Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression.
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 Abeta generation in sporadic AD. Deficiency in Abeta clearance is certainly a possibility, but increased expression of proteins like APP or BACE1/beta-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 Abeta generation in a cell culture model. We propose that loss of specific miRNAs can contribute to increased BACE1 and Abeta levels in sporadic AD.
Hébert
Sébastien S
SS
Center for Human Genetics, Katholieke Universiteit Leuven and Department of Molecular and Developmental Genetics, VIB, Herestraat 49 bus 602, B-3000 Leuven, Belgium.
Horré
Katrien
K
Nicolaï
Laura
L
Papadopoulou
Aikaterini S
AS
Mandemakers
Wim
W
Silahtaroglu
Asli N
AN
Kauppinen
Sakari
S
Delacourte
André
A
De Strooper
Bart
B
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D016229:Amyloid beta-Peptides; D035683:MicroRNAs; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human