A Study of Small RNAs from Cerebral Neocortex of Pathology-Verified Alzheimer's Disease, Dementia with Lewy Bodies, Hippocampal Sclerosis, Frontotemporal Lobar Dementia, and Non-Demented Human Controls

Article type: Research Article

Authors: Hébert, Sébastien S.^{a; b; *} | Wang, Wang-Xia^c | Zhu, Qi^d | Nelson, Peter T.^c

Affiliations: [a] Axe Neurosciences, Centre de recherche du CHU de Québec (CHUL), Québec, QC, Canada | [b] Département de Psychiatrie et de Neurosciences, Université Laval, Québec, QC, Canada | [c] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA | [d] LC Sciences, Houston, TX, USA

Correspondence: [*] Correspondence to: Sébastien S. Hébert, PhD, Centre de recherche du CHU de Québec (CHUL), Neurosciences, 2705 boul. Laurier, RC-9800, Québec, Qc, G1V 4G2, Canada. Tel.: +1 418 656 4141; Fax: +1 418 654 2753; E-mail: [email protected]; Peter T. Nelson, MD, PhD, Sanders-Brown Center on Aging, Rm 311, Sanders-Brown Center, 800 S. Limestone, University of Kentucky, Lexington, KY 40536-0230, USA. Tel.: +1 859 257 1412; Ext. 254; Fax: +1 859 257 6054; E-mail: [email protected].

Abstract: MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual diseases such as Alzheimer's disease (AD), making disease-to-disease comparisons impossible. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at a nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n = 8) and FTLD (n = 14) cases when compared to controls (n = 8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies.

Keywords: Alzheimer's disease, deep sequencing, dementia with Lewy bodies, frontotemporal lobar dementia, hippocampal sclerosis, isomiR, microRNA, progressive supranuclear palsy

DOI: 10.3233/JAD-122350

Journal: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 335-348, 2013