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Multimodal analyses of a non-human primate model harboring mutant amyloid precursor protein transgenes driven by the human EF1α promoter [RNA-seq]

ABSTRACT: Alzheimer’s disease (AD) is the first leading cause of dementia which afflicts tens of millions of people worldwide. Despite many scientific progresses to dissect the molecular basis of AD from studies on various mouse models, it has been suffered from evolutionary species differences between mice and humans. Here, we report generation of a non-human primate, common marmoset (marmoset; Callithrix jacchus) model that ubiquitously expresses Amyloid-beta precursor protein (APP) transgenes with the Swedish (KM670/671NL) and Indiana (V717F) mutations. We generated two female transgenic marmosets (TG1 and TG2), whose transgene integration was thoroughly investigated by genomic PCR, whole genome sequencing (WGS) and Fluorescence in situ hybridization (FISH) analyses. Using the reprogramming technology, we confirmed the validity of the transgene expression in induced neurons in vitro. Moreover, we discovered structural changes in specific brain regions of transgenic marmosets by magnetic resonance imaging (MRI) analysis, including in the entorhinal cortex and hippocampus. In postmortem histological analysis, we detected increased Aβ plaque formation in the TG1 cerebrum at the age of 7 years, although evident neuronal loss or glial inflammation was not observed. Thus, this study summarizes our attempt to establish a non-human primate model of AD, which may be beneficial for drug development and further disease modeling in combination with other genetically engineered models.

ORGANISM(S): Callithrix jacchus

PROVIDER: GSE192674 | GEO | 2022/03/01

REPOSITORIES: GEO

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Multimodal analyses of a non-human primate model harboring mutant amyloid precursor protein transgenes driven by the human EF1α promoter [WGS]

Project description:Alzheimer’s disease (AD) is the first leading cause of dementia which afflicts tens of millions of people worldwide. Despite many scientific progresses to dissect the molecular basis of AD from studies on various mouse models, it has been suffered from evolutionary species differences between mice and humans. Here, we report generation of a non-human primate, common marmoset (marmoset; Callithrix jacchus) model that ubiquitously expresses Amyloid-beta precursor protein (APP) transgenes with the Swedish (KM670/671NL) and Indiana (V717F) mutations. We generated two female transgenic marmosets (TG1 and TG2), whose transgene integration was thoroughly investigated by genomic PCR, whole genome sequencing (WGS) and Fluorescence in situ hybridization (FISH) analyses. Using the reprogramming technology, we confirmed the validity of the transgene expression in induced neurons in vitro. Moreover, we discovered structural changes in specific brain regions of transgenic marmosets by magnetic resonance imaging (MRI) analysis, including in the entorhinal cortex and hippocampus. In postmortem histological analysis, we detected increased Aβ plaque formation in the TG1 cerebrum at the age of 7 years, although evident neuronal loss or glial inflammation was not observed. Thus, this study summarizes our attempt to establish a non-human primate model of AD, which may be beneficial for drug development and further disease modeling in combination with other genetically engineered models.

2022-03-01 | GSE194005 | GEO

Establishment of induced pluripotent stem cells from common marmoset fibroblasts by RNA-based reprogramming

Project description:The common marmoset (marmoset; Callithrix jacchus) shows anatomical and physiological features that are in common with humans. Establishing induced pluripotent stem cells (iPSCs) from marmosets holds promise for enhancing the utility of the animal model for biomedical and preclinical studies. However, in spite of the presence of some previous reports on marmoset iPSCs, the reprogramming technology in marmosets is still under development. In particular, the efficacy of RNA-based reprogramming has not been thoroughly investigated. In this study, we attempted RNA-based reprogramming for deriving iPSCs from marmoset fibroblasts. Although we failed to derive iPSC colonies from marmoset fibroblasts by using a conventional RNA-based reprogramming method previously validated in human fibroblasts, we succeeded in deriving colony-forming cells with a modified induction medium supplemented with a novel set of small molecules. Importantly, following one-week culture of the colony-forming cells in conventional embryonic stem cell (ESC) medium, we obtained iPSCs which express endogenous pluripotent markers and show a differentiation potential into all three germ layers. Taken together, our results indicate that RNA-based reprogramming, which is valuable for deriving transgene-free iPSCs, is applicable to marmosets.

2020-06-12 | GSE152259 | GEO

Profiling study of B cells from lymph nodes in miR-146a over-expression transgenic mice

Project description:B cells were isolated from wild type and miR-146a transgenic mice, and analyzed using microarray assay.WT1 and WT2 were samples repeats, so were TG1 and TG2 .

2012-08-08 | GSE39779 | GEO

Developmental dynamics of the postsynaptic proteome to understand synaptic maturation and dysmaturation

Project description:The postsynaptic density (PSD) is a protein condensate composed of ~1,000 proteins beneath the postsynaptic membrane of excitatory synapses. The number, shape, and plasticity of synapses are altered during development. However, the dynamics of synaptic protein composition across development have not been fully understood. Here we show alterations of PSD protein composition in mouse and primate brains during development. Proteins involved in synapse regulation are enriched in the differentially expressed (288 decreased and 267 increased) proteins on mouse PSD after a 2-week-old, which may be involved in changes of synaptic signal transduction. We find that the changes in PSD protein abundance in mouse brains correlate with gene expression levels in postnatal mice and perinatal primates. Proteome analysis of PSD from developing common marmosets (Callithrix jacchus) shows that the changes of PSD composition in mouse brain after 2-week-old occur in the marmoset brain mainly during the neonatal period and continue until adulthood. We also describe the changes of PSD proteome at the late developmental stage of marmoset, which may be involved in synaptic pruning observed in primate brains. The maturation of PSD composition is likely defective in autism spectrum disorder (ASD). Our results provide a comprehensive architecture of the remodeling of PSD composition across development, which may explain the molecular basics of synapse maturation and the pathology of psychiatric disorders, such as ASD.

2024-01-17 | PXD048549 | Pride

Evaluating the Efficacy of Small Molecules for Neural Differentiation of Common Marmoset ESCs and iPSCs

Project description:The common marmoset (marmoset; Callithrix jacchus) harbors various desired features as a non-human primate (NHP) model for neuroscience research. Recently, efforts have been made to induce neural cells in vitro from marmoset pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), which are characterized by their capacity to differentiate into all cell types from the three germ layers. Successful generation of marmoset neural cells is not only invaluable for understanding neural development and for modeling neurodegenerative and psychiatric disorders, but is also necessary for the phenotypic screening of genetically-modified marmosets. However, differences in the differentiation propensity among PSC lines hamper the applicability and the reproducibility of differentiation methods. To overcome this limitation, we evaluated the efficacy of small molecules for neural differentiation of marmoset ESCs (cjESCs) and iPSCs using multiple differentiation methods. By immunochemical and transcriptomic analyses, we confirmed that our methods using the small molecules are efficient for various differentiation protocols by either enhancing the yield of a mixture of neural cells including both neurons and glial cells, or a pure population of neurons. Collectively, our findings optimized in vitro neural differentiation methods for marmoset PSCs, which would ultimately help enhance the utility of the animal model in neuroscience.

2020-06-12 | GSE152264 | GEO

Follicular B (FoB) cells purified from miR-17-92 transgenic mice, stimulated with LPS/IL-4 for 13.5 or 25.5 hours

Project description:We have generated a miR-17-92 transgenic allele (termed miR-17-92 Tg) whose expression can be turned on conditionally by Cre recombinase (Xiao et al, Nature Immunology, 9:405-14, 2008). The mice were crossed to CD19-Cre mice to turn on the transgene expression specifically in B cells. Follicular B(FoB) cells were purified from CD19-Cre;miR-17~92 Tg/Tg mice (TG1, TG2, TG3) and miR-17~92 Tg/Tg mice (WT1, WT2, WT3) by MACS depletion of cells positive for CD5, CD43, and CD93 (also known as AA4.1). The purified B cells were stimulated with LPS/IL-4 for 13.5hr or 25.5hr. The purity of follicular B cells was examined by flow cytometry and was greater than 95% for all samples. Total RNA was extracted using RNeasy kit (QIAGEN).

2014-04-01 | E-GEOD-56377 | biostudies-arrayexpress

Profiling study of B cells from lymph nodes in miR-146a over-expression transgenic mice

Project description:B cells were isolated from wild type and miR-146a transgenic mice, and analyzed using microarray assay.WT1 and WT2 were samples repeats, so were TG1 and TG2 . Each probe ID of a mouse transcript was ranked by fold change from up to down-regulated comparing to WT control. Sylamer miRNA seed enrichment analysis was performed with Markov correction as described (Nature Method 2008). WT vs. TG.

2012-08-07 | E-GEOD-39779 | biostudies-arrayexpress

The Transglutaminase-2 interactome in the APP23 mouse model of Alzheimer disease

Project description:Amyloid-beta (Aβ) deposition in the brain, is closely linked to development of Alzheimer’s disease (AD). Unfortunately, therapies specifically targeting Aβ deposition have failed to reach their primary clinical endpoints, emphasizing the need to broaden the search strategy for identification of alternative therapeutic targets/mechanisms. Transglutaminase (TG2) catalyses posttranslational modifications, is present in characteristic AD lesions and has AD-associated proteins, including Aβ, tau and apolipoprotein E. However, an unbiased overview of TG2 interactors (TG2 interactome) and the cellular pathways of which these interactors are part in control and AD brain is lacking. Here, anticipating future studies in AD brain, we aimed to identify these interactors and their pathways using a crossbred of the AD-mimicking APP23 mouse model with wildtype and TG2-/- mice. We found that absence of TG2 had no (statistically) significant effect on Aβ pathology, soluble brain levels of Aβ1-40, Aβ1-42, and mRNA levels of TG2 family members compared to APP23 mice. Quantitative proteomics and network analysis revealed a large cluster of TG2 interactors with synaptic transmission/assembly and cell adhesion typical of AD in the APP23 brain. Comparative proteomics were in line with these observations as it also revealed association of proteins of both pathways to be linked to TG2 in APP23 brains Together, our data showed that TG2 deletion led to considerable network alterations consistent with a role of TG2 in (dys)regulation of synaptic transmission and cell adhesion in APP23 brains.

2022-02-22 | PXD030354 | Pride

Maternal weight affects placental DNA methylation of genes invovled in metabolic pathways in the common marmoset monkey (Callithrix jacchus)

Project description:Accumulating evidence suggests that dysregulation of placental DNA methylation (DNAm) is a mechanism linking maternal weight during pregnancy to metabolic programming outcomes. The common marmoset, Callithrix jaccus, is a platyrrhine primate species that has provided much insight into studies of the primate placenta, maternal condition, and metabolic programming, yet the relationships between maternal weight and placental DNAm are unknown. Here, we report genome-wide DNAm from term marmoset placentas using reduced representation bisulfite sequencing. We identified 74 genes whose DNAm pattern is associated with maternal weight during gestation. These genes are predominantly involved in energy metabolism and homeostasis, including regulation of glycolytic and lipid metabolic processes pathways.

2020-01-07 | GSE143200 | GEO

Comparative hippocampal synaptic proteomes of rodents and primates: differences in neuroplasticity-related proteins

Project description:Key to the human brain’s unique capacities are a myriad of neural cell types, specialized molecular expression signatures, and complex patterns of neuronal connectivity. Neurons in the human brain communicate via well over a quadrillion synapses. Their specific contribution might be key to the dynamic activity patterns that underlie primate-specific cognitive function. Recently, functional differences were described in transmission capabilities of human and rat synapses. To test whether unique expression signatures of synaptic proteins are at the basis of this, we performed a quantitative analysis of the hippocampal synaptic proteome of four mammalian species, two primates, human and marmoset, and two rodents, rat and mouse. Abundance differences down to 1.15-fold at an FDR-corrected p-value of 0.005 were reliably detected using SWATH mass spectrometry. The high measurement accuracy of SWATH allowed the detection of a large group of differentially expressed proteins between individual species and rodent versus primate. Differentially expressed proteins between rodent and primate were found highly enriched for plasticity-related proteins.

2018-10-22 | PXD009251 | Pride

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