Selective vulnerability in Alzheimer's disease: amyloid precursor protein and p75(NTR) interaction

Ann Neurol. 2009 Mar;65(3):294-303. doi: 10.1002/ana.21578.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / pharmacology
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Analysis of Variance
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cell Death / genetics
  • Cell Line, Tumor
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay / methods
  • Green Fluorescent Proteins / genetics
  • Humans
  • Immunoprecipitation / methods
  • Luminescent Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Nerve Growth Factor / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuroblastoma
  • Nuclear Proteins / metabolism
  • Protein Binding / drug effects
  • Rats
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism*
  • Transfection / methods
  • Two-Hybrid System Techniques


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Luminescent Proteins
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Receptors, Nerve Growth Factor
  • Green Fluorescent Proteins
  • Nerve Growth Factor