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Epigenetic control of aquaporin 1 expression by the amyloid precursor protein

Sandra Huysseune^*, Pascal Kienlen-Campard^*, Sébastien Hébert^,||,¶, Bernadette Tasiaux^*, Karelle Leroy, Olivier Devuyst, Jean-Pierre Brion, Bart De Strooper^||,¶ and Jean-Noël Octave^*,1

^* Institute of Neurosciences, Experimental Pharmacology, Université Catholique de Louvain, Brussels, Belgium;

Neurosciences, Centre de Recherche du Centre Hospitalier Universitaire de Quebec, Laurier, Québec, Canada;

Laboratory of Histology, Neuroanatomy and Neuropathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium;

Unité de Néphrologie, Université Catholique de Louvain, Brussels, Belgium;

^|| Center for Human Genetics, KU Leuven, Leuven, Belgium; and

^¶ Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Leuven, Belgium

¹ Correspondence: Université Catholique de Louvain, Institute of Neuroscience, FARL5410, Ave. Hippocrate 54, B-1200 Brussels, Belgium. E-mail: jean-noel.octave{at}uclouvain.be

Cellular processing of the amyloid precursor protein (APP) has been extensively studied, but its precise function remains elusive. The intracellular domain of APP has been proposed to regulate expression of several genes by mechanisms that are largely unknown. We report that APP regulates expression of the aquaporin 1 (AQP1) gene in mouse embryonic fibroblasts and in transgenic mice. AQP1 mRNA and protein were down-regulated in fibroblasts lacking APP or presenilin 2 in which AQP1 expression was restored by stable expression of full-length APP or presenilin 2 but not by APP deleted from its carboxy-terminal domain. The transcriptional activity of the AQP1 gene promoter and the stability of AQP1 mRNA were identical in fibroblasts expressing or not expressing APP. Control of AQP1 expression by APP was sensitive to trichostatin A, an histone deacetylase inhibitor, and histone deacetylase activity coimmunoprecipitated with APP. Altogether, these data show that a presenilin-2-dependent -secretase activity releases the intracellular domain of APP involved in the epigenetic control of AQP1 expression. Since AQP1 is found in astrocytes surrounding senile plaques, this epigenetic control of AQP1 expression could have important implications in Alzheimer disease.—Huysseune, S., Kienlen-Campard, P., Hébert, S., Tasiaux, B., Leroy, K., Devuyst, O., Brion, J.-P., De Strooper, B., Octave, J.-N. Epigenetic control of aquaporin 1 expression by the amyloid precursor protein.

Key Words: AICD • Alzheimer’s disease • gene expression • histone acetylation