Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression

Sébastien S. Hébert, Katrien Horré, Laura Nicolaï, Aikaterini S. Papadopoulou, Wim Mandemakers, Asli N. Silahtaroglu, Sakari Kauppinen, André Delacourte, Bart De Strooper*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

987 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6415-6420
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number17
DOIs
Publication statusPublished - 29 Apr 2008
Externally publishedYes

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