Epigenetic control of aquaporin 1 expression by the amyloid precursor protein.
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 gamma-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
Sandra
S
Université Catholique de Louvain, Institute of Neuroscience, FARL5410, Ave. Hippocrate 54, B-1200 Brussels, Belgium.
Kienlen-Campard
Pascal
P
Hébert
Sébastien
S
Tasiaux
Bernadette
B
Leroy
Karelle
K
Devuyst
Olivier
O
Brion
Jean-Pierre
JP
De Strooper
Bart
B
Octave
Jean-Noël
JN
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D016564:Amyloid beta-Protein Precursor; C496021:Aqp1 protein, mouse; C452880:Atp5md protein, rat; D008565:Membrane Proteins; D053763:Presenilins; D012333:RNA, Messenger; D051398:Aquaporin 1