TALEN Editing of APP Gene in WiCell WA09 (H9) Cells to directly express amyloid beta proteins
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE119527 | GEO | 2018/12/31
REPOSITORIES: GEO
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Project description:TALEN Editing of APP Gene in WiCell WA09 (H9) Cells to directly express amyloid beta proteins
| PRJNA489467 | ENA
Project description:Abnormal metal accumulation is associated with Alzheimer’s disease (AD) and has a relevant role in affecting amyloid beta-peptide (Abeta) aggregation and neurotoxicity.In the present study, employing a microarray analysis of 35,129 genes, we analyzed gene expression profile changes due to exposure to Abeta-Zn or Abeta-Cu complexes in neuronal-like cells (SH-SY5Y). Microarray data indicated that Abeta-Zn or Abeta-Cu complexes selectively alter expression of genes mainly related to cell death, inflammatory responses, and apoptosis.Taken together these findings indicate that Abeta-Zn or Abeta-Cu show some commonalities in affecting AD-related target functions. The overall modulatory activity on these genes supports the idea of a possible net result leading to mechanisms that counteract toxic effects of Abeta-Zn or Abeta-Cu.
2012-05-01 | GSE37661 | GEO
Project description:We combined a mouse model of Abeta accumulation and transcriptomics, and identified Klc1 as an Abeta accumulation modifier in vivo.
2014-01-15 | GSE40330 | GEO
Project description:Amyloid-beta peptides which aggregate and accumulate in Alzheimer’s disease (AD) brain are known to have sequential N-terminal truncations and multiple post-translational modifications (PTM) such as isomerization, pyroglutamate formation, phosphorylation, nitration and dityrosine cross-linking. Here we add to the list of PTM citrullination (deimination) of Arg5 residue in plaque-derived Abeta in sporadic AD brains, identified by tandem mass spectrometry. We quantitated the level of citrullination on multiple N-truncated Abeta isoforms present in plaque-associated fractions and found that almost 30 % of pyroGlu3-Abeta pool was citrullinated in plaques from AD temporal cortex. We also documented citrullinated Abeta peptides in the detergent insoluble fractions from AD frontal cortex with ~ 22 % citrullination in the pyroGlu3-Abeta pool. Citrullination of Abeta is a common PTM, closely associated with pyroglutamate-Abeta formation and Abeta accumulation in AD. This may have implications for Abeta toxicity, auto-antigenicity of Abeta, and may be relevant for the design of diagnostic assays and therapeutic targeting.
2021-11-24 | PXD025620 | Pride
Project description:We combined a mouse model of Abeta accumulation and transcriptomics, and identified Klc1 as an Abeta accumulation modifier in vivo. For this transcriptomics analysis, we used 12 arrays (one mouse mRNA sample per array) for inbred mice analyses and 28 arrays for the APP Tg mice of mixed genetic backgrounds. First, 13309 probes whose signals were reliably detectable in all 40 arrays were selected from 25967 probes on the Illumina mouse Ref-8 Expression BeadChip. Second, to select the probes whose expression levels were affected by the DBA genetic background, we compared the expression levels of the 13309 probes in DBA, B6 and SJL inbred (non-Tg) mice (unpaired t-test).M-cM-^@M-^@Using inbred mice means that any change in gene expression is based on their genetic background, not the secondary effects of Abeta accumulation. To minimize the chance of false positives, we applied strict criteria in this selection: the fold change was equal to or more than 1.5 and the false discovery rate (FDR) was set to 0.001. In total 54 probes were identified, with the signals of 47 probes being lower and 7 probes being higher in DBA mice than those in either B6 or SJL. In the final step, we examined the correlation between the expression levels of these 54 probes and Abeta40 levels in the GuHCl fraction in APP Tg mice. Using strict selection criteria (PearsonM-bM-^@M-^Ys product-moment correlation FDR=0.001), we identified a total of four probes which correlated with Abeta levels. Two of these probes were higher in DBA and negatively correlated with the levels of Abeta accumulation. The other two probes were lower in DBA and positively correlated with the levels of Abeta accumulatio. Notably, the two probes (probe ID 4050133 and 6130468) that positively correlated with Abeta accumulation both detected the same transcript: kinesin light chain 1 (Klc1; also known as Kns2).
2014-01-15 | E-GEOD-40330 | biostudies-arrayexpress
Project description:Oligomeric forms of amyloid-beta peptide (Abeta) are presumed to play a pivotal role in the pathogenesis of Alzheimer’s disease (AD). However, it is still unclear how Abeta oligomers contribute to AD pathogenesis in patient neural cells. We generated induced pluripotent stem cells (iPSCs) from a familial AD patient and differentiated them into neural cells. Abeta oligomers were accumulated in neural cells of AD bearing amyloid precursor protein (APP)-E693delta mutation. To uncover Abeta oligomers in AD(APP-E693delta) neural cells, we analyzed gene expression profiles of control and the AD neural cells
2013-03-22 | GSE43326 | GEO
Project description:Transgenic animals were engineered to express human amyloid peptide controlled by a muscle-specific, heat-inducible promoter. At low temperatures (16°C) Abeta expression is minimal, while at higher temperatures (20-25°C) Abeta accummulates in large quantities and causes paralysis. GFP- and GFP::degron (a toxic aggregating GFP mutant)-expressing animals were used as controls. Animals were grown at 16°C till early 3rd larval stage and then upshifted to 25°C. Animals were harvested at the time of upshift (T0), and every 4 hours later until 20 hours postupshift (T4-T20).
2015-02-12 | E-GEOD-65851 | biostudies-arrayexpress
Project description:Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition in the brain. Aβ plaques are produced through sequential β/γ cleavage of amyloid precursor protein (APP), of which there are three main APP isoforms: APP695, APP751 and APP770. KPI-APPs (APP751 and APP770) are known to be elevated in AD, but the reason remains unclear. Transcription activator-like (TAL) effector nucleases (TALENs) induce mutations with high efficiency at specific genomic loci, and it is thus possible to knock out specific regions using TALENs. In this study, we designed and expressed TALENs specific for the C-terminus of APP in HeLa cells, in which KPI-APPs are predominantly expressed. The KPI-APP mutants lack a 12-aa region that encompasses a 5-aa trans-membrane (TM) region and 7-aa juxta-membrane (JM) region. The mutated KPI-APPs exhibited decreased mitochondrial localization. In addition, mitochondrial morphology was altered, resulting in an increase in spherical mitochondria in the mutant cells through the disruption of the balance between fission and fusion. Mitochondrial dysfunction, including decreased ATP levels, disrupted mitochondrial membrane potential, increased ROS generation and impaired mitochondrial dehydrogenase activity, was also found. These results suggest that specific regions of KPI-APPs are important for mitochondrial localization and function.
| S-EPMC4770288 | biostudies-other
Project description:Transgenic animals were engineered to express human amyloid peptide controlled by a muscle-specific, heat-inducible promoter. At low temperatures (16°C) Abeta expression is minimal, while at higher temperatures (20-25°C) Abeta accummulates in large quantities and causes paralysis. GFP- and GFP::degron (a toxic aggregating GFP mutant)-expressing animals were used as controls.
2015-02-12 | GSE65851 | GEO
Project description:We report Transcription Activator-like Effector Nucleases (TALEN)-mediated mutagenesis of the Rett Syndrome gene, methyl-CpG binding protein 2 (Mecp2), in nonhuman primates (NHPs). Microinjection of Mecp2-targeting TALEN plasmids into rhesus and cynomolgus zygotes caused 40-50% of the embryos harboring mutations when examined beyond 8-cell stage. The surrogate pregnancy rates were 28.6% (2/7) and 16.7% (1/6) for rhesus and cynomolgus, respectively. The 2 rhesus surrogates went through miscarriage at 30- and 63/64-days of gestation. Analyses of two 63/64-day-old liter-mate embryos indicated both were male and carried MeCP2 mutations, yet chimeric. Mutation rate was higher in one embryonic brain than the other. RNA sequencing and anatomical analyses indicated that the brain with higher-degree mutations was underdeveloped, which, together with mid-gestation-stage male lethality likely recapitulate the disease. One live delivery of a female cynomolgus monkey occurred after 162 days of gestation, with abundant mutagenesis in peripheral tissues examined. We conclude that TALEN-mediated mutagenesis greatly facilitates disease modeling in NHPs.
2016-12-31 | GSE53434 | GEO