Abstract
Following transcriptome comparison of primary cultures isolated from brain of mice expressing or not the amyloid precursor protein APP, we found transcription of the EGR-1 gene to be regulated by APP. In primary cultures of cortical neurons, APP significantly down regulated EGR-1 expression at both mRNA and protein levels in a γ-secretase independent manner. The intracellular domain of APP did not interact with EGR-1 gene promoter, but enrichment of acetylated histone H4 at the EGR-1 promoter region was measured in APP-/- neurons, as well as in brain of APP-/- mice, in which increase in EGR-1 expression was also measured. These results argue for an important function of APP in the epigenetic regulation of EGR-1 gene transcription both in vitro and in vivo. In APP-/- mice, constitutive overexpression of EGR-1 in brain impaired epigenetic induction of this early transcriptional regulator during exposure to novelty. Altogether, these results indicate an important function of APP in the epigenetic regulation of the transcription of EGR-1, known to be important for memory formation.
Highlights
Among the various functions that have been attributed to APP, regulation of gene expression has been widely investigated due to similarity between Notch and APP processing
Up regulation of EGR-1 gene transcription in APP-/- cells was not impressive, this gene encodes an early transcription factor involved in memory formation, and we further investigated the regulation of EGR-1 expression by APP in primary cultures of cortical neurons
In both non amyloidogenic and amyloidogenic catabolic pathways, APP is cleaved by the γ-secretase activity to release the APP intracellular domain (AICD), which is able to regulate transcription of several genes, including APP itself, the GSK3β, and the Aβ-degrading enzyme neprilysin [3,4,22,23,6,24,25]
Summary
Among the various functions that have been attributed to APP, regulation of gene expression has been widely investigated due to similarity between Notch and APP processing. The γ-secretase cleavage of APP and Notch releases the APP intracellular domain (AICD) and the Notch intracellular domain (NICD), respectively. The α-secretase cleavage generates a substrate for cleavage by the γ-secretase complex. This proteolytic processing mediates release of the NICD, which enters the nucleus to regulate transcription [1]. APP and Notch are processed by the same secretase activities and APP has been suggested to control transcription of several genes [3,4,5,6,7,8]. To study regulation of gene transcription by APP, transcriptomes of primary cultures isolated from brain of APP +/+ and APP-/- mice from the same genetic background were compared using the affymetrix microarray technology, and we identified EGR-1 as a possible target gene controlled by APP
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