Identification of β-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 extracellular deposition in the brain of amyloid β-peptide (Aβ), presumed 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 Aβ-responsive genes in human preneuron NT2 cells, at early stages of Aβ(25-35) exposure, by RNA differential display. Aβ induced the expression of (i) the growth arrest and DNA damage-inducible gene (gadd45) implicated in the DNA excision–repair process; (ii) a stress-signaling kinase gene encoding the mitogen-activated protein kinase/Erk kinase kinase-1 (MEKK1); (iii) a new growth factor-inducible immediate-early gene, CYR61, the product of which functions as an extracellular matrix signaling 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 encoding a constituent of the mitochondrial pyruvate dehydrogenase complex, the dihydrolipoamide dehydrogenase-binding protein (E3-BP); and (vii) an unidentified human gene (KIAA0099). Aβ not only activates but also respresses genes: (i) the gene encoding “hinge” protein, a subunit of the mitochondrial cytochrome-c reductase and (ii) the SRp55 gene encoding a splicing factor involved in constitutive pre-mRNA splicing and alternative splice site selection. Our results underscored Aβ-responsive genes that play key roles in the response (damage/recovery) of neuron cells to Aβ exposure. In particular, the strong upregulation of gadd45, indicating DNA damage, was detected early in Aβ cytotoxicity. This suggests that DNA strand breaks occurred rapidly in cells exposed to Aβ, which may be a critical event in Aβ neurotoxicity.