Possible mechanisms of A beta(1-40)- or A beta(1-42)-induced cell death and their rescue factors

Abstract

Amyloidbetapeptide (A beta) is implicated in neuronal cell death in Alzheimer's disease, but the molecular mechanisms are still unclear. We analyzed its mechanism and found several potential rescue factors against A beta-mediated apoptosis. A beta(1-40) stimulated phosphorylation of tau and JNK and induced cell death in SH-SY5Y cells. The cell death was inhibited by insulin-like growth factor-1, suggesting that the JNK pathway may be involved in A beta(1-40)-induced cytotoxicity. Using the human fetus brain cDNA library-targeted differential display technique, a new gene BF5-1 (32aa) was found as a rescue factor against A beta(1-40). BF5-1 has partially the same amino acid sequences as those of the C-terminus of cytochrome c oxidase subunit VIIb (COX-VIIb). COX-VIIb mRNA is increased in AD brains and its overexpression in cells enhanced A beta(1-40)-toxicity. These data suggest that BF5-1 may act as a dominant negative mutant of COX-VIIb. A beta(1-42) also induced cell death in rat neuroblastoma B104 cells, which was abolished by addition of IL-11. By cDNA subtraction analysis in the cell death, the enhanced expression of L-phosphoserine phosphatase was found, but this was also abolished by IL-11. The glutamate neurotoxicity was stimulated in the presence of D-serine, suggesting that NMDA receptors may be involved in A beta(1-42)-induced cytotoxicity. A beta(1-42) also induced increase of a new gene p18A beta rP (p18-amyloid-beta-responsive protein; 166 aa) mRNA expression; overexpression of this gene in PC12 cells induced cell death. By the application of a death trap method, a new gene, p60TRP (p60-Transcription-Regulating-Protein; rat:539 aa, human:547aa), was found as a potential rescue factor against the cell death by p18A beta rP. Thus, our cell death systems and/or new rescue proteins may provide suitable tools for the establishment of drug screening systems leading to the identification of new low-molecular candidates applicable for the treatment of AD.