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At least 361 records · Page 20Linked to original sources
PubMed1998

Opsin localization and rhodopsin photochemistry in a transgenic mouse model of retinitis pigmentosa.

The VPP mouse is a transgenic strain carrying three mutations (P23H, V20G, P27L) near the N-terminus of opsin, the apoprotein of rhodopsin, the rod photopigment. These animals exhibit a slowly progressive degeneration of the rod photoreceptors, and concomitant changes in retinal function that mimic those seen in humans with autosomal dominant retinitis pigmentosa resulting from a point mutation (P23H) in opsin. In the present study we attempted to determine whether the disease process prevents the translocation of mutant opsin to the rod outer segments of transgenic mice, and whether it affects the photochemical properties of the rhodopsin present within their rod outer segments. Immunocytochemistry with a monoclonal antibody against a region of the C-terminus that recognizes epitopes common to both normal and mutant opsin (monoclonal antibody-1D4), and a polyclonal antibody that reacts preferentially with the mutant opsin (anti-VPP), were used to identify the opsin present in the rods of three-week-old VPP mice and normal littermates. Absorbance spectra, photosensitivity, and regeneration kinetics of rhodopsin in rod outer segment disc membranes were analysed by spectrophotometry. Western blot analysis with anti-VPP antibody indicated the specific binding of this antibody to the mutant opsin. Immunolocalization with monoclonal antibody-1D4 and anti-VPP antibodies suggested a normal translocation of the mutant protein to the outer segments. Aside from a small disparity in the absorbance spectra of rhodopsin obtained from normal and VPP retinas, there were no significant differences in either the ability of opsin to bind 11-cis retinal chromophore, or in the photic sensitivity of rhodopsin. The results indicate that mutant opsin is translated and incorporated into the rod outer segment disc membranes of VPP mice, and that the photochemical properties of rhodopsin in the rods of VPP retinas are similar to those of rhodopsin in normal retinas.

Animals↗
PubMed2005

Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration.

Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of sporadic and familial tauopathies. Because tau gene mutations are pathogenic for the autosomal dominant tauopathy "frontotemporal dementia and parkinsonism linked to chromosome 17," tau abnormalities are implicated directly in the onset and/or progression of disease. Although filamentous tau aggregates are acknowledged to play roles in degenerative mechanisms resulting in neuron loss, the contributions of glial tau pathology to neurodegeneration remain essentially unexplored. To begin to elucidate the role of glial pathology in tauopathies, we generated a transgenic (Tg) mouse model of astrocytic tau pathology by expressing the human tau protein driven by the glial fibrillary acidic protein (GFAP) promoter. Whereas endogenous tau was not detected in astrocytes of control mice, in GFAP/tau Tg mice there was robust astrocytic tau expression that was associated with a redistribution of the GFAP network. Subsequently, there was an age-dependent accumulation of tau pathology in astrocytes that was Gallyas and variably thioflavine S positive as observed in many tauopathies. The tau pathology in these Tg mice was abnormally phosphorylated, ubiquitinated, and filamentous, and the emergence of this pathology coincided with accumulation of insoluble tau protein. Furthermore, in regions with robust astrocytic tau pathology, there was mild blood- brain barrier disruption, induction of low-molecular-weight heat shock proteins, and focal neuron degeneration. Thus, these Tg mice recapitulate key features of astrocytic pathology observed in human tauopathies and demonstrate functional consequences of this pathology including neuron degeneration in the absence of neuronal tau inclusions.

Age Factors↗
PubMed2005

Loss of synaptophysin-positive boutons on lumbar motor neurons innervating the medial gastrocnemius muscle of the SOD1G93A G1H transgenic mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a common form of motor neuron disease (MND) that involves both upper and lower nervous systems. In the SOD1G93A G1H transgenic mouse, a widely used animal model of human ALS, a significant pathology is linked to the degeneration of lower motor neurons in the lumbar spinal cord and brainstem. In the current study, the number of presynaptic boutons immunoreactive for synaptophysin was estimated on retrogradely labeled soma and proximal dendrites of alpha and gamma motor neurons innervating the medial gastrocnemius muscle. No changes were detected on both soma and proximal dendrites at postnatal day 60 (P60) of alpha and gamma motor neurons. By P90 and P120, however, alpha motor neuron soma had a reduction of 14 and 33% and a dendritic reduction of 19 and 36%, respectively. By P90 and P120, gamma motor neuron soma had a reduction of 17 and 41% and a dendritic reduction of 19 and 35%, respectively. This study shows that levels of afferent innervation significantly decreased on surviving alpha and gamma motor neurons that innervate the medial gastrocnemius muscle. This finding suggests that the loss of motor neurons and the decrease of synaptophysin in the remaining motor neurons could lead to functional motor deficits, which may contribute significantly to the progression of ALS/MND.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA).

Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. Only males develop symptoms, while female carriers usually are asymptomatic. A specific treatment for SBMA has not been established. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the first exon of the androgen receptor (AR) gene. The pathologic hallmark is nuclear inclusions (NIs) containing the mutant and truncated AR with expanded polyQ in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. Several transgenic (Tg) mouse models have been created for studying the pathogenesis of SBMA. The Tg mouse model carrying pure 239 CAGs under human AR promoter and another model carrying truncated AR with expanded CAGs show motor impairment and nuclear NIs in spinal motor neurons. Interestingly, Tg mice carrying full-length human AR with expanded polyQ demonstrate progressive motor impairment and neurogenic pathology as well as sexual difference of phenotypes. These models recapitulate the phenotypic expression observed in SBMA. The ligand-dependent nuclear localization of the mutant AR is found to be involved in the disease mechanism, and hormonal therapy is suggested to be a therapeutic approach applicable to SBMA.

Animals↗
PubMed1992

A novel transgenic mouse model for the in vivo evaluation of anti-human immunodeficiency virus type 1 drugs.

We have developed a binary transgenic mouse system that allows easy in vivo evaluation of new anti-human immunodeficiency virus type 1 (HIV-1) drugs or therapies specifically designed to target the viral transactivator protein (TAT) or long terminal repeat (LTR) functions. This approach consists of a simple genetic cross between an "activator" transgenic mouse expressing the HIV-1-tat gene exclusively to T lymphocytes and a "target" transgenic mouse bearing a silent reporter gene whose expression is under the control of the HIV-1-LTR. As expected, most of the target transgenic animals did not express the reporter gene; on the contrary, all the double-transgenic mice bearing both the activator and target transgenes strongly expressed the TAT-induced reporter gene. The choice of a secreted human alpha 1-antitrypsin variant (alpha 1-AT) as reporter gene readily permits in a single animal the quantitative determination of the plasma level of alpha 1-AT protein before and after anti-LTR or anti-TAT treatments. Such mice may be valuable as new laboratory models for the in vivo evaluation of agents with potential anti-HIV-1 activity.

Animals↗
PubMed1998

Disruption of redox homeostasis in the transforming growth factor-alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis.

In previous studies we have demonstrated that transforming growth factor (TGF)-alpha/c-myc double transgenic mice exhibit an enhanced rate of cell proliferation, accumulate extensive DNA damage, and develop multiple liver tumors between 4 and 8 months of age. To clarify the biochemical events that may be responsible for the genotoxic and carcinogenic effects observed in this transgenic model, several parameters of redox homeostasis in the liver were examined prior to development of hepatic tumors. By 2 months of age, production of reactive oxygen species, determined by the peroxidation-sensitive fluorescent dye, 2',7'-dichlorofluorescin diacetate, was significantly elevated in TGF-alpha/c-myc transgenic hepatocytes versus either wild type or c-myc single transgenic cells, and occurred in parallel with an increase in lipid peroxidation. Concomitantly with a rise in oxidant levels, antioxidant defenses were decreased, including total glutathione content and the activity of glutathione peroxidase, whereas thioredoxin reductase activity was not changed. However, hepatic tumors which developed in TGF-alpha/c-myc mice exhibited an increase in thioredoxin reductase activity and a very low activity of glutathione peroxidase. Furthermore, specific deletions were detected in mtDNA as early as 5 weeks of age in the transgenic mice. These data provide experimental evidence that co-expression of TGF-alpha and c-myc transgenes in mouse liver promotes overproduction of reactive oxygen species and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-alpha/c-myc mouse model.

Animals↗
PubMed2001

Cellular changes in motoneurons in a transgenic mouse model for amyotrophic lateral sclerosis as revealed by monoclonal antibody Py.

Transgenic mice (G93A) carrying the human amyotrophic lateral sclerosis (ALS) linked superoxide dismutase 1 (SOD1) mutations develop a motoneuron disease resembling human ALS. The affected motoneurons are characterized by the presence of cellular alterations. The antigen recognized by the monoclonal antibody Py is suggested to be associated with the neurofilamentous and microtubular elements of the cytoskeleton of specific neuron populations including the spinal motoneurons. The aim of the present study was to measure changes in the relative Py-immunoreactivity per identified Choline-Acetyl-Transferase (ChAT)-immunoreactive motoneuron during the disease progression. The relative Py-immunoreactivity of identified spinal motoneurons was measured on double stained (Py and ChAT) motoneurons using a digital imaging system coupled to an inverse microscope. A significant decrease of Py-immunoreactivity was already noted in the pre-symptomatic stages of the disease even before the onset of massive motoneuron degeneration. It is concluded that the Py-antibody detects early intracellular abnormalities related to neurodegenerative changes in spinal motoneurons of transgenic SOD1-(G93A) mice.

Amyotrophic Lateral Sclerosis↗
PubMed1992

Characterization of the ELSV transgenic mouse model of pancreatic carcinoma. Histologic type of large and small tumors.

Carcinomas of the pancreas that developed in Tg(Ela-1, SV40E)Bri18 and Tg(Ela-1, SV40E+Ela-1, neo)Bri19 strains of transgenic mice were classified into eight histologic patterns. Most were variants of acinar cell carcinoma, but cystic and undifferentiated carcinomas were found. The spectrum of phenotypes was similar in small and large carcinomas, but the small group included a higher fraction of well-differentiated tumors and fewer poorly differentiated and anaplastic tumors. The incidence of islet cell tumors was far higher in the Bri18 strain (77%) than in the Bri19 strain (1.6%). Islet cell hyperplasia was much more prevalent in Bri18 than Bri19 mice. In both strains, the nontumorous pancreas showed acinar cell dysplasia with a more abnormal and distinctive pattern in the Bri19 strain. While the spectrum of exocrine tumor phenotypes is similar, significant differences occurred between these two transgenic mouse strains as models for pancreatic carcinogenesis.

Adenoma, Islet Cell↗
PubMed2004

Transgenic mouse models of Alzheimer's disease: how useful have they been for therapeutic development?

Transgenic mice have been created in an attempt to generate models of human Alzheimer's disease, but success has been partial and unpredictable. The overall aim of this paper is to illustrate how genomics can be used in translational research, turning genetic information in the form of pathogenic mutations into clinically useful drugs against a major human disease. This paper will illustrate how genetic information allows researchers to dissect the aetiology of a disease and then replicate the disease in vivo through the process of transgenesis. The limitations of recreating a condition like Alzheimer's disease in a transgenic mouse, how far the mice have advanced understanding of the disease and how useful they have been for the development of therapeutics will then be discussed.

Alzheimer Disease↗
PubMed1993

Transgenic mouse models of vasopressin expression.

Arginine vasopressin is a nine-amino acid neuropeptide hormone important in the regulation of water metabolism. It also may have a role in other physiological functions, such as blood pressure regulation and the response to stress. Whole animal studies have provided a good understanding of vasopressin physiology and regulation of the normal vasopressin gene, and in vitro cell culture studies have demonstrated important features of the intracellular regulation of vasopressin gene expression. Transgenic mice provide useful models for the study of the in vivo regulation of gene expression. Previously reported mouse lines transgenic with vasopressin gene constructs have not expressed the transgene in a tissue distribution similar to that detected for the endogenous mouse vasopressin gene. An 8.2-kb genomic construct of the rat vasopressin gene, including 3 kb each of 5' and 3' flanking sequences, has been used to develop a line of transgenic mice. These animals express the transgene in a tissue-specific manner, demonstrate appropriate osmotic regulation of transgenic vasopressin mRNA, and have normal water metabolism. Animals homozygous for the 8.2-kb transgene have increased basal plasma levels of vasopressin peptide but have no apparent change in basal water metabolism. The findings with this and other previously reported mouse lines transgenic for vasopressin constructs provide a basis for developing future transgenic lines to study the in vivo regulation of the vasopressin gene.

Animals↗
PubMed1996

Transgenic mouse models of sickle cell disease.

An array of sickle cell syndromes has been obtained in transgenic mice, expressing HbS or super HbS, from the asymptomatic phenotype similar to the human A/S state to a syndrome more severe than the human homozygous S/S state, inducing 100% fetal death. Anemia was observed in SAD and SAD (beta th/ beta +) neonates and disappeared during postnatal development. In adults, many features of sickle cell disease are found in transgenic mice, especially in SAD and SAD (beta th/ beta +) mice, including abnormal hemolysis, vasoocclusion, microthrombosis, infarct, priapism, chronic organ defects, and death on hypoxia. These mouse models are relevant to the study of the pathophysiology of sickle cell disease and the induction of vasoocclusion and to evaluate new therapeutic approaches in vivo. Clotrimazole and Mg2+ restore hydration of sickle cells and 12 C79 protected SAD mice from lethal acute hypoxia.

Anemia, Sickle Cell↗
PubMed2004

Visualization of beta-amyloid plaques in a transgenic mouse model of Alzheimer's disease using MR microscopy without contrast reagents.

The visualization of beta-amyloid plaque deposition in brain, a key feature of Alzheimer's disease (AD), is important for the evaluation of disease progression and the efficacy of therapeutic interventions. In this study, beta-amyloid plaques in the PS/APP transgenic mouse brain, a model of human AD pathology, were detected using MR microscopy without contrast reagents. beta-Amyloid plaques were clearly visible in the cortex, thalamus, and hippocampus of fixed brains of PS/APP mice. The distribution of plaques identified by MRI was in excellent agreement with those found in the immunohistological analysis of the same brain sections. It was also demonstrated that image contrast for beta-amyloid plaques was present in freshly excised nonfixed brains. Furthermore, the detection of beta-amyloid plaques was achieved with a scan time as short as 2 hr, approaching the scan time considered reasonable for in vivo imaging.

Alzheimer Disease↗
PubMed2003

The TNF-alpha transgenic mouse model of inflammatory arthritis.

Rheumatoid arthritis is a chronic inflammatory disorder that affects multiple peripheral joints. It is the most common form of inflammatory arthritis and is characterized by synovial hyperplasia, immune cell infiltration, cartilage destruction, and bone erosion. To gain insight into the etiology of the disease, a variety of animal models have been established. Twelve years ago George Kollias' laboratory generated a transgenic (Tg) mouse that over-expresses human TNF-alpha, and develops an erosive polyarthritis with many characteristics observed in rheumatoid arthritis patients. The phenotype of this mouse model validated the theory that TNF-alpha is at the apex of the pro-inflammatory cascade in rheumatoid arthritis, and foreshadowed the remarkable success of anti-TNF-alpha therapy that has transformed the effective management of this disease. As such, the TNF-Tg mice are very useful tools for dissecting the molecular mechanisms of the pathogenic process and evaluating the efficacy of novel therapeutic strategies for rheumatoid arthritis. In this review we (1) provide a brief summary of TNF-alpha biology and the role of this dominant cytokine in rheumatoid arthritis, (2) describe the various TNF-Tg models and their phenotypes, and (3) give examples of how this model has been used experimentally.

Angiogenesis Inhibitors↗
PubMed2005

Transgenic mouse models for APP processing and Alzheimer's disease: early and late defects.

Transgenic mice with neuronal expression of human AD-mutant APP[V7171] in their brain recapitulate robustly the amyloid pathology as seen in Alzheimer's disease (AD) patients. The AD related pathological phenotype consisting of amyloid plaques and vascular amyloid pathology, develop progressively and relative late in ageing APP transgenic mice, between 10 and 15 months of age. In contrast to the late - and clinically irrelevant - amyloid plaque-pathology, the early cognitive defects and behavioural features are clinically more interesting. This review discusses the generation and in depth phenotypic characterization of both aspects of the APP[V7171] transgenic mice. Attention is focussed on the relation of biochemical data of the different APP fragments and amyloid peptides to the formation of the typical early defects and the late parenchymal and vascular amyloid depositions. The APP[V7171] transgenic mice are a perfect model to characterize and investigate early biochemical and cognitive aspects and a potential resource to define pathological interactions of different factors known to be involved in AD. Finally, any therapeutic intervention can be directly tested and explored in these transgenic mice as excellent pre-clinical models.

Alzheimer Disease↗
PubMed1992

Effect of serum amyloid P component level on transthyretin-derived amyloid deposition in a transgenic mouse model of familial amyloidotic polyneuropathy.

To elucidate the pathogenesis of amyloid deposition associated with familial amyloidotic polyneuropathy (FAP), we developed several transgenic mouse lines carrying the human mutant transthyretin (TTR) gene. We found that human TTR and mouse serum amyloid P component (SAP) are deposited as amyloid in tissues of these mouse lines. Because SAP is a major acute-phase reactant in mice, we asked whether repeated injections of Escherichia coli lipopolysaccharide (LPS) would enhance the amyloid deposition in one of these transgenic mouse lines. During the course of repeated LPS injections, serum levels of SAP in the transgenic mice remained between severalfold to about 50-fold higher than seen in the absence of stimulation. As no significant difference was detected in the onset, progression, and tissue distribution of TTR-derived amyloid (ATTR) deposition between the LPS-stimulated and unstimulated transgenic mice, the induction of SAP synthesis by acute inflammation probably does not affect the onset and extent of ATTR deposition.

Amyloid↗
PubMed2002

Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model.

Age-related macular degeneration (AMD) is the major cause of blindness in the developed world. Its pathomechanism is unknown and its late onset, complex genetics and strong environmental components have all hampered investigations. Here we demonstrate the development of an animal model for AMD that reproduces features associated with geographic atrophy; a transgenic mouse line (mcd/mcd) expressing a mutated form of cathepsin D that is enzymatically inactive thus impairing processing of phagocytosed photoreceptor outer segments in the retinal pigment epithelial (RPE) cells. Pigmentary changes indicating RPE cell atrophy and a decreased response to flash electroretinograms were observed in 11- to 12-month-old mcd/mcd mice. Histological studies showed RPE cell proliferation, photoreceptor degeneration, shortening of photoreceptor outer segments, and accumulation of immunoreactive photoreceptor breakdown products in the RPE cells. An accelerated photoreceptor cell death was detected in 12-month-old mcd/mcd mice. Transmission electron microscopy demonstrated presence of basal laminar and linear deposits that are considered to be the hallmarks of AMD. Small hard drusen associated with human age-related maculopathy were absent in the mcd/mcd mouse model at the ages analyzed. In summary, this model presents several features of AMD, thus providing a valuable tool for investigating the underlying biological processes and pathomechanism of AMD.

Aging↗
PubMed2006

DNA-based immunization breaks tolerance in a hepatitis C virus transgenic mouse model.

Chronic hepatitis C infection (HCV) is associated with high morbidity and mortality due to limited treatment options. HCV transgenic mice can be used as surrogate model of chronic HCV infection and may therefore be a small animal model for the evaluation of therapeutic vaccination strategies. We immunized transgenic mice expressing HCV structural proteins with an HCV core and a mouse IL-2 expression plasmid to study the cellular and humoral immune responses. DNA-based immunization induced a significant CD4+ T cell proliferative response and a CD8+ cytotoxic T cell response. Only low amounts of anti-HCV core antibodies were detected after genetic immunization. No liver damage was observed in the liver of immunized mice despite low level HCV core transgene expression and the presence of peripheral cellular immunity. These results demonstrate that DNA-based immunization may result in activation of previously tolerant T cells and is therefore a promising approach for treatment of chronic HCV infection.

Animals↗
PubMed1993

Ph-positive leukemia: a transgenic mouse model.

The presence of the BCR/ABL chimeric gene is the hallmark of defined types of human leukemia. To increase our knowledge of the oncogenic processes and to develop a model for this type of leukemia we generated a BCR/ABL (P190) transgenic mouse line. Over 95% of mice of this line die of leukemia or leukemia/lymphoma within 35-200 days of age. Karyotypically visible genetic alterations were absent from the early stages of BCR/ABL generated leukemia. A high frequency of aneuploidy was found in advanced leukemia indicating a primary and pivotal role for BCR/ABL in leukemogenesis. Moreover, the data suggest that BCR/ABL has a destabilizing effect on the regulation of the cell cycle. BCR/ABL expression was also found in tissues other than hematopoietic cells. However, this did not result in the development of solid tumors, strongly suggesting that the oncogenicity of BCR/ABL is limited to the hematopoietic lineage.

Animals↗