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

Wanli Wei, Xiantao Wang, John W. Kusiak
2002 Journal of Biological Chemistry  
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.
more » ... L) 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.
doi:10.1074/jbc.m111704200 pmid:11882652 fatcat:kwunp75r7napja4i3sudvztxti