Epigenetic Regulations of Immediate Early Genes Expression Involved in Memory Formation by the Amyloid Precursor Protein of Alzheimer Disease

<div><p>We previously demonstrated that APP epigenetically regulates <i>Egr1</i> expression both in cultured neurons and <i>in vivo</i>. Since <i>Egr1</i> is an immediate early gene involved in memory formation, we wondered whether other early genes involved in memory were regulated by APP and we studied molecular mechanisms involved. By comparing prefrontal (PF) cortex from wild type (APP+/+) and APP knockout mice (APP−/−), we observed that APP down regulates expression of four immediate early genes, <i>Egr1</i>, <i>c-Fos</i>, <i>Bdnf</i> and <i>Arc</i>. Down regulation of <i>Egr1</i>, <i>c-Fos</i> and <i>Bdnf</i> transcription resulted from a decreased enrichment of acetylated histone H4 on the corresponding gene promoter. Further characterization of H4 acetylation at <i>Egr1</i> and <i>c-Fos</i> promoters revealed increased acetylation of H4K5 and H4K12 residues in APP−/− mice. Whereas APP affected <i>Egr1</i> promoter activity by reducing access of the CREB transcription factor, its effect on <i>c-Fos</i> appeared to depend on increased recruitment of HDAC2 histone deacetylase to the gene promoter. The physiological relevance of the epigenetic regulation of <i>Egr1</i> and <i>c-Fos</i> gene transcription by APP was further analyzed following exposure of mice to novelty. Although transcription of <i>Egr1</i> and <i>c-Fos</i> was increased following exposure of APP+/+ mice to novelty, such an induction was not possible in APP−/− mice with a high basal level of expression of these immediate early genes. Altogether, these results demonstrate that APP-mediated regulation of <i>c-Fos</i> and <i>Egr1</i> by different epigenetic mechanisms is needed for their induction during exposure to novelty.</p>