Tet1-mediated modulation of Alzheimer's disease.

Abstract

Human sequencing studies have identified roughly 30 risk loci associated Alzheimer's disease (AD). However, these loci only explain a portion of disease pathogenicity. Recent studies support a link between gene-environment interactions and AD, and published work from our lab indicates Tet1 mediates gene-environment interactions and Tet1 KO reduces stress response in mice [1]. Furthermore, DNA deep sequencing studies identified an enrichment of rare Tet2 variants associated with AD [2]. This study examines how knockout of the Tet1, a DNA 5-hydroxymethylcytosine (5hmC) regulator, influences AD-associated transcription and pathological outcomes in the 5xFAD AD mouse model. We measured cognitive/behavioral, 5hmC, and expression profiles of a Tet1 heterozygous knockout in the 5xFAD mouse model to examine the influences of Tet1 KO on AD pathogenicity. We show significant differences in behavior, cognition, 5hmC methylation and expression profiles of FAD/Tet1+/- mice relative to WT and FAD. In relation to FAD, FAD/Tet1+/- improved stress response in the Tail-Suspension Assay (p = 0.0438), and relative to WT mice, FAD/Tet1+/- mice display a reduction in their latency to mount the platform in the Morris water maze (p = 0.01). Analysis of 5hmC capture data revealed 2536 differentially hydroxymethylated regions (DhMRs) upregulated in FADTet1 and 410 DhMRs downregulated relative FAD (FDR > 0.05). Analysis of the expression data highlighted 132 differentially expressed genes (DEGs) in FAD/Tet1+/- relative to FAD (FDR > 0.05). Among the genes exclusive to the FAD/Tet1 mice were Nr4A1, Arc, and APLP1. Notably, Nr4A1 appeared in both the 5hmC and RNA-Seq data with increased levels of 5hmC and gene expression relative to FAD mice. Gene ontology analysis of RNA expression data identified significant changes in pathways involved in regulation of ion transmembrane transport, behavioral fear response, regulation of trans-synaptic signaling, and learning or memory. Taken together, these results suggest Tet1 modulates AD-associated gene regulation, expression and pathology.