The p75 neurotrophin receptor promotes amyloid-β(1-42)-induced neuritic dystrophy in vitro and in vivo

Abstract

Oligomeric forms of amyloid-β(Aβ) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75 NTR) has been implicated in Aβ-induced neurodegeneration. To further define the functions of p75NTR in AD, we examined the interaction of oligomeric Aβ(1-42) with p75NTR, 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 Aβ, and fluorescence resonance energy transfer analysis revealed that Aβ oligomers interact with the extracellular domain of p75NTR. In vitro studies of Aβ-induced death in neuron cultures isolatedfromwild-typeandp75NTR-/- mice, in which the p75 NTR extracellular domain is deleted, showed reduced sensitivity of mutant cells toAβ-induced cell death. Interestingly, Aβ-induced neuritic dystrophy and activation of c-Jun, a known mediator of Aβ-induced deleterious signaling, were completely prevented in p75NTR-/- neuron cultures. Thy1-hAPPLond/Swe X p75NTR-/- mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75NTR. Aβ levels were not affected, suggesting that removal of p75NTR extracellular domain reduced the ability of excess Aβ to promote neuritic degeneration. These findings indicate that although p75NTR likely does not mediate all Aβ effects, it does play a significant role in enabling Aβ-induced neurodegeneration in vitro and in vivo, establishing p75NTR as an important therapeutic target for AD. Copyright © 2009 Society for Neuroscience.