Signaling events in amyloid β-peptide-induced neuronal death and insulin-like growth factor I protection

Amyloid β-peptide (Aβ) is implicated as the toxic agent in Alzheimer's disease and is the major component of brain amyloid plaques. In vitro, Aβ causes cell death, but the molecular mechanisms are unclear. We analyzed the early signaling mechanisms involved in Aβ toxicity using the SH-SY5Y neuroblastoma cell line. Aβ 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 Aβ toxicity in these SEK1-AL-expressing cells suggesting that cdk5 and JNK activation independently contributed to this toxicity. Aβ 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 Aβ-induced cell death, suggesting that these pathways were not important in Aβ toxicity. Insulin-like growth factor I protected against Aβ toxicity by strongly activating ERK and Akt and blocking JNK activation in a PI3K-dependent manner. Pertussis toxin also blocked Aβ-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 Aβ-induced cell death.