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Selective vulnerability in Alzheimer's disease: Amyloid precursor protein and p75 NTR interaction
Author(s) -
Fombonne Joanna,
Rabizadeh Shahrooz,
Banwait Surita,
Mehlen Patrick,
Bredesen Dale E.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21578
Subject(s) - amyloid precursor protein , alzheimer's disease , vulnerability (computing) , neuroscience , amyloid (mycology) , disease , chemistry , medicine , psychology , pathology , computer science , computer security
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‐β 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 β‐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. Ann Neurol 2009;65:294–303