Akt-dependent Expression of NAIP-1 Protects Neurons against Amyloid-β Toxicity

Sylvain Lesné,Cecilia Gabriel,Deirdre A Nelson,Eileen White,Eric T Mackenzie,Denis Vivien,Alain Buisson

doi:10.1074/jbc.m413495200

Abstract

Neurotrophins are a family of growth factors that attenuate several forms of pathological neuronal cell death and may represent a putative therapeutic approach to neurodegenerative diseases. In Alzheimer disease, amyloid-beta (Abeta) is thought to play a central role in the neuronal death occurring in brains of patients. In the present study, we evaluate the ability of neurotrophin-3 (NT-3) to protect neurons against the toxicity induced by aggregated Abeta. We showed that in primary cultures of cortical neurons, NT-3 reduces Abeta-induced apoptosis by limiting caspase-8, caspase-9, and caspase-3 cleavage. This neuroprotective effect of NT-3 was concomitant to an increased level of Akt phosphorylation and was abolished by an inhibitor of the phosphatidylinositol-3 kinase (PI-3K), LY294002. In parallel, NT-3 treatment reduced Abeta induced caspase-3 processing to control levels. In an attempt to link PI-3K/Akt to caspase inhibition, we evaluated the influence of the PI-3K/Akt axis on the expression of a member of the inhibitors of apoptosis proteins (IAPs), the neuronal apoptosis inhibitory protein-1. We demonstrated that NT-3 induces an up-regulation of neuronal apoptosis inhibitory protein-1 expression in neurons that promotes the inhibition of Abeta-induced neuronal apoptosis. Together, these findings demonstrate that NT-3 signaling counters Abeta-dependent neuronal cell death and may represent an innovative therapeutic intervention to limit neuronal death in Alzheimer disease.

Highlights

Alzheimer disease (AD)1 is a neurodegenerative disease characterized by the accumulation of a 40 – 42-amino acid-long peptide termed amyloid-␤ (A␤) into amyloid deposits and by the hyperphosphorylation of the protein tau, leading to neurofibrillary tangles [1,2,3]
We demonstrated that NT-3 induces an up-regulation of neuronal apoptosis inhibitory protein-1 expression in neurons that promotes the inhibition of A␤-induced neuronal apoptosis
AD is a neurodegenerative disease characterized by the abnormal accumulation of small aggregative peptides (A␤s) in brain tissue that leads to severe cortical dystrophy [4]

Summary

Introduction

Alzheimer disease (AD)1 is a neurodegenerative disease characterized by the accumulation of a 40 – 42-amino acid-long peptide termed amyloid-␤ (A␤) into amyloid deposits and by the hyperphosphorylation of the protein tau, leading to neurofibrillary tangles [1,2,3]. Following A␤ treatment, activation of several caspases has been identified in dying neurons (9 –14), and caspase inhibitors block A␤-induced cell death [11, 12, 14, 15], highlighting the contribution of apoptosis to A␤-induced toxicity. NT-3 treatment at 10 ng/ml reduced both A␤-induced neuronal cell death and the activation of caspase-8, caspase-9, and caspase-3 (Fig. 2C).

Results

Conclusion