Contrôle transcriptionnel associé au domaine intracellulaire du précurseur du peptide amyloïd
(2010)
Files
246991_Huysseune_These.pdf
Restricted Access - Adobe PDF
- 19.7 MB
Details
- Authors
- Supervisors
- Octave, Jean-Noël
- Abstract
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neurofibrillary tangles and deposition of β-amyloïd peptide (Aβ) derived from β-amyloïd precursor protein (APP). APP belongs to a gene family including APP-like proteins (APLPs), which could display overlapping functions. Although the mechanisms of Aβ production have been intensely studied, the biological functions of APP and of its proteolytic fragments are poorly understood. APP is cleaved by alpha-, beta- and gamma-secretase activities leading to the production of soluble alpha APP (sαAPP), soluble beta APP (sβAPP), Aβ and an intracellular fragment named APP intracellular domain (AICD). Biochemical and genetic interaction screens have also led to the identification of multiple intracellular binding partners including the adaptor protein Fe65. Several studies suggested that this protein is able to modulate the APP processing, signaling and Aβ production. AICD is thought to regulate gene transcription but the identity of the target genes as well as the mechanisms involved remain highly controversial. <BR> The aim of this work was to clarify the role of Fe65 in APP processing, Aβ production and APP signaling. We also wanted to identify new genes regulated by APP. <BR> Using a human APPGal4 fusion protein in a luciferase-based reporter assay, we showed that AICD triggers the transcription of reporter genes. Coexpression of Fe65 and human APP in CHO cells had no effect on sαAPP, sβAPP and endogenous AICD production but increased luciferase activity and decreased Aβ production, indicating that Fe65 is able to enhance transcription independently of AICD. We profiled gene expression using Gene-chip Micro array in mouse embryonic cells (MEFs) expressing or not APP and presenilins (presenilin 1 and 2), the catalytic core of the gamma-secretase. We found Aquaporin1 (AQP1) as new APP target gene and confirmed our results by qRT-PCR, Western blotting and rescue experiments using retroviral and lentiviral expression of APP and presenilins. In addition, we found, in vivo, an up-regulation of AQP1 in astrocytes located near senile plaques of AD and lower levels of AQP1 in APP knock-out mice. Our results indicate that a PS2-mediated cleavage of APP releases an AICD fragment that interacts with histone deacetylase activities and controls indirectly AQP1 expression. This interaction confers to APP a key role in histone acetylation and chromatin remodelling, a new mechanism possibly involved in the etiology of Alzheimer's disease
- Affiliations
Citations
Huysseune, S. (2010). Contrôle transcriptionnel associé au domaine intracellulaire du précurseur du peptide amyloïd. https://hdl.handle.net/2078.5/111972