Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment

Tao Yang,Qun Lu,Youmei Xie,Timothy Chang,Gerald G Fuller,Qian Wang,Laura A Moore,Juliet K Knowles,Stephen M Massa,Hong Zhang,Jayakumar Rajadas,Ottavio Arancio,Katrin Andreasson,Frank M Longo,David C Rubinsztein

doi:10.1371/journal.pone.0003604

Abstract

The p75 neurotrophin receptor (p75NTR) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75NTR ligands found to promote survival signaling might prevent Aβ-induced degeneration and synaptic dysfunction. These ligands inhibited Aβ-induced neuritic dystrophy, death of cultured neurons and Aβ-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Aβ-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3β and c-Jun, and tau phosphorylation, and prevented Aβ-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Aβ-induced hippocampal LTP impairment. These studies support an extensive intersection between p75NTR signaling and Aβ pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Aβ-induced neuronal dystrophy and death.

Highlights

Slowing the progression of Alzheimer’s disease (AD) will likely require parallel strategies of managing amyloid-beta (Ab) levels and reducing neuronal vulnerability to Ab
The present studies demonstrate that non-peptide small molecule ligands targeting p75 neurotrophin receptor (p75NTR), a receptor upregulated in neurons vulnerable in AD, prevent Abinduced neuritic dystrophy and cell death, while inhibiting Abinduced tau phosphorylation and the activation of several key signaling intermediates, each a candidate therapeutic target in its own right
The inhibition of Ab-induced and transgenic mouserelated synaptic impairment, the prevention of neuritic dystrophy and neuronal death, along with the modulation of multiple intracellular signaling mechanisms involved in AD is a novel activity profile for small molecule ligands acting at a known receptor target

Summary

Introduction

Slowing the progression of Alzheimer’s disease (AD) will likely require parallel strategies of managing amyloid-beta (Ab) levels and reducing neuronal vulnerability to Ab. PLoS ONE | www.plosone.org p75NTR Ligands in AD Models (calpain, GSK3b and c-Jun) which mediates Ab toxicity; iii) upregulating survival signaling (AKT) which is normally inhibited by Ab and which can antagonize Ab mechanisms. We tested the hypothesis that these ligands would interfere with deleterious Ab signalling and its functional consequences We demonstrate that these compounds inhibit Ab-induced neuronal death, neuritic degeneration and activation of calpain/ cdk, GSK3b, and c-Jun; and reverse Ab-mediated inhibition of AKT and CREB activation, and synaptic function. These findings suggest that the use of small molecule p75NTR ligands may be a therapeutically feasible approach to AD capable of simultaneously targeting multiple underlying pathogenic mechanisms

Results

Discussion

Findings

Methods