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

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 single 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.

Mutation in the 3’untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy

“…18 Snap-frozen human cortical brain tissue 19 was used as the material (control individuals, n = 2, average age of 74 years old, average RIN values of 6.8). We used the Ago2 (Cell Signaling, Danvers, MA, USA; cat.…”

Memory formation and retention are affected in adult miR-132/212 knockout mice

“…While these studies point to the potential importance of these miRNAs in cognition, direct evidence implicating endogenous miR-132 and miR-212 in vivo is still lacking. Interestingly, miR-132 and miR-212 are amongst the most robustly downregulated miRNAs in neurodegenerative disorders, including Alzheimer's disease (AD) [22][23][24][25], Huntington's disease (HD) [26,27], Parkinson's disease (PD) [28], and frontotemporal dementia [22,29]. The clinical significance of these observations remains however uncertain.…”

Alzheimer's Disease

“…Functionally, miR-132-3p may regulate tau pathway through FOXO1a. In another study by Hebert et al using sequencing technology, miR-132-3p was also found to be significantly decreased in the temporal cortex of AD patients (Hebert, Wang, Zhu, & Nelson, 2013). In yet another study, Wong et al found downregulation of miR-132 and miR-212 in hippocampus and temporal cortex of AD patients (Wong et al, 2013).…”