Quantitative Sequencing Analysis of the Striatal Transcriptome in a Mouse Model of Alzheimer Disease.

Abstract

Purpose: The purpose of this study was to analyze the transcriptomic changes in the striatum of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and uncover its association with the methyl-CpG binding protein 2 (MeCP2) mediated-changes in striatal epigenetic signature during Alzheimer disease (AD) pathological progression.

Methods: To observe transcriptomic alterations in the striatum before the onset of cognitive impairment in APP/PS1 mice, quantitative 3'mRNA sequencing was performed with RNA extracted from the striatum of 6-month-old and 12-month-old wildtype and APP/PS1 mice. In addition, chromatin immunoprecipitation sequencing was conducted with the DNA from wildtype and APP/PS1 mice of the same age as aforementioned. For transcriptomic analysis, comparison terms were constructed based on aging and transgene expression-normal-aging (12-month-old wildtype/6-month-old wildtype), early-AD (6-month-old APP/PS1/6-month-old wildtype), and late-AD (12-month-old APP/PS1/6-month-old wildtype). To compare the changes in biological pathways and networks, we analyzed gene lists from each comparison term via bioinformatics tools including DAVID (Database for Annotation, Visualization, and Integrated Discovery), STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), and SynGO (Synaptic Gene Ontologies). Furthermore, to assume the effect MeCP2 in AD pathological conditions may have on the transcriptome regulation, analysis of the common genes from Quant-Seq and MeCP2-ChIP-Seq was performed.

Results: Enriched pathways including immune system and inflammatory response were confirmed in normal- aging and lateAD, respectively. In particular, enriched pathways of gene expression regulation, transcriptional regulation, and protein catabolic pathways were found to be significantly altered in early-AD. MeCP2-bound genes that were significantly altered in the transcriptome were suggested to be target genes that have a role in the striatum of the early-stage AD model.

Conclusion: This study confirmed that the alteration of the striatal transcriptomic profile in APP/PS1 mice was involved with several biological pathways. Additionally, comparative analysis of the transcriptomic changes and the MeCP2 bound regions found that a group of differentially expressed genes may be regulated under the epigenetic control of MeCP2.