ABSTRACT: Expression data from Alzheimer's disease (AD) model mouse and AD model mouse overexpressing human mitochondrial transcriptional factor A (hTFAM)
Project description:Transcription profiling by array of microglia purified from wild type and TREM2 deficient microglia in a mouse model of Alzheimer's disease
Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC,) in AD. 5hmC is highly enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD as well as RNA-Seq to correlate changes in methylation status with transcriptional changes. We also utilized the existing AD fly model to further test the functional significance of these epigenetically altered loci. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both the discovery and replication datasets, and these are enriched for pathways involved in neuron projection development and neurogenesis. Of the 325 genes identified, 140 also showed changes in gene expression by RNA-Seq. Proteins encoded by genes identified in the current analysis form direct protein-protein interactions with AD-associated genes, expanding the network of genes implicated in AD. Furthermore, we identified AD-associated single nucleotide polymorphisms (SNPs) located within or near DhMLs, suggesting that these SNPs may identify regions of epigenetic gene regulation that play a role in AD pathogenesis. Finally using the existing AD fly model we showed that some of these genes could modulate the toxicity associated with AD. Our data implicate neuron projection development and neurogenesis pathways as potential targets in AD. These results indicate that incorporating epigenomic and transcriptomic data with GWAS data can expand the known network of genes involved in disease pathogenesis. Combination of epigenome profiling and Drosophila model enables us to identify the epigenetic modifiers of Alzheimer's disease. University of Kentucky Alzheimer's Disease Research Center (3 control, 3 Alzheimer's) and Emory University Alzheimer's Disease Research Center (2 control, 2 Alzheimer's)
Project description:Glucose hypometabolism is one of the major characteristics of Alzheimer's disease (AD). The energy deficiency in AD brain has been at least partially attributed to accelerated mitochondrial dysfunction than normal aging. In earlier publications, we have shown that small molecule mitochondrial complex I inhibitor CP2 facilitated mitochondrial regeneration and rescued mitochondrial deficiency in familial AD mice model APP-PS1. Here in this study, we investigated whether a typical mitochondrial deficiency mouse model could recapitulate molecular expression signatures of AD brain and whether CP2 was able to rescue the AD brain phenotype. Ndufs4 is one of the regulatory subunits of mitochondria complex I. Knockout of Ndufs4 resulted in complex I assembly failure and approximately half mitochondrial function loss. Ndufs4-knockout mice are viable but are short in lifespan (up to about 90 days). This model has been previously used to study Leigh syndrome, a heritable mitochondrial deficiency disease. In this dataset, we performed RNAseq on brains of CP2 treated Ndufs4-knockout mice and examined the expression changes upon CP2 treatment.
Project description:Expression data from the neuron model of Alzheimer's disease (AD) with or without treatment of recombinant human mitochondrial transcriptional factor A (rhTFAM) protein
Project description:Emerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in diverse biological processes, such as neurological diseases. Traditional sncRNA-seq protocols often miss these sncRNAs due to their modifications. We have recently developed PANDORA-seq, a method enabling more comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we have revealed an updated sncRNA profile enriched by tsRNAs/rsRNAs in the mouse cortex and found a particularly significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer's disease (AD) mouse model, compared to genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of cortex gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs are negatively correlated with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provides insights for future mechanistic study of AD with potential therapeutic strategies.