BACE in Alzheimer’s—Does MicroRNA Control Translation?

Call it a case of lost inhibitions. Increased β-site cleavage enzyme 1 (BACE1) is one plausible risk for sporadic Alzheimer disease, but what causes this increase? A study in the April 23 PNAS online suggests that certain microRNAs are to blame. Researchers led by Bart De Strooper at KU Leuven, Belgium, report that several of these pint-sized nucleic acids normally prevent translation of BACE1 into protein, and that some of them are downregulated in sporadic AD brain tissue. The findings help explain why β-secretase is elevated in AD despite normal levels of BACE1 mRNA, and may even offer a new therapeutic target for treating sporadic forms of the disease.

MicroRNAs may be small, but they can certainly pack a punch. By binding to the 5’ or 3’ untranslated regions of messenger RNA, these regulatory molecules can profoundly affect translation. MicroRNAs have recently been linked to Parkinson disease (see ARF related news story). At least one microRNA, miR-107, seems to herald destruction of BACE1 mRNA and may be linked to increased BACE1 transcripts in the AD brain (see ARF related news story). But this latest finding from De Strooper’s lab suggests that other microRNAs act in a different manner.

First author Sebastien Hébert and colleagues looked in the brain of AD patients to see if any other microRNAs are up- or downregulated. In a pilot test of five patients and five age-matched controls, they found that levels of 13 out of 328 human microRNAs were significantly lower in samples of AD cortex. Computer-based structural predictions suggested that seven of those microRNAs potentially bind to the 3’ UTR of BACE1, APP, or PSEN1 genes. To see if those in silico predictions hold water, the researchers used an in-vitro reporter system to test if any of the microRNAs alter translation of a luciferase gene coupled to the BACE1 3’UTR. They found that two of the microRNAs, miR-9 and -29b-1, significantly suppressed translation of the reporter, as did miR-29a. The latter micro RNA is co-transcribed with miR-29b-1 and was also suppressed in AD tissue, though the drop did not reach statistical significance, possibly because of cross-reactivity of microRNA probes, suggest the authors.

Given that these microRNAs suppress BACE1 translation, could their downregulation in AD explain increased levels of BACE1? Hébert and colleagues found that loss of miR-29a and miR-29b-1 correlated with increased BACE1 in a subgroup of 11 patients with high BACE1. In contrast, patients with normal BACE (n = 23) had normal levels of the microRNAs. The scientists also found normal miR-29a/b-1 levels in a group of nine patients with non-AD dementia. “Thus, overall, we find that in the subgroup of AD patients with increased BACE1 expression, miR-29a and -29b-1 expression is significantly and specifically decreased,” write the authors.

There are, of course, various other ways of controlling BACE1 expression. Protein trafficking (see ARF related news story), transcriptional (see ARF related news story), other forms of translational (see ARF related news story), and post-translational regulation (see, e.g., Marambaud et al., 1998) have all been implicated. Where in the pecking order do these microRNAs stand? That remains to be determined, but the authors do provide evidence that these microRNAs have functional significance. They showed that there is co-regulation of miR-29a/b-1 and BACE1 in the brain during development and that expressing the microRNAs in HEK293 cells shuts off BACE1 expression and reduces APP processing and Aβ production. Unfortunately, the researchers found it very difficult to stably express these microRNAs in primary neurons.

Interestingly, microRNAs have been linked to the control of lifespan and aging in worms, and the authors speculate that microRNAs may become compromised during human aging. “Loss of specific microRNAs sets thus the stage for considering a ‘multiple hit hypothesis’ for sporadic AD,” they write.—Tom Fagan

Comments

  1. 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.

    View all comments by Claudia Bagni

  2. 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.

    View all comments by Lawrence Rajendran

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References

News Citations

  1. Research Brief: Do MicroRNAs Cause Parkinson Disease?
  2. Number 107: MicroRNA Gets to First BACE in AD Brain
  3. Madrid: BACE News Roundup, Part 3
  4. New Role for p25/Cdk5 in Regulation of BACE Expression
  5. Follow the Leader to Higher BACE Levels

Paper Citations

  1. Marambaud P, Chevallier N, Ancolio K, Checler F. Post-transcriptional contribution of a cAMP-dependent pathway to the formation of alpha- and beta/gamma-secretases-derived products of beta APP maturation in human cells expressing wild-type and Swedish mutated beta APP. Mol Med. 1998 Nov;4(11):715-23. PubMed.

Further Reading

Primary Papers

  1. 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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