Impact factor: 5.157
Authors: Thuy-Vi V Nguyen; Lin Shen; Lilith Vander Griend; Lisa N Quach; Nadia P Belichenko; Nay Saw; Tao Yang; Mehrdad Shamloo; Tony Wyss-Coray; Stephen M Massa; Frank M Longo Journal: J Alzheimers Dis Date: 2014 Impact factor: 4.472