Signaling Events in Amyloid β-Peptide-induced Neuronal Death and Insulin-like Growth Factor I Protection

Abstract

Amyloid -peptide (A) is implicated as the toxic agent in Alzheimer's disease and is the major component of brain amyloid plaques. In vitro, A causes cell death, but the molecular mechanisms are unclear. We analyzed the early signaling mechanisms involved in A toxicity using the SH-SY5Y neuroblastoma cell line. A caused cell death and induced a 2-to 3-fold activation of JNK. JNK activation and cell death were inhibited by overexpression of a dominant-negative SEK1 (SEK1-AL) construct. Butyrolactone I, a cdk5 inhibitor, had an additional protective effect against A toxicity in these SEK1-AL-expressing cells suggesting that cdk5 and JNK activation independently contributed to this toxicity. A also weakly activated ERK and Akt but had no effect on p38 kinase. Inhibitors of ERK and phosphoinositide 3-kinase (PI3K) pathways did not affect A-induced cell death, suggesting that these pathways were not important in A toxicity. Insulin-like growth factor I protected against A toxicity by strongly activating ERK and Akt and blocking JNK activation in a PI3K-dependent manner. Pertussis toxin also blocked A-induced cell death and JNK activation suggesting that G i/o proteins were upstream activators of JNK. The results suggest that activation of the JNK pathway and cdk5 may be initial signaling cascades in A-induced cell death.