title: The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo.
abstract: Oligomeric forms of amyloid-beta (Abeta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in Abeta-induced neurodegeneration. To further define the functions of p75(NTR) in AD, we examined the interaction of oligomeric Abeta(1-42) with p75(NTR), and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Abeta, and fluorescence resonance energy transfer analysis revealed that Abeta oligomers interact with the extracellular domain of p75(NTR). In vitro studies of Abeta-induced death in neuron cultures isolated from wild-type and p75(NTR-/-) mice, in which the p75(NTR) extracellular domain is deleted, showed reduced sensitivity of mutant cells to Abeta-induced cell death. Interestingly, Abeta-induced neuritic dystrophy and activation of c-Jun, a known mediator of Abeta-induced deleterious signaling, were completely prevented in p75(NTR-/-) neuron cultures. Thy1-hAPP(Lond/Swe) x p75(NTR-/-) mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75(NTR). Abeta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess Abeta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all Abeta effects, it does play a significant role in enabling Abeta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.
authors.affiliation: Department of Neurology and Neurological Science, Stanford University, Stanford, California 94305, USA.
authors.forename: Juliet K
authors.initials: JK
authors.lastname: Knowles
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
authors.forename: Thuy-Vi V
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Melburne C
authors.initials: MC
authors.lastname: LeMieux
authors.forename: Lilith
authors.initials: L
authors.lastname: Vander Griend
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology / Q000523:psychology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005091:Exons / Q000235:genetics; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology*; D016501:Neurites / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D016548:Prosencephalon / Q000166:cytology; D020800:Receptor, Nerve Growth Factor / Q000172:deficiency / Q000502:physiology*; D013054:Spectrophotometry, Atomic / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D020800:Receptor, Nerve Growth Factor; C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase