Brain microRNAs differentially expressed in age-related cerebral pathologies Open Access

Abstract

Multiple age-related cerebral pathologies accumulate in the aging brain; however, we have limited insight into the biology underlying these processes. Here, we aimed to investigate the role of microRNAs, post-transcriptional regulators of gene expression, in nine different age- related cerebral pathologies. To this end, we performed microRNA sequencing of the dorsolateral prefrontal cortex of 617 post-mortem brain donors. After quality control and filtering to verified microRNAs (miRNAs), 528 miRNAs were included in the global miRNA differential expression analysis for each of the nine cerebral pathologies. We found miRNAs differentially expressed in AD pathology, Lewy body pathology, arteriolosclerosis, and cerebral amyloid angiopathy after adjusting for age, sex, education, technical variables, and surrogate variables. Furthermore, after additionally adjusting for co-existing cerebral pathologies, we identified 75 miRNAs associated with AD pathology independently of other co-occurring pathologies, 45 with Lewy body pathology, 3 with arteriolosclerosis, and 1 with cerebral amyloid angiopathy at FDR < 0.05. Among these miRNAs, we found that while several miRNAs showed differential expression exclusively in one pathology, 14 miRNAs exhibited differential expression in both AD pathology and Lewy body pathology, and 1 miRNA in both AD pathology and cerebral amyloid angiopathy. Gene set enrichment analysis of the target genes of the differentially expressed miRNAs in arteriolosclerosis revealed significant enriched biological pathways related to glutathione metabolism, synaptic functions, cellular transport, and innate immune responses. Together, these findings elucidate the potential role of miRNAs in age- related cerebral pathologies, paving the way for future mechanistic studies. 

Table of Contents

Introduction.....................................................................................................1

Methods...........................................................................................................2

ROS/MAP participants..................................................................................2

Age-related cerebral pathologies...................................................................2

miRNA quantification and quality control......................................................4

miRNA differential expression analysis..........................................................5

Gene set enrichment analysis........................................................................6

Results ............................................................................................................ 7

ROS/MAP participants..................................................................................7

Differentially expressed miRNAs in age-related cerebral pathologies...............7

Shared DE miRNAs between age-related cerebral pathologies and AD pathologies.......9

Putative biological pathways in cerebral pathologies......................................9

Discussion.......................................................................................................10

Tables..............................................................................................................17

Figures.............................................................................................................20

Appendix A.......................................................................................................24

Code availability...........................................................................................25

References........................................................................................................26 

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience Health Sciences, Pathology Biology, Genetics
Keyword	age-related cerebral pathology Alzheimer’s disease brain microRNA Lewy body pathology cerebral amyloid angiopathy arteriolosclerosis
Committee Chair / Thesis Advisor	Wingo, Thomas, Emory University Wingo, Aliza, Emory University
Committee Members	Conneely, Karen, Emory University Waldman, Irwin, Emory University

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