Identification of beta-amyloid-responsive genes by RNA differential display: Early induction of a DNA damage-inducible gene, gadd45

Alzheimer's disease is a neurodegenerative disorder characterized by the ex tracellular deposition in the brain of amyloid beta-peptide (A beta), presu med to play a pathogenic role. However, the precise molecular mechanisms of its neurotoxicity are not fully understood. Recent studies have suggested that it may exert its toxic effect via activation of transcription factors. We investigated A beta-responsive genes in human preneuron NT2 cells, at e arly stages of A beta(25-35) exposure, by RNA differential display. A beta induced the expression of (i) the growth arrest and DNA damage-inducible ge ne (gadd45) implicated in the DNA excision-repair process; (ii) a stress-si gnaling kinase gene encoding the mitogen-activated protein kinase/Erk kinas e kinase-1 (MEKK1); (iii) a new growth factor-inducible immediate-early gen e, CYR61, the product of which functions as an extracellular matrix signali ng molecule; (iv) other immediate-early genes, such as c-jun and c-fos; (v) the gene encoding the basic fibroblast growth factor (bFGF); (vi) a gene e ncoding a constituent of the mitochondrial pyruvate dehydrogenase complex, the dihydrolipoamide dehydrogenase-binding protein (E3-BP); and (vii) an un identified human gene (KIAA0099). A beta not only activates but also respre sses genes: (i) the gene encoding "hinge" protein, a subunit of the mitocho ndrial cytochrome-c reductase and (ii) the SRp55 gene encoding a splicing f actor involved in constitutive pre-mRNA splicing and alternative splice sit e selection. Our results underscored A beta-responsive genes that play key roles in the response (damage/recovery) of neuron cells to Ap exposure. In particular, the strong upregulation of gadd45, indicating DNA damage, was d etected early in A beta cytotoxicity. This suggests that DNA strand breaks occurred rapidly in cells exposed to A beta , which may be a critical event in A beta neurotoxicity. (C) 1999 Academic Press.