Effects of RG2833 (HDAC1/3 Inhibitor) on the gene expression of Male TgF344 Alzheimer’s disease Rat model.
Ontology highlight
ABSTRACT: We investigated the long-term therapeutic effects of oral administration of a brain-penetrant HDAC1/3 inhibitor RG2833 in a Fisher transgenic 344-AD (TgF344-AD) rat model of AD. We treated for 6 months, starting at 5 months of age administering the drug in rodent chow at ~30mg/kg of body weight. After treatment we performed experiments to show the effects of drug treatment on spatial memory deficits and gene expression.
Project description:We investigated the long-term therapeutic effects of oral administration of a brain-penetrant HDAC1/3 inhibitor RG2833 in a Fisher transgenic 344-AD (TgF344-AD) rats model of AD. We treated for 6 months, starting at 5 months of age administering the drug in rodent chow at ~30mg/kg of body weight. After treatment we performed experiements to show the effects of drug treatment on spatial memory deficits. We show significantly improved hippocampal-dependent spatial memory performance in TgF344-AD female.
Project description:5 month old Female Fisher transgenic 344-AD (Tg-AD) rats expressing human Swedish amyloid precursor protein (APPsw) and Δ exon 9 presenelin-1 (PS1ΔE9) were treated with BT-11 (cat. no. HY-102013, MCE) at 8.5 mg/kg body weight administered in rodent chow. Following 6 months of BT-11 treatment, rats (11 months of age) were tested for cognitive behavior prior to sacrificing. Hippocampal Brain region were dissected and RNA sequencing (RNAseq) analyses was done on the Isolated sample. Taken together we showed that BT-11 treatment enriched pathways for females included passive transmembrane transporter activity, G protein-coupled receptor activity, G protein-coupled peptide receptor activity.
Project description:5 month old Male Fisher transgenic 344-AD (Tg-AD) rats expressing human Swedish amyloid precursor protein (APPsw) and Δ exon 9 presenelin-1 (PS1ΔE9) were treated with BT-11 (cat. no. HY-102013, MCE) at 8.5 mg/kg body weight administered in rodent chow. Following 6 months of BT-11 treatment, rats (11 months of age) were tested for cognitive behaviour prior to sacrificing. Hippocampal Brain region were dissected and RNA sequencing (RNAseq) analyses was done on the Isolated sample. Taken together we showed that BT-11 treatment enriched pathways in males including salt transmembrane transporter activity, signaling receptor regulator receptor ligand activity, signaling receptor activator activity, and transmembrane transporter activity.
Project description:Chlorpyrifos is an organophosphorus insecticide that despite imposed restricitions on its use by the EPA, is one of the most commonly used insecticides. Although CPF is so widely used little is known about its effect on overall gene expression in vivo. DNA microarray technology was used to determine differential gene expression resulting from chlorpyrifos (CPF) exposure. Experiment Overall Design: Male Fisher 344 rats aged 11-12 weeks were treated with varying doses of chlorpyrifos (CPF) and terminally sacced at 96 hours post-exposure in three separate experiments. An approximate 30mg section of the frontal lobe of the brain was processed for total RNA extraction.
Project description:Epigenetic alterations has been implicated in the pathology of several neurodegenerative diseases. To investigate the role of microglial Hdac1 and 2 in the pathogenesis of Alzheimer's disease (AD), we created microglia specific compound Hdac1 and Hdac2 knock out mice in 5X FAD background. Genetic ablation of Hdac1 and 2 from microglia reduced amyloid plaque burden and improved spatial learning and memory function. To study how Hdac1 and 2 knock out in microglia alters gene expression profile in 5X FAD mice we carry out microarray analysis using 24-28 weeks animals
Project description:Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T cell specific deletion and performed comparative genomic hybridisation using genomic DNA from HDAC1-/-; HDAC2+/- diseased thymocytes and sample-matched, wild-type tail. A data set from a related transcription-profiling study comparing HDAC1-/-; HDAC2+/- mouse thymus tissue against thymus tissues from wild-type counterparts has also been deposited at ArrayExpress under accession E-MTAB-1432: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1432
Project description:5 month old Female Fisher transgenic 344-AD (Tg-AD) rats expressing humanSwedishamyloid precursor protein (APPsw) and Δ exon 9 presenelin-1 (PS1ΔE9) were treated with Ibudilast (cat. no. HY-B0763, MCE) at 10 mg/kg body weight administered in rodent chow. Following 6 months of Ibudilast treatment, rats (11 months of age) were tested for cognitive behaviour prior to sacrificing. Hippocampal Brain region were dissected and RNA sequencing (RNAseq) analyses was done on the Isolated sample. Taken together we showed that Ibudilast treatment: (i) reduces inflammation by decreasing the levels of the pro inflammatory cytokine IL6, interferon receptor 1, the macrophage migration inhibitory factor (MIF), microglial associated proteins such as transmembrane protein 119 (TMEM119), arachidonate 5-lipoxygenase activating protein (Alox5ap), toll like receptor 7 (TLR7), lysosomal protein transmembrane 5 (LAPTM5) and triggering receptor expressed on myeloid cells 2 (TREM2); (ii) increases expression of synaptic proteins such as synaptotagmin 2 (SYT2), which regulates vesicular transport, syntaxins (STX), which participates in neurotransmitter release, and cadherin (CDH1), which maintains synapse structure; and (iii) reduces the expression of the neurotrophic factor BDNF by 2-fold in both male and female treated rats.
Project description:5 month old Male Fisher transgenic 344-AD (Tg-AD) rats expressing humanSwedishamyloid precursor protein (APPsw) and Δ exon 9 presenelin-1 (PS1ΔE9) were treated with Ibudilast (cat. no. HY-B0763, MCE) at 10 mg/kg body weight administered in rodent chow. Following 6 months of Ibudilast treatment, rats (11 months of age) were tested for cognitive behaviour prior to sacrificing. Hippocampal Brain region were dissected and RNA sequencing (RNAseq) analyses was done on the Isolated sample. Taken together we showed that Ibudilast treatment: (i) reduces inflammation by decreasing the levels of the pro inflammatory cytokine IL6, interferon receptor 1, the macrophage migration inhibitory factor (MIF), microglial associated proteins such as transmembrane protein 119 (TMEM119), arachidonate 5-lipoxygenase activating protein (Alox5ap), toll like receptor 7 (TLR7), lysosomal protein transmembrane 5 (LAPTM5) and triggering receptor expressed on myeloid cells 2 (TREM2); (ii) increases expression of synaptic proteins such as synaptotagmin 2 (SYT2), which regulates vesicular transport, syntaxins (STX), which participates in neurotransmitter release, and cadherin (CDH1), which maintains synapse structure; and (iii) reduces the expression of the neurotrophic factor BDNF by 2-fold in both male and female treated rats.
Project description:d-serine is naturally present throughout the human body. It is also used as add-on therapy for treatment-refractory schizophrenia. d-Serine interacts with the strychnine-insensitive glycine binding site of NMDA receptor, and this interaction could lead to potentially toxic activity (i.e., excitotoxicity) in brain tissue. The transcriptomic changes that occur in the brain after d-serine exposure have not been fully explored. Affymetrix microarray technology was used to determine differential gene expression resulting from D-Serine exposure. Keywords: Dose course Male Fisher 344 rats aged 11-12 weeks were treated with various doses (0, 5, 20, 50, 200 and 500 mg/kg) of d-serine and terminally sacrificed 96 hours post-exposure. An approximate 30mg-section of the forebrain was processed for total RNA isolation.
Project description:Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T cell specific deletion.