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Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, De Strooper B. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6415-20. Epub 2008 Apr 23 PubMed.
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Bart De Strooper and his collaborators have characterized a microRNA cluster (miR29a/b-1) that is significantly and specifically downregulated in AD patients. miRNAs are extremely important regulators of gene expression that modulate both translation efficiency and stability of their target mRNAs. Importantly, the miRNA studied by De Strooper's group regulates the β-secretase BACE1. Downregulation of the miRNA cluster correlates with increased expression of BACE1 in AD patients, as well as during development and in primary cells. BACE1 mRNA is apparently not destabilized, indicating that in this case the miRNA controls the translation of the mRNA. If this control is lost, due to a decrease of miRNA expression, an excess of BACE1 is expressed, which will increase the malign processing of APP to form the AD-causing Aβ peptide.
First, this work further establishes BACE1 as a causative agent and hence drug target in AD. In this respect, it is also interesting that this effect is specific to AD patients and not seen in other forms of dementia. Second, this work, together with a parallel study published almost at the same time (Wang et al., 2008), for the first time associates a dysregulation of miRNAs with AD development in humans.
Gene regulation by miRNAs is still a new and poorly understood field, and to have such a strong link to an important human pathology will certainly encourage further studies into the topic.
References:
Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, Rigoutsos I, Nelson PT. The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci. 2008 Jan 30;28(5):1213-23. PubMed.
University of Zurich
An excellent piece of work by Sebastien, Bart, and colleagues. This study underscores the role of BACE elevation in late-onset AD (LOAD).
This study from Bart's group and the recent work from Karen Duff's group on Cdk5's role in BACE transcription (Wen et al., 2008) now show that BACE levels could be regulated by distinct mechanisms acting either at the level of translation or transcription. Upregulation of BACE, either in terms of the enzymatic activity or protein levels, is clearly a risk for LOAD. Hence, understanding the mechanisms by which BACE is upregulated is crucial for AD etiology and also for therapy.
Bob Vassar's results on stress-induced eIF2a phosphorylation causing an increase in BACE levels also come timely [see ARF related Keystone story]. It would be interesting to find mechanisms that cause this eIF2a phosphorylation-induced switch to specific translation. Since cellular stress regulates miRNA levels, it would be interesting to see if there is some stress-miRNA-BACE connection here. It would also be fascinating to see how aging, inflammation, or other factors that influence the risk for LOAD also influence the downregulation of these miRNAs.
References:
Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marié I, Maurin T, Wang L, Figueroa H, Herman M, Krishnamurthy P, Liu L, Planel E, Lau LF, Lahiri DK, Duff K. Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008 Mar 13;57(5):680-90. PubMed.
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