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Review
. 2016 Sep;1862(9):1617-27.
doi: 10.1016/j.bbadis.2016.06.001. Epub 2016 Jun 2.

Are circulating microRNAs peripheral biomarkers for Alzheimer's disease?

Subodh Kumar  1 , P Hemachandra Reddy  2
Affiliations
Review

Are circulating microRNAs peripheral biomarkers for Alzheimer's disease?

Subodh Kumar et al. Biochim Biophys Acta. 2016 Sep.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, multiple cognitive abnormalities and intellectual impairments. Currently, there are no drugs or agents that can delay and/or prevent the progression of disease in elderly individuals, and there are no peripheral biomarkers that can detect AD early in its pathogenesis. Research has focused on identifying biomarkers for AD so that treatment can be begun as soon as possible in order to restrict or prevent intellectual impairments, memory loss, and other cognitive abnormalities that are associated with the disease. One such potential biomarker is microRNAs that are found in circulatory biofluids, such as blood and blood components, serum and plasma. Blood and blood components are primary sources where miRNAs are released in either cell-free form and then bind to protein components, or are in an encapsulated form with microvesicle particles. Exosomal miRNAs are known to be stable in biofluids and can be detected by high throughput techniques, like microarray and RNA sequencing. In AD brain, enriched miRNAs encapsulated with exosomes crosses the blood brain barrier and secreted in the CSF and blood circulations. This review summarizes recent studies that have identified miRNAs in the blood, serum, plasma, exosomes, cerebral spinal fluids, and extracellular fluids as potential biomarkers of AD. Recent research has revealed only six miRNAs - miR-9, miR-125b, miR-146a, miR-181c, let-7g-5p, and miR-191-5p - that were reported by multiple investigators. Some studies analyzed the diagnostic potential of these six miRNAs through receiver operating curve analysis which indicates the significant area-under-curve values in different biofluid samples. miR-191-5p was found to have the maximum area-under-curve value (0.95) only in plasma and serum samples while smaller area-under-curve values were found for miR-125, miR-181c, miR-191-5p, miR-146a, and miR-9. This article shortlisted the promising miRNA candidates and discussed their diagnostic properties and cellular functions in order to search for potential biomarker for AD.

Keywords: Alzheimer's disease; Biomarker; CSF; Cerebral spinal fluid; Circulatory microRNA; Plasma; Serum.

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Figures

Figure 1
Figure 1. miRNA synthesis pathway
miRNA generation pathways include both nucleus and cytoplasmic steps. To generate miRNAs, primary-miRNAs are transcribed from miRNA encoding genes using RNA polymerase II or III. The pri-miRNAs were digested by microprocessor complexes to the hair pin-loop precursor-miRNA. Pre-miRNA is transported to the cytoplasm by the exportin five transporter and processed into a miRNA duplex structure using Dicer and TAR RNA-binding proteins (TRBP). miRNA duplex is separated by helicase into one guide strand, comprised of a mature miRNA-5p or a mature miRNA-3p miRNA and one passenger strand. A passenger strand is degraded while the guide strand forms an RISC complex with Ago2 proteins and targets the 3’UTR of mRNA. The resulting miRNAs modulates gene activity.
Figure 2
Figure 2. Secretion of miRNAS from a cell to extracellular spaces and circulatory biofluids
Stem-loop pre-miRNA and mature miRNAs are secreted from the either in micro particle free form bound with proteins or in encapsulated macrovesicles. There are five main modes by which miRNAs are secreted into extracellular spaces and circulatory biofluids: (1) Non-vesicle bound with high density lipoproteins, (2) Non-vesicle bound with Ago2 proteins, (3) Encapsulated within exosomes, (4) packaged in macrovesicles and (5) Secretion within apoptotic bodies.
Figure 3
Figure 3
Expression patterns of selected miRNAs in biofluids from AD patients. Serum, plasma and CSF are considered primary biofluids as sources for constant expression of circulatory miRNAs: miR-9, miR-125b, miR-146a, miR-181c, miR-191-5p and let-7 g-5p. Respective biological functions of these candidate miRNAs are also shown.
See this image and copyright information in PMC

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