Identification of miRNA Changes in Alzheimer's Disease Brain and CSF Yields Putative Biomarkers and Insights into Disease Pathways

Article type: Research Article

Authors: Cogswell, John P.^{a; *} | Ward, James^b | Taylor, Ian A.^c | Waters, Michelle^d | Shi, Yunling^b | Cannon, Brian^e | Kelnar, Kevin^e | Kemppainen, Jon^e | Brown, David^e | Chen, Caifu^f | Prinjha, Rab K.^g | Richardson, Jill C.^g | Saunders, Ann M.^a | Roses, Allen D.^a | Richards, Cynthia A.^h

Affiliations: [a] Department of Pharmacogenetics, GlaxoSmithKline Inc., Research Triangle Park, NC, USA | [b] Department of Molecular Discovery Research-Informatics, GlaxoSmithKline Inc., Research Triangle Park, NC, USA | [c] Department of Molecular Discovery Research-Core Technology Discovery Group, GlaxoSmithKline Inc., Research Triangle Park, NC, USA | [d] Department of Molecular Discovery Research-Metabolic Discovery Technology Group, GlaxoSmithKline Inc., Research Triangle Park, NC, USA | [e] Asuragen Inc., 2150 Woodard, Austin, TX, USA | [f] Molecular Cell Biology-RandD, Applied Biosystems Foster City, CA, USA | [g] Neurology CEDD, GlaxoSmithKline Inc., Harlow, UK | [h] Department of Molecular Discovery Research-Infectious Disease Discovery Technology Group, GlaxoSmithKline Inc., Research Triangle Park, NC, USA

Correspondence: [*] Corresponding author: John P. Cogswell, GlaxoSmithKline Inc., MAI.A.1229, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Tel.: +1 919 483 3449; Fax: +1 919 315 4174; E-mail: John.P.Cogswell@gsk.com.

Abstract: MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.

Keywords: Alzheimer's disease, inflammation, insulin signaling, microRNA, neurogenesis

DOI: 10.3233/JAD-2008-14103

Journal: Journal of Alzheimer's Disease, vol. 14, no. 1, pp. 27-41, 2008