The p75 Neurotrophin Receptor Promotes Amyloid-β(1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo

Oligomeric forms of amyloid-beta (A beta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in A beta-induced neurodegeneration. To further define the functions of p75NTR in AD, we examined the interaction of oligomeric A beta(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 A beta, and fluorescence resonance energy transfer analysis revealed that A beta oligomers interact with the extracellular domain of p75NTR. In vitro studies of A beta-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 A beta-induced cell death. Interestingly, A beta-induced neuritic dystrophy and activation of c-Jun, a known mediator of A beta-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). A beta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess A beta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all A beta effects, it does play a significant role in enabling A beta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.