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PubMed2005

Virosome-based active immunization targets soluble amyloid species rather than plaques in a transgenic mouse model of Alzheimer's disease.

Active vaccination with amyloid peptides shows promise for the treatment and prevention of Alzheimer's disease (AD). Several studies in transgenic mouse models of AD have revealed the potency of vaccination to prevent or even clear amyloid plaques from mouse brain. However, the idea that soluble oligomeric species of beta-amyloid (Abeta), rather than plaques, trigger the disease has gained momentum, and current active vaccination strategies affect the levels of total or soluble brain Abeta little or not at all. We describe an active vaccination method based on Abeta1-16 presented on the surface of virosomes, which triggered a dramatic decrease in both soluble Abeta40 (75% reduction; p=0.01) and soluble Abeta42 (62% reduction; p=0.03) in a double transgenic mouse model of AD. Whereas Abeta40 and Abeta42 levels in the insoluble fraction tended to be reduced (by 30% and 27%, respectively), the number of thioflavine-S-positive amyloid plaques was not affected. The high specific antibody responses, obtained without eliciting T-cell reactivity, demonstrate that immunostimulating reconstituted influenza virosomes are a promising antigen carrier system against the neuropathology of AD.

Alzheimer Disease↗
PubMed2001

Transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by a progressive loss of cognitive function. Despite considerable progress, a complete description of the molecular pathology of this disease has yet to be elucidated. In this respect, the need for an animal model that develops some or all aspects of this uniquely human disease in a reproducible fashion is crucial for the development and testing of potential treatments. A valid animal model for AD should exhibit (1) progressive AD-like neuropathology and (2) cognitive deficits, and (3) should be verified in several laboratories. Transgenic models should be able to (4) discern pathogenic effects of familial forms (FAD) mutations from those of transgene overexpression. Models derived from microinjection of FAD mutant alleles should (5) encompass more than one Tg line. At present, however, no model that replicates all of these desirable features exists. In this review, we discuss transgenic mouse models with well-characterized AD-like neuropathology that show some form of cognitive impairment. We argue that conclusions drawn from a limited selection of cross-sectional experiments should be verified in longitudinally designed experiments. Future studies should attempt to establish a closer relationship between molecular pathology and the degree of cognitive impairment. While exact replication of AD in mice may not attainable (due to phylogenetic differences and fundamental differences in behavioral ecology), rigorous comparative analysis of cognitive behavior observed in various mouse models of AD should provide a framework for better understanding of molecular mechanisms underlying cognitive impairment observed in AD patients.

Aged↗
PubMed2001

A novel mouse model of lipotoxic cardiomyopathy.

Inherited and acquired cardiomyopathies are associated with marked intracellular lipid accumulation in the heart. To test the hypothesis that mismatch between myocardial fatty acid uptake and utilization leads to the accumulation of cardiotoxic lipid species, and to establish a mouse model of metabolic cardiomyopathy, we generated transgenic mouse lines that overexpress long-chain acyl-CoA synthetase in the heart (MHC-ACS). This protein plays an important role in vectorial fatty acid transport across the plasma membrane. MHC-ACS mice demonstrate cardiac-restricted expression of the transgene and marked cardiac myocyte triglyceride accumulation. Lipid accumulation is associated with initial cardiac hypertrophy, followed by the development of left-ventricular dysfunction and premature death. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cytochrome c release in transgenic hearts suggest that cardiac myocyte death occurs, in part, by lipid-induced programmed cell death. Taken together, our data demonstrate that fatty acid uptake/utilization mismatch in the heart leads to accumulation of lipid species toxic to cardiac myocytes. This novel mouse model will provide insight into the role of perturbations in myocardial lipid metabolism in the pathogenesis of inherited and acquired forms of heart failure.

Animals↗
PubMed1997

Demonstration of two different processes of beta-cell regeneration in a new diabetic mouse model induced by selective perfusion of alloxan.

To clarify the regeneration process of pancreatic beta-cells, we established a new mouse model of diabetes induced by selective perfusion of alloxan after clamping the superior mesenteric artery. In this model, diabetes could be induced by the destruction of beta-cells in alloxan-perfused segments, while beta-cells in nonperfused segments were spared. Intraperitoneal glucose tolerance tests showed glucose intolerance, which gradually ameliorated and was completely normalized in 1 year with a concomitant increase of insulin content in the pancreas. Histological examination showed neo-islet formation in the alloxan-perfused segment and the proliferation of spared beta-cells in the nonperfused segment. In the alloxan-perfused segment, despite a marked reduction of islets in size and number at an early stage, both the number of islets, including islet-like cell clusters (ICCs), and the relative islet area significantly increased at a later stage. Increased single beta-cells and ICCs were located in close contact with duct cell lining, suggesting that they differentiated from duct cells and that such extra-islet precursor cells may be important for beta-cell regeneration in beta-cell-depleted segment. In addition to beta-cells, some nonhormone cells in ICCs were positive for nuclear insulin promoter factor 1, which indicated that most, if not all, nonhormone cells positive for this factor were beta-cell precursors. In the nonperfused segment, the islet area increased significantly, and the highest 5-bromo-2-deoxyuridine-labeling index in beta-cells was observed at day 5, while the number of islets did not increase significantly. This indicated that the regeneration of islet endocrine cells occurs mostly through the proliferation of preexisting intra-islet beta-cells in the nonperfused segment. In conclusion, the regeneration process of beta-cells varied by circumstance. Our mouse model is useful for studying the mechanism of regeneration, since differentiation and proliferation could be analyzed separately in one pancreas.

Alloxan↗
PubMed2005

Behavioral assessment in mouse models of neuronal ceroid lipofuscinosis using a light-cued T-maze.

Learning impairment is a common feature of the neuronal ceroid lipofuscinoses (NCL), a family of lysosomal storage disorders associated with progressive neurodegeneration. Murine models for the neuronal ceroid lipofuscinoses include the well-characterized motor neuron degeneration (mnd/mnd) model for one variant of late infantile NCL (CLN8), and the more recently generated models for the infantile (CLN1) and juvenile (CLN3) forms of NCL. To determine whether these mouse models exhibit behavioral deficits analogous to the learning impairment characteristic of the human disorders, the performance of these animals on an associative learning task was assessed. The abilities of affected and normal control mice to associate a light stimulus with a food reward were evaluated in 14-16-week-old animals using a T-maze. Normal mice were able to reach a criterion for having learned to make the association within a mean of 9.4 trials. The CLN8 and CLN3 mice, on the other hand, required means of 26.2 and 27.5 trials, respectively, to reach the same performance criterion (p<0.05), whereas none of the CLN1 mice were able to reach the criterion within a limit of 30 trials. The poor performance of the mutant mice did not appear to result from impaired retinal function; mice of all three strains exhibited retinal electrophysiological responses to dim light flashes and displayed robust pupillary light reflexes. Associative learning deficits appear to be an early disease phenotype in the NCL mouse models that will be useful for assessing the efficacy of therapeutic interventions such as gene or stem cell therapies.

Analysis of Variance↗
PubMed1999

A mouse model utilising human transferrin to study protection against Neisseria meningitidis serogroup B induced by outer membrane vesicle vaccination.

We have previously developed a mouse model based on transient bacteraemia in normal B10.M mice to evaluate the protective efficacy of outer membrane vesicle vaccines against serogroup B meningococci. To obtain a course of infection similar to that observed in man, we have in this work modified the mouse model by administration of human holo-transferrin upon bacterial challenge. Co-challenge with holo-transferrin induced increasing bacteraemia and subsequent death in normal non-immune mice, but not in vaccinated animals. The model system is dependent on challenge with meningococci expressing the transferrin receptor which is obtained by culturing the bacteria under iron restriction. The modified model system for protection against meningococcal infection presented here makes it possible to measure outer membrane vesicle vaccine induced protection by using bacteraemia as well as survival as parameters.

Animals↗
PubMed2006

Examination of cancer in mouse models using high-frequency quantitative ultrasound.

Two mouse models of mammary cancer (a carcinoma and sarcoma) were examined using quantitative ultrasound (QUS). Scatterer property estimates, i.e., the average scatterer diameter (ASD) and average acoustic concentration (AAC), were estimated from regions-of-interest (ROIs) inside the tumors. Initially, the spherical Gaussian model was used over an analysis bandwidth of 10 to 25 MHz to obtain ASD and AAC estimates. ASD estimates were 31.7 +/- 9.36 microm and 31.0 +/- 7.20 microm for the carcinomas and sarcomas, respectively. AAC estimates were 6.77 +/- 8.75 dB[mm(-3)] and 9.87 +/- 9.24 dB[mm(-3)], respectively. The initial ASD and AAC estimates did not yield statistically significant differences between the two kinds of tumors (p = 0.83, 0.86 for the ASD and AAC estimates, respectively). However, optical photomicrographs revealed distinct morphologic differences between the tumors. F-tests on the average power spectra from the tumors revealed statistically significant differences between the spectra over the range of 16 to 25 MHz. ASD and AAC estimates using the spherical Gaussian model were then obtained over the new analysis bandwidth of 16 to 25 MHz. The new ASD estimates were 42.1 +/- 4.01 microm and 32.1 +/- 3.81 microm for the carcinomas and sarcomas, respectively. The new AAC estimates were 16.4 +/- 17.1 dB[mm(-3)] and 36.4 +/- 11.9 dB[mm(-3)], respectively. Statistically significant differences were observed for both the ASD and AAC estimates when using the new analysis bandwidth. Structural differences between the tumors were revealed by both QUS and optical photomicrographs.

Animals↗
PubMed1986

A mouse model for the study of necrotizing enterocolitis.

A mouse model for the study of necrotizing enterocolitis is presented. It is a model of temporary intestinal ischemia and consists of occluding both superior mesenteric vessels with a bulldog clamp for varying periods of time. The resultant lesions resemble the intestinal lesions seen in necrotizing enterocolitis in respect to the gradual development of the necrotizing lesions and their patchy distribution. We also studied the effect of intravenous saline and low molecular weight dextran in preventing the development of these ischemic lesions. In moderate ischemia, saline and dextran show a similar protective effect, and in severe ischemia, both show a protective effect, with dextran being more effective than saline.

Animals↗
PubMed2002

A mouse model of neuropathic cancer pain.

We developed a mouse model of neuropathic cancer pain by inoculating Meth A sarcoma cells to the immediate proximity of the sciatic nerve in BALB/c mice. The tumor grows predictably with time and gradually compresses the nerve, thereby causing nerve injury. Time courses of thermal hyperalgesia and mechanical sensitivity to von Frey hairs were determined and signs of spontaneous pain were evaluated. We compared this model with the chronic constriction injury (CCI) model, which is a neuropathic pain model widely utilized in the rat. Furthermore, to characterize the difference in nerve injury between the two models, we performed histological examination of the nerve of the two models by light and electron microscopy. Progressive compression of the sciatic nerve by growth of a tumor mass resulted in a gradual development of thermal hyperalgesia and mechanical allodynia in the ipsilateral hind paw. Signs of spontaneous pain, such as lifting of the paw, were also observed. However, further growth of the tumor reversed the mechanical hypersensitivity and produced mechanical hyposensitivity, while thermal hyperalgesia and signs of spontaneous pain still persisted. Histologically, gradual compression by the tumor resulted in a progressive damage to both myelinated and unmyelinated fibers. However, the severity of damage to the myelinated fibers was considerably less compared to that of the CCI mice. In the CCI mice, severe damage to myelinated fibers, especially large fibers, was observed and unmyelinated fibers were damaged to a lesser degree. These results suggest that gradual compression of a nerve by a malignant tumor results in nerve damage with a profile considerably different from that of chronic constriction injury produced by loose ligation of the nerve. Our new tumor model may be useful in studies of neuropathic cancer pain due to nerve compression by malignant tumors.

Animals↗
PubMed2000

SEREX analysis for tumor antigen identification in a mouse model of adenocarcinoma.

Evaluation of immunotherapy strategies in mouse models of carcinoma is hampered by the limited number of known murine tumor antigens (Ags). Although tumor Ags can be identified based on cytotoxic T-cell activation, this approach is not readily accomplished for many tumor types. We applied an alternative strategy based on a humoral immune response, SEREX, to the identification of tumor Ags in the murine colon adenocarcinoma cell line MC38. Immunization of syngeneic C57BL/6 mice with MC38 cells by three different methods induced a protective immune response with concomitant production of anti-MC38 antibodies. Immunoscreening of an MC38-derived expression library resulted in the identification of the endogenous ecotropic leukemia virus envelope (env) protein and the murine ATRX protein as candidate tumor Ags. Northern blot analysis demonstrated high levels of expression of the env transcript in MC38 cells and in several other murine tumor cell lines, whereas expression in normal colonic epithelium was absent. ATRX was found to be variably expressed in tumor cell lines and in normal tissue. Further analysis of the expressed env sequence indicated that it represents a nonmutated tumor Ag. Polynucleotide immunization with DNA encoding the env polypeptide resulted in strong and specific antibody responses to this self Ag in all immunized mice. Thus, SEREX offers a rapid means of identifying tumor Ags in murine cancer models.

Adenocarcinoma↗
PubMed2006

Inhibiting vascular endothelial growth factor receptor-2 signaling reduces tumor burden in the ApcMin/+ mouse model of early intestinal cancer.

The Apc(Min/+) mouse model is a clinically relevant model of early intestinal cancer. We used AZD2171, an oral, highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor, to investigate the role of VEGF receptor-2 (VEGFR-2) signaling in adenoma development and growth in Apc(Min/+) mice. AZD2171 (5 mg/kg body wt/day) was administered once daily for 28 days to 6-week-old (early-intervention) or 10-week-old (late intervention) mice. In the early-intervention study, AZD2171 reduced the number of macroscopic polyps in the small bowel and colon. Macropolyp diameter was lower in the small bowel, but remained unchanged in the colon. In animals receiving AZD2171, microscopic evaluation of the small intestine showed a significant reduction in the number of larger lesions. In the late-intervention study, AZD2171 treatment reduced macropolyp diameter (but not number) in the small intestine. Microscopic analysis revealed that AZD2171 significantly reduced the number of larger micropolyps in the small bowel, with no large micropolyps present in the colon. AZD2171 treatment had no effect on microvessel density or localization of beta-catenin staining in adenomas or non-tumor intestinal tissue, but significantly reduced the number of cells expressing VEGFR-2 mRNA. In conclusion, the effects of AZD2171 in the small intestine of Apc(Min/+) mice are consistent with an antiangiogenic mechanism of action, limiting growth of adenomas to < or =1 mm. These data also suggest that an early step in adenoma development may depend on VEGFR-2 signaling. Together, these results indicate that VEGFR-2 signaling may play key roles in the development and progression of intestinal adenomas.

Adenoma↗
PubMed2006

CCL27 is a critical factor for the development of atopic dermatitis in the keratin-14 IL-4 transgenic mouse model.

The keratin-14 IL-4 transgenic (Tg) mouse model of atopic dermatitis (AD) is characterized by skin infiltration of T cells, early up-regulation of T(h)2 cytokines and late surge of T(h)1 cytokines. In the present study, we investigated the role of CCL27, a T cell skin-homing chemokine known to be elevated in sera of human AD patients, in disease development in our animal model of AD. The results showed that the mRNA and protein levels of CCL27 in the skin and serum were significantly increased in IL-4 Tg mice. The percentage of T cells expressing CCR10 in skin draining lymph nodes of IL-4 Tg mice was increased, consistent with the findings of >80% of skin-infiltrating T cells in Tg mice expressing CCR10. Chemotaxis transmigration assay demonstrated that CCL27 promotes a greater degree of migration of T cells in diseased Tg mice. Subcutaneous injection of neutralizing anti-CCL27 to IL-4 Tg mice with early skin lesions resulted in reduced clinical progression of inflammation, accompanied with decreased T cell and mast cell infiltration in the skin, and down-regulation of inflammatory cytokines. In conclusion, CCL27 and CCR10 interaction is important for the development of skin inflammation in our AD model.

Animals↗
PubMed2006

Botulinum toxin B-induced mouse model of keratoconjunctivitis sicca.

PURPOSE: To develop a mouse model of human chronic dry eye (keratoconjunctivitis sicca [KCS]). METHODS: Under direct visualization with an operating microscope, CBA/J mice received a transconjunctival injection of saline or 1.25, 5, or 20 milliunits (mU) of botulinum toxin B (BTX-B) into the lacrimal gland. The mice were either left unstressed or were subjected to an air blower for 5 h/d, 5 d/wk in fixed temperature and humidity conditions. Tear production and corneal fluorescein staining were evaluated in all groups before injection and at several time points after. Tear production was measured with phenol red-impregnated cotton threads. Corneal fluorescein staining was photographed under cobalt blue light with a digital camera fitted with a macro lens. RESULTS: BTX-B-injected mice displayed significantly decreased tear production until the 4-week time point. Throughout all time points, the addition of environmental blower stress did not appear to alter tear production significantly. Linear regression models, used to evaluate the effects of various doses of BTX-B on tear production, showed that doses higher than 1.25 mU did not provide significantly different outcomes. After 3 days, saline-injected mice showed no corneal staining, whereas BTX-B-injected mice displayed various amounts of staining. At the early time point (day 3), there did not appear to be an additional effect of the blower on corneal fluorescein staining. However, at 1, 2, and 4 weeks, the blower stress appeared to increase the amount of corneal fluorescein staining at each BTX-B dose, although not significantly. Furthermore, at 8 to 10 weeks, in the BTX B-injected groups, corneas had persistent staining, even though tear production had already returned to normal levels. Histopathologic analyses revealed no inflammatory cell infiltration of the stroma or acini of the lacrimal glands and conjunctivae of both saline-injected and BTX-B-injected animals. CONCLUSIONS: Intralacrimal gland injection of BTX-B resulted in persistent corneal fluorescein staining within 3 days, and a significant decrease in aqueous tear production that persisted for 1 month. Intralacrimal gland injection of BTX-B suppressed lacrimation, thereby establishing a dry eye state. This animal model could be a useful tool for investigating the pathogenesis of the chronic condition KCS in humans.

Animals↗
PubMed1999

Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease.

We used two mouse models of Huntington's disease (HD) to examine changes in glutamate receptor sensitivity and striatal electrophysiology. One model, a transgenic, consisted of mice expressing exon 1 of the human HD gene and carrying 141-157 CAG repeat sequences (R6/2 line). The second model, a CAG repeat "knockin," consisted of mice with different lengths of CAG repeats (CAG71 and CAG94 repeats). The effects of glutamate receptor activation were examined by visualizing neurons in brain slices with infrared videomicroscopy and differential interference contrast optics to determine changes in somatic area (cell swelling). Striatal and cortical neurons in both models (R6/2 and CAG94) displayed more rapid and increased swelling to N-methyl-D-aspartate (NMDA) than those in controls. This effect was specific as there were no consistent group differences after exposure to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate (KA). Intracellular recordings revealed that resting membrane potentials (RMPs) in the R6/2 transgenics were significantly more depolarized than those in their respective controls. RMPs in CAG94 mice also were more depolarized than those in CAG71 mice or their controls in a subset of striatal neurons. Confirming previous results, R6/2 mice expressed behavioral abnormalities and nuclear inclusions. However, CAG71 and CAG94 knockins did not, suggesting that increased sensitivity to NMDA may occur early in the disease process. These findings imply that NMDA antagonists or compounds that alter sensitivity of NMDA receptors may be useful in the treatment of HD.

Animals↗
PubMed1992

A mouse model of coxsackievirus myocarditis.

OBJECTIVE: To develop a mouse model of coxsackievirus B3 (CVB3) myocarditis. DESIGN: Preliminary studies have indicated that mice infected with CVB3 alone erratically responded with viral myocarditis. Prospective evaluation of the effect of cyclophosphamide at two time intervals resulted in consistency for the development of myocarditis. ANIMALS: Juvenile five- to nine-week-old male mice CD-1 type (Charles River Canada Limited). INTERVENTIONS: Infection with coxsackie B3 enterovirus. Pretreatment with cyclophosphamide two days and 4 h before inoculation of 0.2 or 0.15 mg/g. Animals were killed seven, nine, 28 and 63 days post infection. MAIN RESULTS: Following cyclophosphamide conditioning, a tissue response infection with CVB3 was uniformly observed. Virus, however, was infrequently recovered from the myocardium whereas myocarditis became chronic after 28 days. CONCLUSIONS: Pretreatment of juvenile mice with cyclophosphamide results in a reproducible model of viral myocarditis with chronic changes in the myocardium.

Animals↗
PubMedDate not supplied

Evaluation of the neurotoxicity of dapsone in the mouse model.

Effect of DDS was studied using the mouse model. It was observed that DDS did not have any neurotoxic effect. On the contrary it showed a protective action towards the nerve, when administered in the early stages following definite establishment of nerve lesions.

Animals↗
PubMedDate not supplied

Orthotopic SCID mouse model with two newly established human lung squamous carcinoma cell lines.

The objective of this study was to present an orthotopic SCID mouse model using two newly established human cell lines derived from squamous cell carcinomas of the lung. GO-LCC1 cells (1 x 10(6)) and GO-LCC2 cells (3 x 10(6)) were implanted orthotopically into the right lungs of 10 C.B. 17 scid/scid mice. In both groups, aggressive tumor growth with partial infiltration of the thoracic wall, heart and diaphragm was observed. In only one case distant metastases in the contralateral lung were detected, while all animals developed tumors at the site of inoculation. Xenografted GO-LCC1 cells showed enhanced tumor propagation compared to GO-LCC2 cells. Our data underscore the usefulness of the SCID mouse model to study the biological behaviour of cultuved human tumor cells and furthemore demonstrate the clinical applicability of xenograft techniques using human tumor cell lines derived from pneumonectomy specimens of squamous lung carcinomas.

Animals↗
PubMed2006

Determination of human transferrin concentrations in mouse models of neisserial infection.

Transferrin constitutes the major protein involved in the transport of iron from the sites of absorption to the sites of storage and utilization. Despite the high affinity of transferrin for iron, most bacterial pathogens, such as the human restricted Neisseria meningitidis, have developed iron acquisition mechanisms. Several animal models of bacterial infection that include the exogenous supply of human transferrin have been implemented, and tests using transgenic mouse models are underway. Here we describe an ELISA sandwich procedure based on two monoclonal antibodies with negligible cross-reactivity to murine transferrin, to estimate human transferrin concentrations in mouse sera. The assay can detect as little as 10 ng/ml of human transferrin with coefficients of variation ranging from 1.6% to 4.4% (intra-assay) and 3.8% to 5% (inter-assay). The recovery values range from 90% to 110% in the assay working range (25-400 ng/ml). Human transferrin concentrations estimated in sera from 41 human transferrin transgenic mice ranged from 2 to 14 microg/ml. Further estimations of human transferrin levels in mouse sera of a previously described mouse model of N. meningitidis were also carried out. The intraperitoneal injection of 8 mg of human transferrin achieved a sustained value of human transferrin in mouse sera in the range of 1-2mg/ml over the first 24h, indicating that bacteria reaching the blood stream during this time would be exposed to levels of hTf found in normal human serum.

Animals↗