Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology.

Abstract

Synapse and dendritic spine loss induced by amyloid-β oligomers is one of the main hallmarks of the early phases of Alzheimer's disease (AD) and is directly correlated with the cognitive decline typical of this pathology. The p75 neurotrophin receptor (p75NTR) binds amyloid-β oligomers in the nM range. While it was shown that µM concentrations of amyloid-β mediate cell death, the role and intracellular signaling of p75NTR for dendritic spine pathology induced by sublethal concentrations of amyloid-β has not been analyzed. We describe here p75NTR as a crucial binding partner in mediating effects of soluble amyloid-β oligomers on dendritic spine density and structure in non-apoptotic hippocampal neurons. Removing or over-expressing p75NTR in neurons rescues or exacerbates the typical loss of dendritic spines and their structural alterations observed upon treatment with nM concentrations of amyloid-β oligomers. Moreover, we show that binding of amyloid-β oligomers to p75NTR activates the RhoA/ROCK signaling cascade resulting in the fast stabilization of the actin spinoskeleton. Our results describe a role for p75NTR and downstream signaling events triggered by binding of amyloid-β oligomers and causing dendritic spine pathology. These observations further our understanding of the molecular mechanisms underlying one of the main early neuropathological hallmarks of AD.