Epigenetic regulation of immediate early genes by the amyloid precrusor protein (APP) of Alzheimer's disease

AD is characterized by the presence of two kinds of lesions in the brain: neurofibrillary tangles and senile plaques (SP) containing a core of amyloid beta (Ab) aggregates. Ab peptide is obtained from the amyloidogenic cleavage of a larger precursor, the amyloid precursor protein (APP). Since its identification, a huge effort has been made in order to further understand the metabolism and the function of APP. Among others, a role in regulation of gene transcription is allocated to the c-terminal fragment of APP (AICD) but this hypothesis remains matter of debate. During my PhD, we investigated target genes of APP using a model of mice knock-out for APP gene. By comparing transcripts coming from APP +/+ and APP -/- astrocytes we discovered that the transcription of Egr-1 was regulated by APP. Egr-1 belongs of the immediate early genes (IEG) family of transcription factors involved in memory formation making it a good candidate for further investigations. As Egr-1 is known to be regulated by histone acetylation, we focused our study on this type of epigenetic modification. Such addition of acetyl groups on lysines located on histone tails has a positive impact on gene transcription as it let the chromatin in an opened status. By studying primary culture of APP+/+ and APP-/- neurons, we observed that Egr-1 transcription was up-regulated in absence of APP. Further analyzes of the promoter region of Egr-1 gene by chromatin immunoprecipitation (ChIP) showed that the level of histone H4 accetylation was increased in APP-/- neurons, arguing for an epigenetic regulation by APP. Using ChIP analysis combined with pharmacological treatment we demonstrated that this regulation was occurring in an AICD independent way. Later, we moved to a model of prefrontal (PF) cortex of APP+/+ and APP-/-mice, where we showed that Egr-1 expression together with other IEGs like c-Fos, Bdnf and Arc were also upregulated in APP -/-. This increase of expression was followed by a greater enrichment of histone H4 acetylation at the promoter of Egr-1, c-Fos and BDNF. Deciphering the molecular mechanisms underlying this regulation, we observed that APP dependent regulation of Egr-1 depended of the binding of the neuronal induced transcription factor CREB while APP affected c-Fos expression by increasing the recruitment of a histone deacetylase (HDAC) on its promoter. Finally, we assessed the physiological relevance of this regulation by measuring the induction of c-Fos and Egr-1 after exposition to novelty, a stimulus described as fostering expression of these IEGs and important to initiate the first step of event underlying memory formation. We report that APP -/- mice were not able to induce properly c-Fos and Egr-1 in PF cortex after novelty exposure, suggesting a major role of APP in regulation of IEGs transcription mediating neuronal plasticity.