Project description:AD drug discovery has rarely been addressed in the context of aging even though sporadic AD accounts for 99% of the cases. Phenotypic screens based upon old age-associated brain toxicities were used to develop the potent AD drug candidate J147. Here, we hypothesized that J147 would be effective against both brain aging and AD-associated pathology in rapidly aging SAMP8 mice, a model for early sporadic AD. An inclusive and integrative multi-omics approach was used to investigate protein expression, RNA expression, metabolite levels as well as cognition in old and young SAMP8 mice. J147 not only reduced the cognitive deficits and associated metabolic changes observed in old SAMP8 mice, it restored the levels of multiple markers of AD, vascular pathology, synaptic function, and inflammation to those approaching the young phenotype. Our data show that a drug candidate selected upon the basis of preventing old age-related brain toxicities also reduces AD-associated pathology.
Project description:A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered an useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors. Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control. SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages in reference to age mated SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively, 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals. In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression towards a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer’s Disease (AD) and age-related cognitive impairment.
Project description:A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered an useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors. Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control. SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages in reference to age mated SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively, 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals. In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression towards a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer’s Disease (AD) and age-related cognitive impairment.
Project description:Purpose: The aim of this study is to compare brain transcriptome profile (RNA-seq) after G9a inhibition. Methods: Hippocampus profiles of 7-month-old SAMP8 Control and SAMP8 Treated mice groups were generated by deep sequencing, pooled using Ilumnia Hiseq. Results: G9a inhibition with UNC0642 induces a transcriptional profile that allows beneficial effects on cognitive performance. Differential expression analysis identified 697 differentially expressed genes (DEG) (fold change cutoff of ≥1.3, p-value<0.05). Of which 217 are reduced, and 480 are increased in SAMP8 UNC0642. Conclusions: Our study showed the first transcriptome analysis of whole brain after G9a inhibition, generated by RNA-seq technology, demonstrating transcriptomic changes.
Project description:Purpose: The aim of this study is to compare brain transcriptome profile (RNA-seq) after G9a inhibition. Methods: Hippocampus profiles of 7-month-old SAMP8 Control and SAMP8 Treated mice groups were generated by deep sequencing, pooled using Ilumnia Hiseq. Results: G9a inhibition with UNC0642 induces a transcriptional profile that allows beneficial effects on cognitive performance. Differential expression analysis identified 697 differentially expressed genes (DEG) (fold change cutoff of ≥1.3, p-value<0.05). Of which 217 are reduced, and 480 are increased in SAMP8 UNC0642. Conclusions: Our study showed the first transcriptome analysis of whole brain after G9a inhibition, generated by RNA-seq technology, demonstrating transcriptomic changes.
Project description:Aging is a universal biological phenomenon linked to many diseases, such as cancer or neurodegeneration. However, the molecular mechanisms underlying aging, or how lifestyle interventions such as cognitive stimulation can ameliorate this process, are yet to be clarified. Here, we performed a multi-omic profiling, including RNA-seq, ATAC-seq, ChIP-seq, EM-seq, SWATH-MS and single cell Multiome scRNA and scATAC-seq, in the dorsal hippocampus of young and old mouse subjects which were subject to cognitive stimulation using the paradigm of environmental enrichment. In this study we were able to describe the epigenomic landscape of aging and cognitive stimulation.
Project description:Our aim was to identify genes that were differentially expressed in microglia stimulated with Lipopolysaccharide, Luteolin, or both. Affymetrix microarrays were used to analyze RNA samples Experiment Overall Design: RNA from control BV-2 cells, and cells treated for 24h with LPS, Luteolin, or LPS+Luteolin was analyzed with Affymetrix GeneChip Mouse Genome 430 2.0 Arrays. Biological triplicates were analyzed for each condition