Sébastien S. Hébert1,2, Katrien Horré1,2, Laura Nicolaï1,2, Aikaterini S. Papadopoulou1,2, Wim Mandemakers1,2, Asli Silahtaroglu3, Sakari Kauppinen4,3, André Delacourte5, Bart De Strooper1,2
1*Center for Human Genetics, Katholieke Universiteit Leuven and
2Department of Molecular and Developmental Genetics, VIB, Herestraat 49 bus 602, B-3000 Leuven, Belgium;
3Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark;
4Santaris Pharma, Bøge Alle 3, DK-2970 Hørsholm, Denmark; and
5Institut National de la Santé et de la Recherche Médicale, U. 837, Bâtiment G. Biserte, 1 Place de Verdun, 59045 Lille Cedex, France
Tóm tắt
Although the role of
APP
and
PSEN
genes in genetic Alzheimer's disease (AD) cases is well established, fairly little is known about the molecular mechanisms affecting Aβ generation in sporadic AD. Deficiency in Aβ clearance is certainly a possibility, but increased expression of proteins like APP or BACE1/β-secretase may also be associated with the disease. We therefore investigated changes in microRNA (miRNA) expression profiles of sporadic AD patients and found that several miRNAs potentially involved in the regulation of APP and BACE1 expression appeared to be decreased in diseased brain. We show here that miR-29a, -29b-1, and -9 can regulate BACE1 expression
in vitro
. The miR-29a/b-1 cluster was significantly (and AD-dementia-specific) decreased in AD patients displaying abnormally high BACE1 protein. Similar correlations between expression of this cluster and BACE1 were found during brain development and in primary neuronal cultures. Finally, we provide evidence for a potential causal relationship between miR-29a/b-1 expression and Aβ generation in a cell culture model. We propose that loss of specific miRNAs can contribute to increased BACE1 and Aβ levels in sporadic AD.
