Profiles of Extracellular miRNA in Cerebrospinal Fluid and Serum from Patients with Alzheimer's and Parkinson's Diseases Correlate with Disease Status and Features of Pathology

Abstract

The discovery and reliable detection of markers for neurodegenerative diseases have been complicated by the inaccessibility of the diseased tissue- such as the inability to biopsy or test tissue from the central nervous system directly. RNAs originating from hard to access tissues, such as neurons within the brain and spinal cord, have the potential to get to the periphery where they can be detected non-invasively. The formation and extracellular release of microvesicles and RNA binding proteins have been found to carry RNA from cells of the central nervous system to the periphery and protect the RNA from degradation. Extracellular miRNAs detectable in peripheral circulation can provide information about cellular changes associated with human health and disease. In order to associate miRNA signals present in cell-free peripheral biofluids with neurodegenerative disease status of patients with Alzheimer's and Parkinson's diseases, we assessed the miRNA content in cerebrospinal fluid and serum from postmortem subjects with full neuropathology evaluations. We profiled the miRNA content from 69 patients with Alzheimer's disease, 67 with Parkinson's disease and 78 neurologically normal controls using next generation small RNA sequencing (NGS). We report the average abundance of each detected miRNA in cerebrospinal fluid and in serum and describe 13 novel miRNAs that were identified. We correlated changes in miRNA expression with aspects of disease severity such as Braak stage, dementia status, plaque and tangle densities, and the presence and severity of Lewy body pathology. Many of the differentially expressed miRNAs detected in peripheral cell-free cerebrospinal fluid and serum were previously reported in the literature to be deregulated in brain tissue from patients with neurodegenerative disease. These data indicate that extracellular miRNAs detectable in the cerebrospinal fluid and serum are reflective of cell-based changes in pathology and can be used to assess disease progression and therapeutic efficacy.

Identification of aberrant circulating miRNAs in Parkinson's disease plasma samples

“…compared serum miRNA profiles in 67 PD‐diagnosed patients and 78 healthy controls, finding five deregulated miRNAs in PD‐diagnosed patients. The increased levels of miR‐338‐3p, miR‐30e‐3p, and miR‐30a‐3p and decreased levels of miR‐16‐2‐3p and miR‐1294 were detected (Burgos et al., 2014). In another study (Cardo et al., 2014), miR‐135b showed the most significant difference between patients and healthy donors.…”

MicroRNA-511 Binds to FKBP5 mRNA, Which Encodes a Chaperone Protein, and Regulates Neuronal Differentiation

“…Using miRNAs as potential biomarkers is also an appealing strategy because more and more effort is being directed at a personalized medicine approach. Our findings that miR-511 expression can be controlled by GR signaling suggest that it is possible that individuals with single nucleotide polymorphisms in FKBP5 may display altered miR-511 expression, which could be detected in serum or cerebrospinal fluid, as has been accomplished in patients with AD or major depression (29,34). This approach would permit selective targeting of miR-511 when warranted and could potentially enhance regulation of processes implicated in disease such as neurogenesis.…”

microRNAs in lipoprotein and lipid metabolism: from biological function to clinical application

“…Interestingly, miRNAs have also been found in virtually all biological fluids, including cerebrospinal fluid, tears, saliva, breast milk, amniotic fluid, urine, as well as feces [38][39][40][41][42] …”