Number 107: MicroRNA Gets to First BACE in AD Brain

The discovery of microRNAs (miRNAs) opened a door on a previously unsuspected world of genetic regulation, exposing a mechanism that has been proven to play important roles in normal development and cancer. But what of neurodegenerative disease? As with any new field, the reports trickle in slowly at first, and gradually a case is emerging for the involvement of miRNAs in neuron health and disease (see ARF related news story, ARF live discussion, and recent reviews by Hebert and De Strooper, 2007 and Nelson and Keller, 2007). In the case of Alzheimer disease, changes in the levels of some miRNAs have been reported in AD brain (Lukiw, 2007), but no miRNA has been linked to altered expression of any gene important in the disease.

Enter the group of Peter Nelson of the University of Kentucky, Lexington. In the January 30 issue of the Journal of Neuroscience, Nelson and colleagues present data showing that the microRNA miR-107 is significantly decreased over the course of AD in human brain. Moreover, the decrease may contribute to an upregulation of mRNA for the amyloid-producing enzyme β-secretase (BACE1), the authors suggest. A BACE increase in late-onset AD is well established (e.g., Fukumoto et al., 2002). The work links for the first time changes in a specific microRNA to alterations in a putative target messenger RNA with the capability of affecting the progression of AD.

In the study, first authors Wang-Xia Wang and Bernard Rajeev profiled expression of RNA extracted from tissue derived from 23 human brain samples. The samples, from the cortical grey matter of clinically well-documented elderly patients, broke down into four groups: non-demented subjects with no AD pathology, non-demented with early AD pathology, mild cognitive impairment with moderate AD pathology, and AD. Of 70 miRNAs whose expression levels were high enough to make comparisons, the researchers found a few that showed a consistent change over the course of disease. One of these, miR-107, showed a statistically significant decrease between the non-demented/no pathology subjects and the MCI group. The levels in the non-demented-with-plaques group was intermediate between the two. Thus, expression profiling suggested that miR-107 levels decreased early in disease. Other miRNAs also changed, but more often, the differences emerged when non-demented subjects were compared to the AD group. The investigators focused on miR-107 because it showed the greatest change, and that change occurred early on.

The decrease in miR-107 as disease progressed was confirmed by Northern blot and by in-situ hybridization. The latter identified the location of the miRNA in neurons and showed that it was present only in certain layers of the temporal gyrus. In this initial study, the loss of miR-107 seemed specific to AD. When the investigators looked at patients diagnosed with dementia with Lewy bodies, they found no change in the miR-107.

What genes might be affected by miR-107 changes? Computational analysis of AD-related genes revealed that the BACE1 mRNA bears several miR-107 target sequences in its 3’ untranslated region. In all, BACE1 had binding sites for at least 25 known microRNAs, leaving room for further discoveries. The investigators looked further at the putative miR-107/BACE1 interaction in 11 of the brain samples, and found that BACE1 mRNA increased as miR-107 went down. The correlation held up when the scientists looked at BACE protein levels in additional brain samples. Finally, they showed that a reporter gene construct carrying a BACE1 miR-107 response element came under regulation by endogenous miRNAs or by small interfering RNAs added to cells in transfection experiments.

The work provides data “indicating that miR-107 contributes to BACE posttranscriptional regulation and that this pathway is predicted to exacerbate pathology in AD brains,” the authors write. The current study raises the possibility that alterations in microRNA expression could contribute to the noted BACE increase in LOAD. In addition, microRNAs might eventually provide a handle to lower BACE levels therapeutically, the authors suggest.—Pat McCaffrey

Comments

  1. The role of miRNAs in fundamental biology and more recently in neurodegenerative disorders is gaining popularity (1). Now, Peter Nelson’s group provides the first evidence that changes in miRNA expression could contribute to Alzheimer disease development. These observations add to the recently published work on miRNAs in Parkinson disease (2).

    Here, the authors performed miRNA microarray profiling and found miR-107 (and perhaps miR-103, which belongs to the same family) to be specifically decreased in “pre”-AD patients. For those who are not fully aware of miRNA literature, a decrease in miRNA levels would theoretically lead to increased protein expression. Interestingly, one of the candidate target genes for miR-107/103 is BACE1, and the authors show that, in vitro at least, miR-107 can indeed regulate BACE1 expression. While a follow-up study is now needed in a larger cohort of patients, these results support the hypothesis that changes in miRNA expression could be involved (perhaps early on) in sporadic AD development and that BACE1 can be regulated by miRNAs.

    Overall, these results are in line with our own observations that we presented last year at the centennial meeting on AD in Tübingen, Germany, and the AD/PD conference in Salzburg, Austria. Now that an independent group has demonstrated similar findings, hopefully our work will soon be accepted for publication.

    References:

    Hébert SS, De Strooper B. Molecular biology. miRNAs in neurodegeneration. Science. 2007 Aug 31;317(5842):1179-80. PubMed.

    Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, Hannon G, Abeliovich A. A MicroRNA feedback circuit in midbrain dopamine neurons. Science. 2007 Aug 31;317(5842):1220-4. PubMed.

    View all comments by Sébastien S. Hébert

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References

News Citations

  1. Research Brief: Do MicroRNAs Cause Parkinson Disease?

Webinar Citations

  1. Non-coding RNAs in Neurodegeneration

Paper Citations

  1. Hébert SS, De Strooper B. Molecular biology. miRNAs in neurodegeneration. Science. 2007 Aug 31;317(5842):1179-80. PubMed.
  2. Nelson PT, Keller JN. RNA in brain disease: no longer just "the messenger in the middle". J Neuropathol Exp Neurol. 2007 Jun;66(6):461-8. PubMed.
  3. Lukiw WJ. Micro-RNA speciation in fetal, adult and Alzheimer's disease hippocampus. Neuroreport. 2007 Feb 12;18(3):297-300. PubMed.
  4. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002 Sep;59(9):1381-9. PubMed.

Further Reading

Primary Papers

  1. 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.

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