Abstract
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.
Document Type
Article
Publication Date
1-30-2008
Digital Object Identifier (DOI)
https://doi.org/10.1523/JNEUROSCI.5065-07.2008
Funding Information
The work was supported by National Institutes of Health (NIH) Grants K08 NS050110 and KY-INBRE P20 RR16481.
Repository Citation
Wang, Wang-Xia; Rajeev, Bernard W.; Stromberg, Arnold J.; Ren, Na; Tang, Guiliang; Huang, Qingwei; Rigoutsos, Isidore; and Nelson, Peter T., "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" (2008). Sanders-Brown Center on Aging Faculty Publications. 102.
https://uknowledge.uky.edu/sbcoa_facpub/102
Supplemental file
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Notes/Citation Information
Published in The Journal of Neuroscience, v. 28, issue 5, p, 1213-1223.
Copyright © 2008 Society for Neuroscience
This article is available to the public to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/).