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The Journal of Neuroscience, January 30, 2008, 28(5):1213-1223; doi:10.1523/JNEUROSCI.5065-07.2008

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Neurobiology of Disease
The Expression of MicroRNA miR-107 Decreases Early in Alzheimer's Disease and May Accelerate Disease Progression through Regulation of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1

Wang-Xia Wang,^1 * Bernard W. Rajeev,^1 * Arnold J. Stromberg,² Na Ren,² Guiliang Tang,³ Qingwei Huang,¹ Isidore Rigoutsos,⁵ and Peter T. Nelson^1,4

¹Sanders-Brown Center on Aging, ²Department of Statistics, ³Department of Plant Sciences, and ⁴Department of Pathology and Division of Neuropathology, University of Kentucky, Lexington, Kentucky 40536, and ⁵Bioinformatics and Pattern Discovery Group, IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598

Correspondence should be addressed to Dr. Peter T. Nelson, 311 Sanders-Brown Center on Aging, University of Kentucky, 800 South Limestone, Lexington, KY 40536-0230. Email: pnels2{at}email.uky.edu

MicroRNAs (miRNAs) are small regulatory RNAs that participate in posttranscriptional gene regulation in a sequence-specific manner. However, little is understood about the role(s) of miRNAs in Alzheimer's disease (AD). We used miRNA expression microarrays on RNA extracted from human brain tissue from the University of Kentucky Alzheimer's Disease Center Brain Bank with near-optimal clinicopathological correlation. Cases were separated into four groups: elderly nondemented with negligible AD-type pathology, nondemented with incipient AD pathology, mild cognitive impairment (MCI) with moderate AD pathology, and AD. Among the AD-related miRNA expression changes, miR-107 was exceptional because miR-107 levels decreased significantly even in patients with the earliest stages of pathology. In situ hybridization with cross-comparison to neuropathology demonstrated that particular cerebral cortical laminas involved by AD pathology exhibit diminished neuronal miR-107 expression. Computational analysis predicted that the 3'-untranslated region (UTR) of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA is targeted multiply by miR-107. From the same RNA material analyzed on miRNA microarrays, mRNA expression profiling was performed using Affymetrix Exon Array microarrays on nondemented, MCI, and AD patients. BACE1 mRNA levels tended to increase as miR-107 levels decreased in the progression of AD. Cell culture reporter assays performed with a subset of the predicted miR-107 binding sites indicate the presence of at least one physiological miR-107 miRNA recognition sequence in the 3'-UTR of BACE1 mRNA. Together, the coordinated application of miRNA profiling, Affymetrix microarrays, new bioinformatics predictions, in situ hybridization, and biochemical validation indicate that miR-107 may be involved in accelerated disease progression through regulation of BACE1.

Key words: Alzheimer's; miRNAs; microarray; in situ; BACE; noncoding

---

Received Oct. 4, 2007; revised Dec. 7, 2007; accepted Dec. 9, 2007.

Correspondence should be addressed to Dr. Peter T. Nelson, 311 Sanders-Brown Center on Aging, University of Kentucky, 800 South Limestone, Lexington, KY 40536-0230. Email: pnels2{at}email.uky.edu

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