Comparative transcriptome analysis of APPsα-DM and APLP2-KO brains
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE27888 | GEO | 2011/05/10
SECONDARY ACCESSION(S): PRJNA138003
REPOSITORIES: GEO
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Project description:Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and of its proteolytic fragments are still poorly understood. The secreted APPs? ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The ?-secretase generated APP intracellular domain, AICD, functions as a transcriptional regulator in heterologous reporter assays although its role for endogenous gene regulation has remained controversial. Previously, we have generated APPs? knockin (KI) mice expressing solely the secreted ectodomain APPs?. Here, we generated double mutants (APPs?-DM) by crossing APPs?-KI mice onto an APLP2-deficient background and show that APPs? rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPs?-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP. To gain further mechanistic insight into which domains/proteolytic fragments are crucial for hippocampal APP/APLP2 mediated functions, we performed a DNA microarray transcriptome profiling of prefrontal cortex and hippocampus of adult APLP2-KO (APLP2-/-) and APPs?-DM mice (APP?/?APLP2-/- mice).Interestingly, this analysis failed to reveal major genotype-related transcriptional differences. Expression differences between cortex and hippocampus were, however, readily detectable. Prefrontal cortices and hippocampi of adult mice (38 - 40 weeks) of the following genotypes were analyzed: APLP2-KO (APLP2-/-) (n=3) and APPs?-DM (APP?/?APLP2-/-) (n=3).
2011-05-10 | E-GEOD-27888 | biostudies-arrayexpress
Project description:The β-amyloid precursor protein APP and the related APLPs, undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that Aβ accumulation is a central trigger for Alzheimer disease (AD), the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsα ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The γ-secretase generated APP intracellular domain AICD, functions as a transciptional regulator in heterologous reporter assays, although its role for endogenous gene regulation has remained controversial. To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators we performed a DNA microarray transcriptome profiling of the frontal cortex of adult wild type, APP-/-, APLP2-/- and APPsα knockin (KI) mice, APPα/α, expressing solely the secreted APPsα ectodomain. Biological pathways affected by the lack of APP family members included regulation of neurogenesis, regulation of transcription and regulation of neuron projection development. Comparative analysis of transcriptome changes and qPCR validation identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity related genes that were down-regulated in knock-out cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including Bace1, Kai1, Gsk3b, p53, Tip60 and Vglut2. Only Egfr was slightly up-regulated in APLP2-/- mice. Comparison of APP-/- and APPα/α with wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2-/- on different genetic backgrounds revealed that background related transcriptome changes may dominate over changes due to the knockout of a single gene. Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells. Prefrontal cortices of adult male mice (24 - 28 weeks) of the following genotypes were analyzed: WT (n=3), APP-/- (n=3), APPα/α (n=3), APLP2-/- (n=3), APLP2(R1)-/- (n=3). WT, APP-/-, APPα/α, APLP2-/- had been backcrossed for six generations to C57BL/6 mice. APLP2(R1)-/- harbors the identical knockout allele as APLP2-/- but was back-crossed only once.
2011-03-18 | E-GEOD-25926 | biostudies-arrayexpress
Project description:The β-amyloid precursor protein APP and the related APLPs, undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that Aβ accumulation is a central trigger for Alzheimer disease (AD), the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsα ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The γ-secretase generated APP intracellular domain AICD, functions as a transciptional regulator in heterologous reporter assays, although its role for endogenous gene regulation has remained controversial. To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators we performed a DNA microarray transcriptome profiling of the frontal cortex of adult wild type, APP-/-, APLP2-/- and APPsα knockin (KI) mice, APPα/α, expressing solely the secreted APPsα ectodomain. Biological pathways affected by the lack of APP family members included regulation of neurogenesis, regulation of transcription and regulation of neuron projection development. Comparative analysis of transcriptome changes and qPCR validation identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity related genes that were down-regulated in knock-out cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including Bace1, Kai1, Gsk3b, p53, Tip60 and Vglut2. Only Egfr was slightly up-regulated in APLP2-/- mice. Comparison of APP-/- and APPα/α with wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2-/- on different genetic backgrounds revealed that background related transcriptome changes may dominate over changes due to the knockout of a single gene. Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells.
2011-03-18 | GSE25926 | GEO
Project description:Gene expression analysis of 2-month-old APP/APLP2 double-conditional Knockout (N-dCKO) mice and littermate APLP2 knockout controls, APP knockout and wildtype controls. Mouse hippocampus were dissected for RNA extraction and hybridization on Affymetrix microarrays.
2013-07-10 | E-GEOD-48622 | biostudies-arrayexpress
Project description:Gene expression analysis of 2-month-old APP/APLP2 double-conditional Knockout (N-dCKO) mice and littermate APLP2 knockout controls, APP knockout and wildtype controls.
2013-07-10 | GSE48622 | GEO
Project description:Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer’s disease. APP has two homologs, amyloid precursor-like protein 1 and 2 (APLP1 and APLP2), and they have functional redundancy. APP intracellular c-terminal domain (AICD), produced by sequential α- or β- and γ-secretase cleavages, is thought to control gene expression, similarly as the ICD of Notch. To investigate the role of APP family in transcriptional regulation, we examined gene expression changes in the cerebral cortex of APP/APLP1/APLP2 conditional triple knockout (cTKO) mice, in which APP family members are selectively inactivated in excitatory neurons of the postnatal forebrain. Of the 12 previously reported AICD target genes, only Nep and Npas4 mRNA levels were significantly reduced in the cerebral cortex of cTKO mice, compared to littermate controls. We further examined global transcriptional changes by RNA-seq and identified 189 and 274 differentially expressed genes in the neocortex and hippocampus, respectively, of cTKO mice relative to controls. Gene Ontology analysis indicated that these genes are involved in a variety of cellular functions, including extracellular organization, learning and memory, and ion channels. Thus, inactivation of APP family alters transcriptional profiles of the cerebral cortex and affects wide-ranging molecular pathways.
2022-01-07 | GSE181936 | GEO
Project description:Complement C3aR is primarily expressed in microglial cells in the brain. Our study found elevated expression of C3aR in microglia in Alzheimer's disease. To understand the underlying molecular mechanism, we sorted microglia based on their C3aR expression from 9-month-old wild-type and APP-KI mice. Through RNA-seq analysis, we identified metabolic perturbations in C3aR-positive microglia from 9-month-old APP-KI mice. Furthermore, we performed RNA-seq on sorted microglial cells from wild-type, C3aR knockout, APP-KI, and APP-KI;C3aR knockout mice. This analysis revealed a dampening of metabolic dysfunction in the absence of C3aR.
2023-06-25 | GSE228258 | GEO
Project description:RNAseq differential gene expression profiling of olfactory mucosa in young wild type, aged wild type, APP deficient, APLP2 deficient and PSEN2 deficient mice. Purpose: Next-generation gene expression profiling has revolutionized analysis of molecular pathways. The goals of this study were to compare NGS-derived olfactory mucosa transcriptome profiles (RNAseq) of aged wild-type mice, APP knockout mice, APLP2 knockout mice and PSEN2 knockout mice with young wild-type controls. Selected genes and pathways will be analyze further by low-throughput techniques such as real-time RT-PCR. Methods: Olfactory mucosa mRNA profiles of 2 months old wild-type (WT), 2 years old wild-type, APP knockout, APLP2 knockout and PSEN2 knockout mice were generated by deep sequencing, in triplicate, using Illumina NovaSeq6000 . For inspecting the quality of RNA-Seq data, the 100 most abundant genes are taken from all the samples and heatmaps were generated to observe the relation between samples/conditions. The sequence reads that passed the quality filters were analyzed at the transcript isoform level with TopHat followed by Cufflinks. Results: Using our data analysis workflow, we mapped at least 30 million sequence reads per sample to the mouse genome (build mm10) and identified approximately 25,867 transcripts in the olfactory epithelium of WT and genetically modified mice with TopHat workflow. RNAseq data confirmed stable expression of 20 known housekeeping genes, and 3 of them were validated with qRT-PCR. Approximately 20% of transcripts showed differential expression between WT and aged samples and 0.1-1.0 % showed differential expression between WT and genetically modified lines (fold change >1.5; p value < 0.05). Altered expression of 20 genes for aged samples and 10 genes for PS-deficient samples was confirmed by qRT-PCR, demonstrating the high degree of sensitivity of RNAseq approach. Conlusion: Our study represent the first detailed analysis of differential gene expression by RNAseq technology in murine olfactory mucosa in aged animals. It is also the first study examining effects of gene knockout for APP, APLP2 and PSEN2 on gene expression profile in murine olfactory mucosa. We conclude that these data would help future studies in olfactory mucosa cells aimed to reveal molecular mechanisms associated with aging and biological function of APP, APLP2 and PSEN2 genes. RNAseq differential gene expression profiling of olfactory mucosa in young wild type, aged wild type, APP deficient, APLP2 deficient and PSEN2 deficient mice. Purpose: Next-generation gene expression profiling has revolutionized analysis of molecular pathways. The goals of this study were to compare NGS-derived olfactory mucosa transcriptome profiles (RNAseq) of aged wild-type mice, APP knockout mice, APLP2 knockout mice and PSEN2 knockout mice with young wild-type controls. Selected genes and pathways will be analyze further by low-throughput techniques such as real-time RT-PCR. Methods: Olfactory mucosa mRNA profiles of 2 months old wild-type (WT), 2 years old wild-type, APP knockout, APLP2 knockout and PSEN2 knockout mice were generated by deep sequencing, in triplicate, using Illumina NovaSeq6000 . For inspecting the quality of RNA-Seq data, the 100 most abundant genes are taken from all the samples and heatmaps were generated to observe the relation between samples/conditions. The sequence reads that passed the quality filters were analyzed at the transcript isoform level with TopHat followed by Cufflinks. Results: Using our data analysis workflow, we mapped at least 30 million sequence reads per sample to the mouse genome (build mm10) and identified approximately 24,000 transcripts in the olfactory epithelium of WT and genetically modified mice with TopHat workflow. RNAseq data confirmed stable expression of 20 known housekeeping genes, and 3 of them were validated with qRT-PCR. Approximately 20% of transcripts showed differential expression between WT and aged samples and 0.1-1.0 % showed differential expression between WT and genetically modified lines (fold change >1.5; p value < 0.05). Altered expression of 20 genes for aged samples and 10 genes for PS-deficient samples was confirmed by qRT-PCR, demonstrating the high degree of sensitivity of RNAseq approach. Conlusion: Our study represent the first detailed analysis of differential gene expression by RNAseq technology in murine olfactory mucosa in aged animals. It is also the first study examining effects of gene knockout for APP, APLP2 and PSEN2 on gene expression profile in murine olfactory mucosa. We conclude that these data would help future studies in olfactory mucosa cells aimed to reveal molecular mechanisms associated with aging and biological function of APP, APLP2 and PSEN2 genes. This RNAseq project has been supported by a grant of Polish National Science Centre (UMO-2013/09/NZ3/02359).
2020-03-31 | GSE147771 | GEO
Project description:In a series of slice electrophysiology experiments, we demonstrated that female APPSwe-Psen1dE9 Alzheimer's disease model mice show greater impairments in hippocampal synaptic plasticity than male mice of the same age and genotype. Female APP/PS1 mice also showed greater impairments in behavioural associative memory, higher amyloid plaque burden and increased microglial activation in the hippocampus than males at age 4-5 months. We thus profiled hippocampal mRNA from these mice to investigate the underlying molecular mechanisms. Compared to wild-type mice of the same sex, we found that female APP/PS1 mice showed a greater upregulation of microglial and inflammatory genes than males. Moreover, downregulation of genes associated with memory and plasticity was observed uniquely in female APP/PS1 mice. These data provide insight into the potential mechanisms of the greater prevalence and faster progression of AD in females.
2021-10-30 | GSE186710 | GEO
Project description:The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA-sequencing.We identified 1690 increased AD-associated chromatin accessible regions in the hippocampal tissues of APP/PS1 mice and 1003 decreased chromatin accessible regions were considered to be related with declined AD-associated biological processes.In the APP/PS1 hippocampus, 1090 genes were found to be up-regulated and 1081 down-regulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting up-regulated mRNA levels.Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.
2020-07-09 | GSE145907 | GEO