scholarly journals PrPCGoverns Susceptibility to Prion Strains in Bank Vole, While Other Host Factors Modulate Strain Features

2016 ◽  
Vol 90 (23) ◽  
pp. 10660-10669 ◽  
Author(s):  
J. C. Espinosa ◽  
R. Nonno ◽  
M. Di Bari ◽  
P. Aguilar-Calvo ◽  
L. Pirisinu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Bank Vole ◽  
Differential Susceptibility ◽  
Transgenic Mouse Model ◽  
Host Factors ◽  
Bank Voles ◽  
Prion Strains ◽  
Species Specific

ABSTRACTBank vole is a rodent species that shows differential susceptibility to the experimental transmission of different prion strains. In this work, the transmission features of a panel of diverse prions with distinct origins were assayed both in bank vole expressing methionine at codon 109 (Bv109M) and in transgenic mice expressing physiological levels of bank vole PrPC(the BvPrP-Tg407 mouse line). This work is the first systematic comparison of the transmission features of a collection of prion isolates, representing a panel of diverse prion strains, in a transgenic-mouse model and in its natural counterpart. The results showed very similar transmission properties in both the natural species and the transgenic-mouse model, demonstrating the key role of the PrP amino acid sequence in prion transmission susceptibility. However, differences in the PrPSctypes propagated by Bv109M and BvPrP-Tg407 suggest that host factors other than PrPCmodulate prion strain features.IMPORTANCEThe differential susceptibility of bank voles to prion strains can be modeled in transgenic mice, suggesting that this selective susceptibility is controlled by the vole PrP sequence alone rather than by other species-specific factors. Differences in the phenotypes observed after prion transmissions in bank voles and in the transgenic mice suggest that host factors other than the PrPCsequence may affect the selection of the substrain replicating in the animal model.

scholarly journals Functional and structural connectome properties in the 5XFAD transgenic mouse model of Alzheimer’s disease

2018 ◽  
Vol 2 (2) ◽  
pp. 241-258 ◽  
Author(s):  
Shelli R. Kesler ◽  
Paul Acton ◽  
Vikram Rao ◽  
William J. Ray
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Amyloid Beta ◽  
Molecular Mechanisms ◽  
Diffusion Tensor ◽  
Transgenic Mouse Model ◽  
Structural Connectome

Neurodegeneration in Alzheimer’s disease (AD) is associated with amyloid-beta peptide accumulation into insoluble amyloid plaques. The five-familial AD (5XFAD) transgenic mouse model exhibits accelerated amyloid-beta deposition, neuronal dysfunction, and cognitive impairment. We aimed to determine whether connectome properties of these mice parallel those observed in patients with AD. We obtained diffusion tensor imaging and resting-state functional magnetic resonance imaging data for four transgenic and four nontransgenic male mice. We constructed both structural and functional connectomes and measured their topological properties by applying graph theoretical analysis. We compared connectome properties between groups using both binarized and weighted networks. Transgenic mice showed higher characteristic path length in weighted structural connectomes and functional connectomes at minimum density. Normalized clustering and modularity were lower in transgenic mice across the upper densities of the structural connectome. Transgenic mice also showed lower small-worldness index in higher structural connectome densities and in weighted structural networks. Hyper-correlation of structural and functional connectivity was observed in transgenic mice compared with nontransgenic controls. These preliminary findings suggest that 5XFAD mouse connectomes may provide useful models for investigating the molecular mechanisms of AD pathogenesis and testing the effectiveness of potential treatments.

scholarly journals Transplantation of Adipose-Derived Stem Cells Alleviates Striatal Degeneration in a Transgenic Mouse Model for Multiple System Atrophy

2020 ◽  
Vol 29 ◽  
pp. 096368972096018
Author(s):  
Christine Chang ◽  
Jen-Wei Liu ◽  
Bo Cheng Chen ◽  
Zhe Sheng Jiang ◽  
Chi Tang Tu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Multiple System Atrophy ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Transgenic Mouse Model ◽  
Intracerebral Injection ◽  
Nigrostriatal Pathway ◽  
Striatal Degeneration

Patients with multiple system atrophy (MSA), a progressive neurodegenerative disorder of adult onset, were found less than 9 years of life expectancy after onset. The disorders include bradykinesia and rigidity commonly seen in Parkinsonism disease and additional signs such as autonomic dysfunction, ataxia, or dementia. In clinical treatments, MSA poorly responds to levodopa, the drug used to remedy Parkinsonism disease. The exact cause of MSA is still unknown, and exploring a therapeutic solution to MSA remains critical. A transgenic mouse model was established to study the feasibility of human adipose-derived stem cell (ADSC) therapy in vivo. The human ADSCs were transplanted into the striatum of transgenic mice via intracerebral injection. As compared with sham control, we reported significantly enhanced rotarod performance of transgenic mice treated with ADSC at an effective dose, 2 × 105 ADSCs/mouse. Our ex vivo feasibility study supported that intracerebral transplantation of ADSC might alleviate striatal degeneration in MSA transgenic mouse model by improving the nigrostriatal pathway for dopamine, activating autophagy for α-synuclein clearance, decreasing inflammatory signal, and further cell apoptosis, improving myelination and cell survival at caudate-putamen.

scholarly journals The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3341-3345 ◽  
Author(s):  
Ke Cheng ◽  
Paolo Sportoletti ◽  
Keisuke Ito ◽  
John G. Clohessy ◽  
Julie Teruya-Feldstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Transgenic Mouse Model ◽  
Acute Myeloid

Abstract Although NPM1 gene mutations leading to aberrant cytoplasmic expression of nucleophosmin (NPMc+) are the most frequent genetic lesions in acute myeloid leukemia, there is yet no experimental model demonstrating their oncogenicity in vivo. We report the generation and characterization of a transgenic mouse model expressing the most frequent human NPMc+ mutation driven by the myeloid-specific human MRP8 promoter (hMRP8-NPMc+). In parallel, we generated a similar wild-type NPM trans-genic model (hMRP8-NPM). Interestingly, hMRP8-NPMc+ transgenic mice developed myeloproliferation in bone marrow and spleen, whereas nontransgenic littermates and hMRP8-NPM transgenic mice remained disease free. These findings provide the first in vivo evidence indicating that NPMc+ confers a proliferative advantage in the myeloid lineage. No spontaneous acute myeloid leukemia was found in hMPR8-NPMc+ or hMRP8-NPM mice. This model will also aid in the development of therapeutic regimens that specifically target NPMc+.

scholarly journals B.1.1.7 and B.1.351 variants are highly virulent in K18-ACE2 transgenic mice and show different pathogenic patterns from early SARS-CoV-2 strains

2021 ◽  
Author(s):  
Peter Radvak ◽  
Hyung Joon Kwon ◽  
Martina Kosikova ◽  
Uriel Ortega-Rodriguez ◽  
Ruoxuan Xiang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Internal Organs ◽  
Medical Interventions ◽  
Enhanced Resistance ◽  
Prior Infection ◽  
Highly Virulent ◽  
D Dimer

SARS-CoV-2 continues to circulate globally resulting in emergence of several variants of concern (VOC), including B.1.1.7 and B.1.351 that show increased transmissibility and enhanced resistance to antibody neutralization. In a K18-hACE2 transgenic mouse model, we demonstrate that Both B.1.1.7 and B.1.351 are 100 times more lethal than the original SARS-CoV-2 bearing 614D. Mice infected with B.1.1.7 and B.1.351 exhibited more severe lesions in internal organs than those infected with early SARS-CoV-2 strains bearing 614D or 614G. Infection of B.1.1.7 and B.1.351 also results in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death as compared to the mice infected with early SARS-CoV-2 strains. However, K18-hACE2 mice with the pre-existing immunity from prior infection or immunization were resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC. Our study reveals distinguishing pathogenic patterns of B.1.1.7 and B.1.351 variants from those early SARS-CoV-2 strains in K18-hACE2 mice, which will help to inform potential medical interventions for combating COVID-19.

scholarly journals Transmission of Prion Strains in a Transgenic Mouse Model Overexpressing Human A53T Mutated α-Synuclein

2011 ◽  
Vol 70 (5) ◽  
pp. 377-385 ◽  
Author(s):  
Anne-Laure J. Mougenot ◽  
Anna Bencsik ◽  
Simon Nicot ◽  
Johann Vulin ◽  
Eric Morignat ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Prion Strains

scholarly journals Specific overexpression of IL-7 in the intestinal mucosa: the role in intestinal intraepithelial lymphocyte development

2008 ◽  
Vol 294 (6) ◽  
pp. G1421-G1430 ◽  
Author(s):  
Hua Yang ◽  
Blair Madison ◽  
Deborah L. Gumucio ◽  
Daniel H. Teitelbaum
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Critical Role ◽  
Transgenic Mouse Model ◽  
Intraepithelial Lymphocytes ◽  
Specific Expression ◽  
And Function

IL-7 plays a crucial role in controlling T cell development and homeostasis. Since IL-7 may be derived from extraintestinal sources, and exogenous IL-7 broadly affects lymphoid populations, the actions of epithelial cell (EC)-derived IL-7 are not fully understood. The effect of intestinal specific expression of IL-7 on intestinal mucosal lymphocytes was investigated by using an IL-7 transgenic mouse model. We generated an intestinal EC-specific overexpressing IL-7 transgenic mouse model (IL-7vill) and compared their phenotype and function to wild-type C57BL/6J mice. EC-derived IL-7 overexpression was found to be exclusively in the small and large intestine. Numbers and subtypes of mucosal lymphocytes, including intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL), significantly changed in IL-7vill mice. From a functional standpoint, IEL proliferation also significantly increased in IL-7vill mice. IEL cytokine expression significantly changed in both T cell receptor (TCR)-αβ+ and TCR-γδ+ IEL subpopulations, including a significant increase in IFN-γ and TNF-α as well as an increase in keratinocyte growth factor expression. EC expression of CD103 (integrin αEβ7), the ligand of E-cadherin, markedly upregulated and may account for a mechanism of the massive expansion of IEL in transgenic mice. Systemic lymphoid populations did not change in transgenic mice. IL-7 overexpression by intestinal EC significantly affected IEL phenotype and function. These results offer insight into the role of IL-7 in IEL development and suggest a critical role of EC-derived expression of IL-7 in the phenotype and function of IEL.

scholarly journals Bystander Activation of Cytotoxic T Cells: Studies on the Mechanism and Evaluation of In Vivo Significance in a Transgenic Mouse Model

1997 ◽  
Vol 185 (7) ◽  
pp. 1241-1252 ◽  
Author(s):  
Stephan Ehl ◽  
Joachim Hombach ◽  
Peter Aichele ◽  
Hans Hengartner ◽  
Rolf M. Zinkernagel
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Vaccinia Virus ◽  
Transgenic Mouse ◽  
Rare Event ◽  
Transgenic Mouse Model ◽  
Bystander Activation

Bystander activation, i.e., activation of T cells specific for an antigen X during an immune response against antigen Y may occur during viral infections. However, the low frequency of bystander-activated T cells has rendered it difficult to define the mechanisms and possible in vivo relevance of this nonspecific activation. This study uses transgenic mice expressing a major histocompatibility complex class I–restricted TCR specific for glycoprotein peptide 33-41 of lymphocytic choriomeningitis virus (LCMV) to overcome this limitation. CD8+ T cells from specific pathogen-free maintained, unimmunized “naive” TCR transgenic mice can differentiate into LCMV-specific cytolytic effector CTL during infections with vaccinia virus or Listeria monocytogenes in vivo or mixed lymphocyte culture in vitro. We show that in these model situations (a) nonspecifically activated CTL are able to confer antiviral protection in vivo, (b) bystander activation is largely independent of the expression of a second T cell receptor of different specificity, (c) bystander activation is not mediated by a broadly cross-reactive TCR, but rather by cytokines, (d) bystander activation can be mediated by cytokines such as IL-2, but not α/β-IFN in vitro; (e) bystander activation is, overall, a rare event, occuring in vivo in roughly 1 in 200 of the LCMV-specific CTL during infection of TCR transgenic mice with vaccinia virus; (f) bystander activation does not have a significant functional impact on nontransgenic CTL memory under the conditions tested; and (g) even in the TCR transgenic situation, where unphysiologically high numbers of T cells of a single specificity are present, bystander activation is not sufficient to cause clinically manifest autoimmune disease in a transgenic mouse model of diabetes. We conclude that although bystander activation via cytokines may generate cytolytically active CTL from naive precursors, quantitative considerations suggest that this is usually not of major biological consequence.

scholarly journals Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

2018 ◽  
Author(s):  
Takako I. Jones ◽  
Guo-Liang Chew ◽  
Pamela Barraza-Flores ◽  
Spencer Schreier ◽  
Monique Ramirez ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Muscle Weakness ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Transgenic Mouse Model ◽  
Large Variability ◽  
Low Level

AbstractBackgroundAll types of facioscapulohumeral muscular dystrophy (FSHD) are caused by the aberrant myogenic activation of the somatically silent DUX4 gene, which initiates a cascade of cellular events ultimately leading to FSHD pathophysiology. Therefore, FSHD is a dominant gain-of-function disease that is amenable to modeling by DUX4 overexpression. However, there is large variability in the patient population. Typically, progressive skeletal muscle weakness becomes noticeable in the second or third decade of life, yet there are many genetically FSHD individuals who develop symptoms much later in life or remain relatively asymptomatic throughout their lives. Conversely, in rare cases, FSHD may present clinically prior to 5-10 yrs of age, ultimately manifesting as a very severe early onset form of the disease. Thus, there is a need to control the timing and severity of pathology in FSHD-like models.MethodsWe have recently described a line of conditional DUX4 transgenic mice, FLExDUX4, that develop a myopathy upon induction of human DUX4-fl expression in skeletal muscle. Here, we use the FLExDUX4 mouse crossed with the skeletal muscle-specific and tamoxifen inducible line ACTAl-MerCreMer to generate a highly versatile bi-transgenic mouse model with chronic, low-level DUX4-fl expression and mild pathology, that can be induced to develop more severe FSHD-like pathology in a dose-dependent response to tamoxifen. We identified conditions to reproducibly generate models exhibiting mild, moderate, or severe DUX4-dependent pathophysiology, and characterized their progression.ResultsWe assayed DUX4-fl mRNA and protein levels, fitness, strength, global gene expression, histopathology, and immune response, all of which are consistent with an FSHD-like myopathic phenotype. Importantly, we identified sex-specific and muscle-specific differences that should be considered when using these models for preclinical studies.ConclusionsThe ACTA1-MCM;FLExDUX4 bi-transgenic mouse model expresses a chronic low level of DUX4-fl and has mild pathology and detectable muscle weakness. The onset and progression of moderate to severe pathology can be controlled via tamoxifen injection to provide consistent and readily screenable phenotypes for assessing therapies targeting DUX4-fl mRNA and protein. Thus, these FSHD-like mouse models can be used to study a range of DUX4-fl expression and pathology dependent upon investigator need, through controlled mosaic expression of DUX4.

scholarly journals Lymphocyte Activation Gene 3 (Lag3) Contributes to α-Synucleinopathy in α-Synuclein Transgenic Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Hao Gu ◽  
Xiuli Yang ◽  
Xiaobo Mao ◽  
Enquan Xu ◽  
Chen Qi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Disease Progression ◽  
Transgenic Mouse ◽  
Lewy Bodies ◽  
Lymphocyte Activation ◽  
Transgenic Mouse Model ◽  
Behavioral Deficits ◽  
Lymphocyte Activation Gene

Aggregation of misfolded α-synuclein (α-syn) is the major component of Lewy bodies and neurites in Parkinson’s disease (PD) and related α-synucleinopathies. Some α-syn mutations (e.g., A53T) in familial PD recapitulate the α-syn pathology in transgenic mice, which supports the importance of pathologic α-syn in driving the pathogenesis of α-synucleinopathies. Lymphocyte activation gene 3 (Lag3) is a receptor of α-syn fibrils facilitating pathologic α-syn spread; however, the role of Lag3 in mediating the pathogenesis in α-syn transgenic mice is not clear. Here, we report that depletion of Lag3 in human α-syn A53T transgenic (hA53T) mice significantly reduces the level of detergent-insoluble α-syn aggregates and phosphorylated ser129 α-syn, and inhibits activation of microglia and astrocytes. The absence of Lag3 significantly delays disease progression and reduces the behavioral deficits in hA53T transgenic mice leading to prolonged survival. Taken together, these results show that Lag3 contributes to the pathogenesis in the α-syn A53T transgenic mouse model.

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