Akt-dependent expression of NAIP-1 protects neurons against amyloid-β toxicity

Sylvain Lesné, Cecilia Gabrieli, Deirdre A. Nelson, Eileen White, Eric T. MacKenzie, Denis Vivien, Alain Buisson

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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-β (Aβ) 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 Aβ. We showed that in primary cultures of cortical neurons, NT-3 reduces Aβ-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 Aβ 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 Aβ-induced neuronal apoptosis. Together, these findings demonstrate that NT-3 signaling counters Aβ-dependent neuronal cell death and may represent an innovative therapeutic intervention to limit neuronal death in Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)24941-24947
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number26
DOIs
StatePublished - Jul 1 2005

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lesné, S., Gabrieli, C., Nelson, D. A., White, E., MacKenzie, E. T., Vivien, D., & Buisson, A. (2005). Akt-dependent expression of NAIP-1 protects neurons against amyloid-β toxicity. Journal of Biological Chemistry, 280(26), 24941-24947. https://doi.org/10.1074/jbc.M413495200