title: Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer's disease.
abstract: MicroRNAs (miRNAs) are attractive molecules to utilize as one of the blood-based biomarkers for neurodegenerative disorders such as Alzheimer's disease (AD) because miRNAs are relatively stable in biofluid, including serum or plasma. To determine blood miRNA biomarkers for AD with next-generation sequencing genome-wide, we first surveyed 45 serum samples. These came from 27 AD patients and 18 controls (discovery set) that underwent autopsy within two weeks after their serum sampling and were neuropathologically diagnosed. We found that three miRNAs, hsa-miR-501-3p, hsa-let-7f-5p, and hsa-miR-26b-5p, were significantly deregulated between the AD samples and the controls. The deregulation for hsa-miR-501-3p was further confirmed by quantitative reverse transcription polymerase chain reaction (PCR) in a validation set composed of 36 clinically diagnosed AD patients and 22 age-matched cognitively normal controls with a sensitivity and specificity of 53% and 100%, respectively (area under the curve = 0.82). Serum hsa-miR-501-3p levels were downregulated in AD patients, and its lower levels significantly correlated with lower Mini-Mental State Examination scores. Contrary to its serum levels, we found that hsa-miR-501-3p was remarkably upregulated in the same donors' AD brains obtained at autopsy from the discovery set. The hsa-miR-501-3p overexpression in cultured cells, which mimicked the hsa-miR-501-3p upregulation in the AD brains, induced significant downregulation of 128 genes that overrepresented the Gene Ontology terms, DNA replication, and the mitotic cell cycle. Our results suggest that hsa-miR-501-3p is a novel serum biomarker that presumably corresponds to pathological events occurring in AD brains.
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Hara
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Miyashita
authors.affiliation: Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.affiliation: Department of Pathology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.|Center for Transdisciplinary Research, Niigata University, Niigata, Japan.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Kasuga
authors.affiliation: Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan. ryosun@bri.niigata-u.ac.jp.|Asahigawaso Research Institute, Asahigawaso Medical-Welfare Center, Okayama, Japan. ryosun@bri.niigata-u.ac.jp.|Department of Molecular Genetics, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata, 951-8585, Japan. ryosun@bri.niigata-u.ac.jp.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D017423:Sequence Analysis, RNA
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D035683:MicroRNAs; C528163:MIRN26 microRNA, human; C582676:MIRN501 microRNA, human; C487931:mirnlet7 microRNA, human
keywords: Alzheimer’s disease; Autopsied brain; Blood-based biomarker; Braak staging; Next-generation sequencing; miR-501-3p; microRNA