Displaying publications 21 - 40 of 59 in total

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  1. Fulltext In Silico Prediction and Validation of Gfap as an miR-3099 Target in Mouse Brain
    Abidin SZ, Leong JW, Mahmoudi M, Nordin N, Abdullah S, Cheah PS, et al.
    Neurosci Bull, 2017 Aug;33(4):373-382.
    PMID: 28597341 DOI: 10.1007/s12264-017-0143-0
    MicroRNAs are small non-coding RNAs that play crucial roles in the regulation of gene expression and protein synthesis during brain development. MiR-3099 is highly expressed throughout embryogenesis, especially in the developing central nervous system. Moreover, miR-3099 is also expressed at a higher level in differentiating neurons in vitro, suggesting that it is a potential regulator during neuronal cell development. This study aimed to predict the target genes of miR-3099 via in-silico analysis using four independent prediction algorithms (miRDB, miRanda, TargetScan, and DIANA-micro-T-CDS) with emphasis on target genes related to brain development and function. Based on the analysis, a total of 3,174 miR-3099 target genes were predicted. Those predicted by at least three algorithms (324 genes) were subjected to DAVID bioinformatics analysis to understand their overall functional themes and representation. The analysis revealed that nearly 70% of the target genes were expressed in the nervous system and a significant proportion were associated with transcriptional regulation and protein ubiquitination mechanisms. Comparison of in situ hybridization (ISH) expression patterns of miR-3099 in both published and in-house-generated ISH sections with the ISH sections of target genes from the Allen Brain Atlas identified 7 target genes (Dnmt3a, Gabpa, Gfap, Itga4, Lxn, Smad7, and Tbx18) having expression patterns complementary to miR-3099 in the developing and adult mouse brain samples. Of these, we validated Gfap as a direct downstream target of miR-3099 using the luciferase reporter gene system. In conclusion, we report the successful prediction and validation of Gfap as an miR-3099 target gene using a combination of bioinformatics resources with enrichment of annotations based on functional ontologies and a spatio-temporal expression dataset.
  2. miR-3099 promotes neurogenesis and inhibits astrogliogenesis during murine neural development
    Zainal Abidin S, Fam SZ, Chong CE, Abdullah S, Cheah PS, Nordin N, et al.
    Gene, 2019 May 20;697:201-212.
    PMID: 30769142 DOI: 10.1016/j.gene.2019.02.014
    MicroRNA-3099 is highly expressed during neuronal differentiation and development of the central nervous system. Here we characterised the role of miR-3099 during neural differentiation and embryonic brain development using a stable and regulatable mouse embryonic stem cell culture system for miR-3099 expression and in utero electroporation of miR-3099 expression construct into E15.5 embryonic mouse brains. In the in vitro system, miR-3099 overexpression upregulated gene related to neuronal markers such as Tuj1, NeuN, Gat1, vGluT1 and vGluT2. In contrast, gene related to astrocyte markers (Gfap, S100β and Slc1a3) were suppressed upon overexpression of miR-3099. Furthermore, miR-3099 overexpression between E15.5 and E18.5 mouse embryonic brains led to disorganised neuronal migration potentially due to significantly decreased Gfap+ cells. Collectively, our results indicated that miR-3099 plays a role in modulating and regulating expression of key markers involved in neuronal differentiation. In silico analysis was also performed to identify miR-3099 homologues in the human genome, and candidates were validated by stem-loop RT-qPCR. Analysis of the miR-3099 seed sequence AGGCUA against human transcriptomes revealed that a potential miRNA, mds21 (Chr21:39186698-39186677) (GenBank accession ID: MK521584), was 100% identical to the miR-3099 seed sequence. Mds21 expression was observed and validated in various human cell lines (293FT, human Wharton's jelly and dental pulp mesenchymal stem cells, and MCF-7, MDA-MB-231, C-Sert, SW780, RT112, 5637, EJ28 and SH-SY5Y cells), with the highest levels detected in human mesenchymal stem cell lines. The analysis validated mds21 as a novel miRNA and a novel homologue of miR-3099 in the human genome.
  3. Fulltext AAV9 transduction mediated by systemic delivery of vector via retro-orbital injection in newborn, neonatal and juvenile mice
    Prabhakar S, Lule S, da Hora CC, Breakefield XO, Cheah PS
    Exp Anim, 2021 Nov 10;70(4):450-458.
    PMID: 34039790 DOI: 10.1538/expanim.20-0186
    Adeno-associated virus (AAV)-based gene therapy is gaining popularity owing to its excellent safety profile and effective therapeutic outcomes in a number of diseases. Intravenous (IV) injection of AAV into the tail vein, facial vein and retro-orbital (RO) venous sinus have all been useful strategies to infuse the viral vector systemically. However, tail vein injection is technically challenging in juvenile mice, and injection at young ages (≤ postnatal day-(P)21) is essentially impossible. The temporal or facial vein is localized anterior to the ear bud and is markedly visible in the first couple of days postnatally. However, this method is age-dependent and requires a dissecting microscope. Retro-orbital injection (ROI), on the other hand, is suitable for all murine ages, including newborn and older mice, and is relatively less stressful to animals compared to tail vein injection. Although many reports have shown ROI as an effective route of AAV delivery, herein we aim to highlight and summarize the methods and benefits of ROI. To capture the full spectrum of transduction efficiency mediated by ROI, we transduced the editing-dependent reporter mice (Ai9 Cre reporter mice) with the AAV9 vector, which targets a wide range of peripheral tissues with exceptional brain tropism. We also provide a comprehensive description of the ROI technique to facilitate viral vector administration without complications.
  4. Fulltext Mitochondria dysfunction and bipolar disorder: From pathology to therapy
    Lam XJ, Xu B, Yeo PL, Cheah PS, Ling KH
    IBRO Neurosci Rep, 2023 Jun;14:407-418.
    PMID: 37388495 DOI: 10.1016/j.ibneur.2023.04.002
    Bipolar disorder (BD) is one of the major psychiatric diseases in which the impairment of mitochondrial functions has been closely connected or associated with the disease pathologies. Different lines of evidence of the close connection between mitochondria dysfunction and BD were discussed with a particular focus on (1) dysregulation of energy metabolism, (2) effect of genetic variants, (3) oxidative stress, cell death and apoptosis, (4) dysregulated calcium homeostasis and electrophysiology, and (5) current as well as potential treatments targeting at restoring mitochondrial functions. Currently, pharmacological interventions generally provide limited efficacy in preventing relapses or recovery from mania or depression episodes. Thus, understanding mitochondrial pathology in BD will lead to novel agents targeting mitochondrial dysfunction and formulating new effective therapy for BD.
  5. Fulltext Step-by-step approach: Stereotaxic surgery for in vivo extracellular field potential recording at the rat Schaffer collateral-CA1 synapse using the eLab system
    Azimzadeh M, Mohd Azmi MAN, Reisi P, Cheah PS, Ling KH
    MethodsX, 2024 Jun;12:102544.
    PMID: 38283759 DOI: 10.1016/j.mex.2023.102544
    In vivo extracellular field potential recording is a commonly used technique in modern neuroscience research. The success of long-term electrophysiological recordings often depends on the quality of the implantation surgery. However, there is limited use of visually guided stereotaxic neurosurgery and the application of the eLab/ePulse electrophysiology system in rodent models. This study presents a practical and functional manual guide for surgical electrode implantation in rodent models using the eLab/ePulse electrophysiology system for recording and stimulation purposes to assess neuronal functionality and synaptic plasticity. The evaluation parameters included the input/output function (IO), paired-pulse facilitation or depression (PPF/PPD), long-term potentiation (LTP), and long-term depression (LTD).•Provides a detailed picture-guided procedure for conducting in vivo stereotaxic neurosurgery.•Specifically covers the insertion of hippocampal electrodes and the recording of evoked extracellular field potentials.
  6. Fulltext Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study
    Kura AU, Cheah PS, Hussein MZ, Hassan Z, Tengku Azmi TI, Hussein NF, et al.
    Nanoscale Res Lett, 2014;9(1):261.
    PMID: 24948886 DOI: 10.1186/1556-276X-9-261
    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant (p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant (p 
  7. Fulltext Acute oral toxicity and biodistribution study of zinc-aluminium-levodopa nanocomposite
    Kura AU, Saifullah B, Cheah PS, Hussein MZ, Azmi N, Fakurazi S
    Nanoscale Res Lett, 2015;10:105.
    PMID: 25852400 DOI: 10.1186/s11671-015-0742-5
    Layered double hydroxide (LDH) is an inorganic-organic nano-layered material that harbours drug between its two-layered sheets, forming a sandwich-like structure. It is attracting a great deal of attention as an alternative drug delivery (nanodelivery) system in the field of pharmacology due to their relative low toxic potential. The production of these nanodelivery systems, aimed at improving human health through decrease toxicity, targeted delivery of the active compound to areas of interest with sustained release ability. In this study, we administered zinc-aluminium-LDH-levodopa nanocomposite (ZAL) and zinc-aluminium nanocomposite (ZA) to Sprague Dawley rats to evaluate for acute oral toxicity following OECD guidelines. The oral administration of ZAL and ZA at a limit dose of 2,000 mg/kg produced neither mortality nor acute toxic signs throughout 14 days of the observation. The percentage of body weight gain of the animals showed no significant difference between control and treatment groups. Animal from the two treated groups gained weight continuously over the study period, which was shown to be significantly higher than the weight at the beginning of the study (P 
  8. Understanding perspectives and research trends in Down syndrome neuropathogenesis: A bibliometric analysis
    Huang T, Lam XJ, Lim CT, Jusoh N, Fakurazi S, Cheah PS, et al.
    J Intellect Disabil, 2024 Nov 13.
    PMID: 39533897 DOI: 10.1177/17446295241299160
    Down syndrome (DS), characterised by compromised brain development and intellectual challenges, often manifests Alzheimer's disease (AD) -like symptoms. Utilising the Web of Science Core Collection (WOSCC) database from January 1, 2000, to July 31, 2023, we conducted a comprehensive bibliometric analysis using VOSviewer, CiteSpace, and the R package "bibliometrix." Analyses included co-authorship, co-citation, co-occurrence, cooperative network, reference, and keyword burst citation. Analysing 5,082 papers, the U.S. demonstrated prominence with the highest number of research organisations and citations. Keyword analysis revealed promising research areas, including "Alzheimer's disease," "development," "inflammation," and "neurogenesis". This 22-year survey of the brain with trisomy 21 research unveils key trends, contributors, and focal areas in DS neuropathogenesis. Notably, Alzheimer 's-related genes and proteins play a pervasive role in DS neuropathological processes across patients' lifespans. The study contributes foundational knowledge for advancing research and care in the DS neuropathogenesis domain.
  9. Fulltext The resin-embedded cornea prepared via rapid processing protocol : a good histomorphometric target for clinical investigation in ophthalmology and optometry
    Cheah PS, Mohidin N, Mohd Ali B, Maung M, Latif AA
    Malays J Med Sci, 2008 Jul;15(3):49-54.
    PMID: 22570589
    This study illustrates and quantifies the changes on corneal tissue between the paraffin-embedded and resin-embedded blocks and thus, selects a better target in investigational ophthalmology and optometry via light microscopy. Corneas of two cynomolgus monkeys (Macaca fascicularis) were used in this study. The formalin-fixed cornea was prepared in paraffin block via the conventional tissue processing protocol (4-day protocol) and stained with haematoxylin and eosin. The glutaraldehyde-fixed cornea was prepared in resin block via the rapid and modified tissue processing procedure (1.2-day protocol) and stained with toluidine blue. The paraffin-embedded sample exhibits various undesired tissue damage and artifact such as thinner epithelium (due to the substantial volumic extraction from the tissue), thicker stroma layer (due to the separation of lamellae and the presence of voids) and the distorted endothelium. In contrast, the resin-embedded corneal tissue has demonstrated satisfactory corneal ultrastructural preservation. The rapid and modified tissue processing method for preparing the resin-embedded is particularly beneficial to accelerate the microscopic evaluation in ophthalmology and optometry.
  10. Fulltext Phenotype microarrays reveal metabolic dysregulations of neurospheres derived from embryonic Ts1Cje mouse model of Down syndrome
    Seth EA, Lee HC, Yusof HHBM, Nordin N, Cheah YK, Ho ETW, et al.
    PLoS One, 2020;15(7):e0236826.
    PMID: 32730314 DOI: 10.1371/journal.pone.0236826
    Down syndrome (DS), is the most common cause of intellectual disability, and is characterized by defective neurogenesis during perinatal development. To identify metabolic aberrations in early neurogenesis, we profiled neurospheres derived from the embryonic brain of Ts1Cje, a mouse model of Down syndrome. High-throughput phenotypic microarray revealed a significant decrease in utilisation of 17 out of 367 substrates and significantly higher utilisation of 6 substrates in the Ts1Cje neurospheres compared to controls. Specifically, Ts1Cje neurospheres were less efficient in the utilisation of glucose-6-phosphate suggesting a dysregulation in the energy-producing pathway. T Cje neurospheres were significantly smaller in diameter than the controls. Subsequent preliminary study on supplementation with 6-phosphogluconic acid, an intermediate of glucose-6-phosphate metabolism, was able to rescue the Ts1Cje neurosphere size. This study confirmed the perturbed pentose phosphate pathway, contributing to defects observed in Ts1Cje neurospheres. We show for the first time that this comprehensive energetic assay platform facilitates the metabolic characterisation of Ts1Cje cells and confirmed their distinguishable metabolic profiles compared to the controls.
  11. Fulltext Anatomic Variation in Morphometry of Human Coracoid Process among Asian Population
    Fathi M, Cheah PS, Ahmad U, Nasir MN, San AA, Abdul Rahim E, et al.
    Biomed Res Int, 2017;2017:6307019.
    PMID: 28484716 DOI: 10.1155/2017/6307019
    Ethnic origin plays an important role in bone morphometry. Studies examining the influence of coracoid process have focused primarily on adults and have not included people from diverse Asian ethnic backgrounds. Our goal was to explore ethnic differences in morphometry of coracoid among Asian population. We performed morphometric measurements of coracoid process on cadaveric shoulders and shoulder CT scans from 118 specimens. The cadaveric sample included Indian (46%), Chinese (27%), and Myanmarese (27%) subjects, while the CT scans sample included Chinese (67%) and Malay (33%) subjects. The morphometric measurements were performed using digital caliper and software developed at Golden Horses Health Sanctuary (GHHS). In the Indian cadaveric shoulders, the coracoid process is better developed than the other groups with the exception of the tip width of coracoid process. There are significant differences in almost all measurements (P< 0.05) between the ethnic groups. On the other hand, the morphometry of coracoid process from CT scans data is bigger in Chinese than Malay subjects when stratified by sex (P< 0.05). Moreover, in all morphometric measurements, the females had smaller measurements than males (P< 0.05). Understanding such differences is important in anatomy, forensic and biological identity, and orthopaedic and shoulder surgeries.
  12. Fulltext Plasmon-Enhanced Biosensing for Multiplexed Profiling of Extracellular Vesicles
    Min J, Son T, Hong JS, Cheah PS, Wegemann A, Murlidharan K, et al.
    Adv Biosyst, 2020 12;4(12):e2000003.
    PMID: 32815321 DOI: 10.1002/adbi.202000003
    Extracellular vesicles (EVs)-nanoscale phospholipid vesicles secreted by cells-present new opportunities for molecular diagnosis from non-invasive liquid biopsies. Single EV protein analysis can be extremely valuable in studying EVs as circulating cancer biomarkers, but it is technically challenging due to weak detection signals associated with limited amounts of epitopes and small surface areas for antibody labeling. Here, a new, simple method that enables multiplexed analyses of EV markers with improved sensitivities is reported. Specifically, plasmon-enhanced fluorescence detection is implemented that amplifies fluorescence signals using surface plasmon resonances excited by periodic gold nanohole structures. It is shown that fluorescence signals in multiple channels are amplified by one order of magnitude, and both transmembrane and intravesicular markers can be detected at the single EV level. This approach can offer additional insight into understanding subtypes, heterogeneity, and production dynamics of EVs during disease development and progression.
  13. In vitro cytotoxicity assessment of ruxolitinib on oligodendrocyte precursor cell and neural stem/progenitor cell populations
    Lim CW, Hamanaka G, Liang AC, Chan SJ, Ling KH, Lo EH, et al.
    Neurotoxicology, 2024 Aug 28;105:10-20.
    PMID: 39209271 DOI: 10.1016/j.neuro.2024.08.004
    JAK-STAT signaling cascade has emerged as an ideal target for the treatment of myeloproliferative diseases, autoimmune diseases, and neurological disorders. Ruxolitinib (Rux), is an orally bioavailable, potent and selective Janus-associated kinase (JAK) inhibitor, proven to be effective to target activated JAK-STAT pathway in the diseases previously described. Unfortunately, limited studies have investigated the potential cytotoxic profile of Rux on other cell populations within the heterogenous CNS microenvironment. Two stem and progenitor cell populations, namely the oligodendrocyte precursor cells (OPCs) and neural stem/progenitor cells (NSPCs), are important for long-term maintenance and post-injury recovery response of the CNS. In light of the limited evidence, this study sought to investigate further the effect of Rux on proliferating and differentiating OPCs and NSPCs populations. In the present study, cultured rat OPCs and NSPCs were treated with various concentrations of Rux, ranging from 2 μM to 20 μM. The effect of Rux on proliferating OPCs (PDGF-R-α+) and proliferating NSPCs (nestin+) was assessed via a 3-day Rux treatment, whereas its effect on differentiating OPCs (MBP+/PDGF-R-α+) and differentiating NSPCs (neurofilament+) was assessed after a 7-day treatment. Cytotoxicity of Rux was also assessed on OPC populations by examining its influence on cell death and DNA synthesis via YO-PRO-1/PI dual-staining and BrdU assay, respectively. The results suggest that Rux at a dosage above 10 μM reduces the number proliferating OPCs, likely via the induction of apoptosis. On the other hand, Rux treatment from 2.5 μM to 20 μM significantly reduces the number of differentiating OPCs by inducing necrosis. Meanwhile, Rux treatment has no observable untoward impact on NSPC cultures within the dosage range tested. Taken together, OPCs appears to be more vulnerable to the dosage effect of Rux, whereas NSPCs are not significantly impacted by Rux, suggesting a differential mechanism of actions of Rux on the cell types.
  14. Fulltext Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks
    Ling KH, Hewitt CA, Tan KL, Cheah PS, Vidyadaran S, Lai MI, et al.
    BMC Genomics, 2014;15:624.
    PMID: 25052193 DOI: 10.1186/1471-2164-15-624
    The Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16 (MMU16), which is partially homologous to human chromosome 21. These mice develop various neuropathological features identified in DS individuals. We analysed the effect of partial triplication of the MMU16 segment on global gene expression in the cerebral cortex, cerebellum and hippocampus of Ts1Cje mice at 4 time-points: postnatal day (P)1, P15, P30 and P84.
  15. Fulltext Transcriptional profiling of the postnatal brain of the Ts1Cje mouse model of Down syndrome
    Tan KL, Ling KH, Hewitt CA, Cheah PS, Simpson K, Gordon L, et al.
    Genom Data, 2014 Dec;2:314-7.
    PMID: 26484118 DOI: 10.1016/j.gdata.2014.09.009
    The Ts1Cje mouse model of Down syndrome (DS) has partial trisomy of mouse chromosome 16 (MMU16), which is syntenic to human chromosome 21 (HSA21). It develops various neuropathological features demonstrated by DS patients such as reduced cerebellar volume [1] and altered hippocampus-dependent learning and memory [2,3]. To understand the global gene expression effect of the partially triplicated MMU16 segment on mouse brain development, we performed the spatiotemporal transcriptome analysis of Ts1Cje and disomic control cerebral cortex, cerebellum and hippocampus harvested at four developmental time-points: postnatal day (P)1, P15, P30 and P84. Here, we provide a detailed description of the experimental and analysis procedures of the microarray dataset, which has been deposited in the Gene Expression Omnibus (GSE49050) database.
  16. Fulltext Long-Term Therapeutic Efficacy of Intravenous AAV-Mediated Hamartin Replacement in Mouse Model of Tuberous Sclerosis Type 1
    Prabhakar S, Cheah PS, Zhang X, Zinter M, Gianatasio M, Hudry E, et al.
    Mol Ther Methods Clin Dev, 2019 Dec 13;15:18-26.
    PMID: 31534984 DOI: 10.1016/j.omtm.2019.08.003
    Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome caused by mutations in TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins act as a complex that inhibits mammalian target of rapamycin (mTOR)-mediated cell growth and proliferation. Loss of either protein leads to overgrowth in many organs, including subependymal nodules, subependymal giant cell astrocytomas, and cortical tubers in the human brain. Neurological manifestations in TSC include intellectual disability, autism, hydrocephalus, and epilepsy. In a stochastic mouse model of TSC1 brain lesions, complete loss of Tsc1 is achieved in homozygous Tsc1-floxed mice in a subpopulation of neural cells in the brain by intracerebroventricular (i.c.v.) injection at birth of an adeno-associated virus (AAV) vector encoding Cre recombinase. This results in median survival of 38 days and brain pathology, including subependymal lesions and enlargement of neuronal cells. Remarkably, when these mice were injected intravenously on day 21 with an AAV9 vector encoding hamartin, most survived at least up to 429 days in apparently healthy condition with marked reduction in brain pathology. Thus, a single intravenous administration of an AAV vector encoding hamartin restored protein function in enough cells in the brain to extend lifespan in this TSC1 mouse model.
  17. Fulltext Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells
    Lucero R, Zappulli V, Sammarco A, Murillo OD, Cheah PS, Srinivasan S, et al.
    Cell Rep, 2020 02 18;30(7):2065-2074.e4.
    PMID: 32075753 DOI: 10.1016/j.celrep.2020.01.073
    Glioblastoma (GBM) is characterized by aberrant vascularization and a complex tumor microenvironment. The failure of anti-angiogenic therapies suggests pathways of GBM neovascularization, possibly attributable to glioblastoma stem cells (GSCs) and their interplay with the tumor microenvironment. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To further elucidate EV-mediated mechanisms of neovascularization in vitro, we perform RNA-seq and DNA methylation profiling of human brain endothelial cells exposed to GSC-EVs. To correlate these results to tumors in vivo, we perform histoepigenetic analysis of GBM molecular profiles in the TCGA collection. Remarkably, GSC-EVs and normal vascular growth factors stimulate highly distinct gene regulatory responses that converge on angiogenesis. The response to GSC-EVs shows a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Our results provide insights into targetable angiogenesis pathways in GBM and miRNA candidates for liquid biopsy biomarkers.
  18. Gene and protein expression profiles of JAK-STAT signalling pathway in the developing brain of the Ts1Cje down syndrome mouse model
    Lee HC, Md Yusof HH, Leong MP, Zainal Abidin S, Seth EA, Hewitt CA, et al.
    Int J Neurosci, 2019 Sep;129(9):871-881.
    PMID: 30775947 DOI: 10.1080/00207454.2019.1580280
    Aims: The JAK-STAT signalling pathway is one of the key regulators of pro-gliogenesis process during brain development. Down syndrome (DS) individuals, as well as DS mouse models, exhibit an increased number of astrocytes, suggesting an imbalance of neurogenic-to-gliogenic shift attributed to dysregulated JAK-STAT signalling pathway. The gene and protein expression profiles of JAK-STAT pathway members have not been characterised in the DS models. Therefore, we aimed to profile the expression of Jak1, Jak2, Stat1, Stat3 and Stat6 at different stages of brain development in the Ts1Cje mouse model of DS. Methods: Whole brain samples from Ts1Cje and wild-type mice at embryonic day (E)10.5, E15, postnatal day (P)1.5; and embryonic cortex-derived neurospheres were collected for gene and protein expression analysis. Gene expression profiles of three brain regions (cerebral cortex, cerebellum and hippocampus) from Ts1Cje and wild-type mice across four time-points (P1.5, P15, P30 and P84) were also analysed. Results: In the developing mouse brain, none of the Jak/Stat genes were differentially expressed in the Ts1Cje model compared to wild-type mice. However, Western blot analyses indicated that phosphorylated (p)-Jak2, p-Stat3 and p-Stat6 were downregulated in the Ts1Cje model. During the postnatal brain development, Jak/Stat genes showed complex expression patterns, as most of the members were downregulated at different selected time-points. Notably, embryonic cortex-derived neurospheres from Ts1Cje mouse brain expressed lower Stat3 and Stat6 protein compared to the wild-type group. Conclusion: The comprehensive expression profiling of Jak/Stat candidates provides insights on the potential role of the JAK-STAT signalling pathway during abnormal development of the Ts1Cje mouse brains.
  19. Fulltext Defects in nerve conduction velocity and different muscle fibre-type specificity contribute to muscle weakness in Ts1Cje Down syndrome mouse model
    Bala U, Leong MP, Lim CL, Shahar HK, Othman F, Lai MI, et al.
    PLoS One, 2018;13(5):e0197711.
    PMID: 29795634 DOI: 10.1371/journal.pone.0197711
    BACKGROUND: Down syndrome (DS) is a genetic disorder caused by presence of extra copy of human chromosome 21. It is characterised by several clinical phenotypes. Motor dysfunction due to hypotonia is commonly seen in individuals with DS and its etiology is yet unknown. Ts1Cje, which has a partial trisomy (Mmu16) homologous to Hsa21, is well reported to exhibit various typical neuropathological features seen in individuals with DS. This study investigated the role of skeletal muscles and peripheral nerve defects in contributing to muscle weakness in Ts1Cje mice.

    RESULTS: Assessment of the motor performance showed that, the forelimb grip strength was significantly (P<0.0001) greater in the WT mice compared to Ts1Cje mice regardless of gender. The average survival time of the WT mice during the hanging wire test was significantly (P<0.0001) greater compared to the Ts1Cje mice. Also, the WT mice performed significantly (P<0.05) better than the Ts1Cje mice in the latency to maintain a coordinated motor movement against the rotating rod. Adult Ts1Cje mice exhibited significantly (P<0.001) lower nerve conduction velocity compared with their aged matched WT mice. Further analysis showed a significantly (P<0.001) higher population of type I fibres in WT compared to Ts1Cje mice. Also, there was significantly (P<0.01) higher population of COX deficient fibres in Ts1Cje mice. Expression of Myf5 was significantly (P<0.05) reduced in triceps of Ts1Cje mice while MyoD expression was significantly (P<0.05) increased in quadriceps of Ts1Cje mice.

    CONCLUSION: Ts1Cje mice exhibited weaker muscle strength. The lower population of the type I fibres and higher population of COX deficient fibres in Ts1Cje mice may contribute to the muscle weakness seen in this mouse model for DS.

  20. Fulltext Expression Profiling of Notch Signalling Pathway and Gamma-Secretase Activity in the Brain of Ts1Cje Mouse Model of Down Syndrome
    Yusof HH, Lee HC, Seth EA, Wu X, Hewitt CA, Scott HS, et al.
    J Mol Neurosci, 2019 Apr;67(4):632-642.
    PMID: 30758748 DOI: 10.1007/s12031-019-01275-2
    Notch signalling pathway is involved in the proliferation of neural progenitor cells (NPCs), to inhibit neuronal cell commitment and to promote glial cell fate. Notch protein is cleaved by gamma-secretase, a multisubunit transmembrane protein complex that releases the Notch intracellular domain (NICD) and subsequently activates the downstream targets. Down syndrome (DS) individuals exhibit an increased number of glial cells (particularly astrocytes), and reduced number of neurons suggesting the involvement of Notch signalling pathway in the neurogenic-to-gliogenic shift in DS brain. Ts1Cje is a DS mouse model that exhibit similar neuropathology to human DS individuals. To date, the spatiotemporal gene expression of the Notch and gamma-secretase genes have not been characterised in Ts1Cje mouse brain. Understanding the expression pattern of Notch and gamma-secretase genes may provide a better understanding of the underlying mechanism that leads to the shift. Gene expression analysis using RT-qPCR was performed on early embryonic and postnatal development of DS brain. In the developing mouse brain, mRNA expression analysis showed that gamma-secretase members (Psen1, Pen-2, Aph-1b, and Ncstn) were not differentially expressed. Notch2 was found to be downregulated in the developing Ts1Cje brain samples. Postnatal gene expression study showed complex expression patterns and Notch1 and Notch2 genes were found to be significantly downregulated in the hippocampus at postnatal day 30. Results from RT-qPCR analysis from E15.5 neurosphere culture showed an increase of expression of Psen1, and Aph-1b but downregulation of Pen-2 and Ncstn genes. Gamma-secretase activity in Ts1Cje E15.5 neurospheres was significantly increased by fivefold. In summary, the association and the role of Notch and gamma-secretase gene expression throughout development with neurogenic-to-gliogenic shift in Ts1Cje remain undefined and warrant further validation.
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