TY - JOUR
T1 - Akt-dependent expression of NAIP-1 protects neurons against amyloid-β toxicity
AU - Lesné, Sylvain
AU - Gabrieli, Cecilia
AU - Nelson, Deirdre A.
AU - White, Eileen
AU - MacKenzie, Eric T.
AU - Vivien, Denis
AU - Buisson, Alain
PY - 2005/7/1
Y1 - 2005/7/1
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M413495200
DO - 10.1074/jbc.M413495200
M3 - Article
C2 - 15797869
AN - SCOPUS:21644467296
SN - 0021-9258
VL - 280
SP - 24941
EP - 24947
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -