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PubMed1999

Assembly of paired helical filaments from mouse tau: implications for the neurofibrillary pathology in transgenic mouse models for Alzheimer's disease.

In Alzheimer's disease and related dementias, human tau protein aggregates into paired helical filaments and neurofibrillary tangles. However, such tau aggregates have not yet been demonstrated in transgenic mouse models of the disease. One of the possible explanations would be that mouse tau has different properties which prevents it from aggregating. We have cloned several murine tau isoforms, containing three or four repeats and different combinations of inserts, expressed them in Escherichia coli and show here that they can all be assembled into paired helical filaments similar to those in Alzheimer's disease, using the same protocols as with human tau. Therefore, the absence of pathologically aggregated tau in transgenic mice cannot be explained by intrinsic differences in mouse tau protein and instead must be explained by other as yet unknown factors.

Alzheimer Disease↗
PubMed2006

Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease.

PURPOSE: Autosomal dominant Stargardt-like (STGD3) disease results from mutations in the ELOVL4 gene (elongation of very-long-chain fatty acids). This study was undertaken to characterize a mouse model with a targeted deletion of Elovl4 and to explore the role of this gene in retinal/macular degeneration. METHODS: A construct targeted to exon 2 of the Elovl4 gene was used to suppress expression of the gene. Elovl4 homozygous pups were nonviable and were not available for study. Hence, the analysis was performed on heterozygous Elovl4(+/-) mice 16 to 22 month of age and littermate wild-type (WT) control mice of the same age. Characterization included examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition. RESULTS: Although the level of Elovl4 mRNA was reduced in Elovl4(+/-) retinas, only minimal morphologic abnormalities were found, and the retinal (ERG) function was essentially normal in Elovl4(+/-) retinas compared with the WT control retinas. Systemic fatty acid profiles of Elovl4(+/-) mice were unremarkable, although the concentration of several fatty acids was significantly lower in Elovl4(+/-) retinas, particularly the monounsaturated fatty acids. CONCLUSIONS: The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.

Animals↗
PubMed2001

N-chlorotaurine, a novel endogenous antimicrobial agent: tolerability testing in a mouse model.

OBJECTIVE: To investigate the tolerability of N-chlorotaurine, a new antimicrobial agent, by application to the middle ear in a mouse model. METHODS: Five BALB/c mice were each injected through the tympanic membrane with 5 microL of 0.1%, 1.0%, and 10% N-chlorotaurine and compared with animals in which 0.9% isotonic sodium chloride solution, 0.2% gentamicin sulfate, and 0.25% trimethyltin chloride were instilled. Auditory brainstem responses to clicks were evaluated repeatedly between 4 and 75 days after injection, and histologic investigations of the inner ear were performed subsequently. Three additional groups of mice were injected with isotonic sodium chloride solution, 1.0% N-chlorotaurine, and 0.25% trimethyltin, and brainstem responses to tone bursts of 8, 16, and 32 kHz were tested. In addition, the middle ear was examined histologically. RESULTS: Mice treated with isotonic sodium chloride solution, 0.1% N-chlorotaurine, and 0.2% gentamicin sulfate did not show changes in response threshold. Treatment with 1.0% and 10% N-chlorotaurine caused a reversible increase in auditory brainstem response threshold by 20 dB 4 days after application because of local irritation around the perforation of the tympanic membrane. In contrast, 0.25% trimethyltin showed a permanent elevation of auditory brainstem response threshold of 10 to 15 dB and a scattered loss of outer hair cells predominantly in the apical turn. No alterations of the inner ear were observed in the other treatment groups. The mucous membrane of the middle ear remained unaffected in all test groups. CONCLUSION: Application of N-chlorotaurine to the middle ear is well tolerated without adverse effects and may be a useful new endogenous antimicrobial agent for local treatment of otologic infections.

Animals↗
PubMed2006

Development of a mouse model of ethanol addiction: naltrexone efficacy in reducing consumption but not craving.

The aim of the present study was validating pharmacologically a mouse model of alcohol addiction. Mice (n = 60) were offered ethanol (5% and 10%) and water in a free choice paradigm consisting of four phases: free choice (10 weeks), withdrawal (2 weeks), re-exposure (2 weeks) and quinine- adulteration (2 weeks). Control mice (n = 10) had access to water. They were housed individually with food ad libitum. The animals' behaviour was evaluated at the beginning of the treatment and during the withdrawal period. After the exposure to the model, mice received i.p. naltrexone (0.0; 0.125; 2.0 and 16.0 mg/kg) or saline. Mice were characterized as: addicted (n = 15, preference for ethanol without reducing intake when ethanol were adulterated with quinine); heavy drinker (n = 14, preference for ethanol but reduced intake when ethanol were adulterated); and light drinker (n = 16, no preference for ethanol). Naltrexone reduced ethanol intake in the heavy and light groups (p <or= 0.01 and p <03= 0.05, respectively, compared to saline-treated group) with no effect on water intake. It is discussed that naltrexone may be acting in the positive reinforcing properties of ethanol but does not seem to have anti-craving properties. It was concluded that the addicted mice had a compulsive behavior manifested by the continued ethanol intake even under aversive conditions and under naltrexone treatment suggesting that this model might be useful to study addiction.

Alcoholism↗
PubMed2006

A mouse model of sensorimotor controlled cortical impact: characterization using longitudinal magnetic resonance imaging, behavioral assessments and histology.

The present study establishes a new mouse model for traumatic brain injury (TBI), using an electromechanically driven linear motor impactor device to deliver a lateral controlled cortical impact (CCI) injury to the sensorimotor cortex. Lesion cavity size was measured, and inter-animal consistency demonstrated, at 14 days post injury. Qualitative information regarding damage progression over time was obtained by scanning with high field magnetic resonance imaging (MRI) at five time points following injury. Functional impairment and recovery were measured with the Rotarod, gridwalk and cylinder tests, and lesion cavity volume was measured post mortem with thionin-stained tissue sections. The study establishes the reliability of a linear-motor based device for producing repeatable damage in a CCI model, demonstrates the power of longitudinal MRI in studying damage evolution, and confirms that a simple battery of functional tests record sensorimotor impairment and recovery.

Animals↗
PubMed2005

Induction of protective immunity by Legionella pneumophila flagellum in an A/J mouse model.

The capacity of a purified preparation of Legionella pneumophila flagella (FLA) to induce protective immune responses was studied in an A/J mouse model. Animals immunized with FLA promptly mounted an anti-FLA antibody response and also developed a strong activation of both innate and adaptive cell-mediated immunity, as shown by an early release of pro-inflammatory cytokines in the peritoneal cavity, and by a positive cutaneous delayed-type hypersensitivity reaction and in vitro splenic lymphocyte proliferation in response to FLA antigens. Mice treated with FLA either i.v. or i.p. also survived (100% rate) a lethal i.p. challenge with L. pneumophila. Protection induced by FLA lasted for at least 30 days after treatment, but less than 60, and was effective against the challenge with different serogroups of L. pneumophila. Resistance conferred by FLA immunization could be partially transferred to naïve animals by the adoptive transfer of immune splenocytes but not by passive immunization with anti-FLA iperimmune sera. The capacity to induce protective immunity was specifically attributable to flagellar components, as demonstrated by the lack of protection in mice immunized with a sham flagella preparation from a non-flagellated bacterial strain or with protease-digested FLA. In addition, heat-denatured FLA was inactive, suggesting loss of immunogenicity following denaturation. The present study provides evidence that L. pneumophila flagellum is strongly immunogenic and capable to stimulate, without adjuvants, early natural and acquired, T-cell-mediated immune responses and to induce significant protection against a lethal bacterial challenge in A/J mice. Antigenic characterization of this bacterial organelle and elucidation of mechanisms underlying flagella-induced protection would be of great value in understanding the immunopathogenesis of the disease and in developing possible therapeutic strategies for human legionellosis.

Adoptive Transfer↗
PubMed1995

Immunocytochemical location and hormonal control of androgen receptors in lacrimal tissues of the female MRL/Mp-lpr/lpr mouse model of Sjögren's syndrome.

Androgen therapy suppresses lymphocyte infiltration in, and improves the functional activity of, lacrimal glands in a female mouse model (MRL/Mp-lpr/lpr [MRL/lpr]) of Sjögren's syndrome. To extend these findings, the current investigation was designed to identify the cellular target(s) within lacrimal tissue that may mediate this androgen effect. In addition, we explored the endocrine regulation of androgen receptors in autoimmune lacrimal glands. Adult, female MRL/lpr mice were exposed systemically to vehicle, steroid hormones or immunosuppressive agents for varying time intervals after the onset of disease. Immediately before or after treatment, lacrimal glands were obtained and processed to determine the cellular distribution and nuclear density of androgen receptors by immunoperoxidase and image analysis techniques. Our findings demonstrated that: (1) androgen receptors exist almost exclusively within nuclei of acinar and ductal epithelial cells in lacrimal tissue of MRL/lpr mice; (2) androgen receptors are not detectable in the extensive lymphocytic populations that infiltrate the gland; (3) testosterone administration induces a significant increase in the number of androgen receptor-containing cells in, as well as the density of androgen receptors in epithelial cell nuclei of, lacrimal tissue; (4) hormone action is steroid-specific: administration of androgen analogues, but not estrogens, glucocorticoids or cyclophosphamide, stimulate the accumulation of androgen receptors; and (5) androgen receptor density is significantly reduced following the withdrawal of androgen therapy. These results show that epithelial cells, but not lymphocytes, are the androgen target cells in lacrimal tissue, and suggest that these cells may mediate the androgen-related immunosuppression and functional enhancement in lacrimal glands of autoimmune female mice. Our findings also demonstrate that androgens increase the expression of their own receptors in MRL/lpr lacrimal tissue.

Animals↗
PubMed2006

Acute trichinellosis increases susceptibility to Giardia lamblia infection in the mouse model.

The intestinal protozoan parasite Giardia lamblia causes diarrhoea in humans and animals. In the present study, we used the C57BL/6 inbred mouse model to assess the impact of a nematode (Trichinella spiralis) infection on the course of a G. lamblia (clone GS/M-83-H7) infection. Acute trichinellosis coincided with transient intestinal inflammation and generated an intestinal environment that strongly promoted growth of G. lamblia trophozoites although the local anti-Giardia immunoglobulin (Ig) A production was not affected. This increased G. lamblia infection intensity correlated with intestinal mast cell infiltration, mast cell degranulation, and total IgE production. Furthermore, a G. lamblia single-infection investigated in parallel also resulted in intestinal mast cell accumulation but severe infiltration was triggered in the absence of IgE. Recently, intestinal mast cells emerging during a G. lamblia infection were reported to be involved in those immunological mechanisms that control intestinal proliferation of the parasite in mice. This anti-giardial activity was assumed to be related to the capacity of mast cells to produce IL-6. However, this previous assumption was questioned by our present immunohistological findings indicating that murine intestinal mast cells, activated during a G. lamblia infection were IL-6-negative. In the present co-infection experiments, mast cells induced during acute trichinellosis were not able to control a concurrent G. lamblia infection. This observation makes it feasible that the T. spiralis infection created an immunological and physiological environment that superimposed the anti-giardial effect of mast cells and thus favoured intestinal growth of G. lamblia trophozoites in double-infected mice. Furthermore, our findings raise the possibility that intestinal inflammation e.g. as a consequence of a 'pre-existing' nematode infection is a factor which contributes to increased susceptibility of a host to a G. lamblia infection. The phenomenon of a 'pre-existing' nematode infection prior to a G. lamblia infection is a frequent constellation in endemic areas of giardiasis and may therefore have a direct impact on the epidemiological situation of the disease.

Animals↗
PubMed1988

Investigation of tumor angiogenesis in an id mouse model: role of host-tumor interactions.

The role of host-tumor interactions in tumor angiogenesis was studied in an id mouse model. Although many previous studies have described the effects of certain host factors (age, nutritional status, tumor location, etc.) on experimental tumor systems, the effects of these factors on tumor angiogenesis have not been reported. In preliminary studies we inoculated cloned tumor cells id into syngeneic mice and found positional differences in tumor growth that did not correlate with measured angiogenesis levels. In addition, while tumor growth was inhibited by radiation, tumor-induced (but not fibroblast-induced) angiogenesis was not. This id system may provide an assay not only for examining the effect of host factors on tumor angiogenesis, but also for elucidation of the mechanisms underlying neovascular induction and host response.

Animals↗
PubMed2005

Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(-) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model.

Alopecia areata (AA) is a suspected hair follicle specific autoimmune disease. The potential for cell transfer of AA using the C3H/HeJ mouse model was examined. Cells isolated from lymph nodes and spleens of AA-affected mice using magnetic bead conjugated monoclonal antibodies were subcutaneously injected into normal C3H/HeJ recipients. Within 5 wk, all CD8(+) cell-injected mice exhibited localized hair loss exclusively at the site of injection that persisted until necropsy. In contrast, some CD4(+) and CD4(+)/CD25(-) cell-injected mice developed extensive, systemic AA, and a combination of CD8(+) and CD4(+)/CD25(-) cells injected yielded the highest frequency of systemic AA induction. CD4(+)/CD25(+) cells were less able to transfer the disease phenotype, partially blockaded systemic AA induction by CD4(+)/CD25(-) cells, and prevented CD8(+) cell-induced, injection site-localized hair loss. CD11c(+) and CD19(+) cells failed to promote significant phenotype changes. Increases in co-stimulatory ligands CD40 and CD80, plus increased leukocyte apoptosis resistance with reduced CD95, CD95L, and CD120b expression, were associated with successful alopecia induction. The results suggest that CD8(+) cells may be the primary instigators of the hair loss phenotype. However, systemic disease expression fate is, apparently determined by CD4(+)/CD25(-) cells, while CD4(+)/CD25(+) lymphocytes may play a predominantly regulatory role.

Adoptive Transfer↗
PubMedDate not supplied

A clinically relevant orthotopic implantation nude mouse model of human epithelial ovarian cancer--based on consecutive observation.

The aim of this study is to establish an orthotopic implantation nude mouse model of epithelial ovarian cancer (EOC) and observe its biologic features. A human ovarian tumor line SKOV3ipl previously grown subcutaneously was implanted orthotopically as intact tissue into the ovarian capsule of 64 nude mice. Every week eight mice were taken randomly, and the tumor growth pattern and extent of metastatic disease were monitored continuously. Those mice that died of disease were necropsied and the end date was recorded. The orthotopic implanted tumors demonstrated a 100% take rate. Three weeks after implantation the tumors grew fast and weighed 1149 +/- 152 mg, and 5 weeks after implantation the tumors reached a flat stage. The tumors metastasized more often to peritoneum (32/56) and diaphragm (18/56), then to pelvic lymph nodes (11/56) and lung (10/56), and then to the seldom invaded organs including the pancreas, the liver, the contralateral ovary, and the para-aortic lymph node. Eight nude mice became exhausted 7 weeks after implantation and died within 68 days after implantation. Our study, utilizing the SKOV3ipl cell, is the first model of consecutive observation of the process of invasion and metastasis of EOC. It should be useful in understanding the molecular biology of EOC and in the development of therapeutic modalities against metastasis.

Animals↗
PubMed1997

Knockout-transgenic mouse model of sickle cell disease.

When transgenic mice that expressed human sickle hemoglobin were mated with mice having knockout mutations of the mouse alpha- and beta-globin genes, animals were produced that synthesized only human hemoglobin in adult red blood cells. Similar to many human patients with sickle cell disease, the mice developed a severe hemolytic anemia and extensive organ pathology. Numerous sickled erythrocytes were observed in peripheral blood. Although chronically anemic, most animals survived for 2 to 9 months and were fertile. Drug and genetic therapies can now be tested in this mouse model of sickle cell disease.

Anemia, Sickle Cell↗
PubMed1995

Evaluation of maduramicin and alborixin in a SCID mouse model of chronic cryptosporidiosis.

Two polyether ionophores, maduramicin and alborixin, were evaluated for anticryptosporidial activity in a severe combined immune deficient (SCID) mouse model of cryptosporidiosis. Groups of SCID mice were inoculated with 10(6) oocysts of bovine origin by oral gavage. Maduramicin or alborixin was administered beginning 4 weeks postinfection at 3 mg/kg of body weight per day. Maduramicin treatment resulted in a 96% reduction in fecal parasite load over the 3-week treatment period (P < 0.003). This reduction correlated with decreases in tissue parasite loads observed in histological sections of the small intestine (P < 0.000002) and the colon (P < 0.000006). A significant decrease in oocyst shedding was also observed after a 3-week treatment with alborixin (71% reduction, P < 0.01). Maduramicin was also evaluated in a relapsing model of cryptosporidiosis in which the infection was observed to recur after treatments were discontinued. Some toxicity, as demonstrated by weight loss, was observed with both maduramicin and alborixin. Both drugs exhibited significant anticryptosporidial activities with concomitant moderate toxicity. These polyether ionophores should be valuable as positive controls in compound evaluation studies and as lead compounds for chemical optimization (modification).

Animals↗
PubMed2000

Efficacy of FK463, a new lipopeptide antifungal agent, in mouse models of disseminated candidiasis and aspergillosis.

The efficacy of intravenous injection of FK463, a novel water-soluble lipopeptide, was evaluated in mouse models of disseminated candidiasis and aspergillosis and was compared with those of fluconazole (FLCZ) and amphotericin B (AMPH-B). In the candidiasis model, FK463 significantly prolonged the survival of intravenously infected mice at doses of 0.125 mg/kg of body weight or higher. In disseminated candidiasis caused by Candida species, including FLCZ-resistant Candida albicans, FK463 exhibited an efficacy 1.4 to 18 times inferior to that of AMPH-B, with 50% effective doses (ED(50)s) ranging from 0.21 to 1.00 mg/kg and 0.06 to 0.26 mg/kg, respectively, and was much more active than FLCZ. The protective effect of FK463 was not obviously influenced by the fungal inoculum size, the starting time of the treatment, or the immunosuppressed status of the host. The reduction in efficacy was less than that observed with FLCZ or AMPH-B. The efficacy of FK463 was also evaluated in the disseminated candidiasis target organ assay and was compared with those of FLCZ and AMPH-B. Efficacies were evaluated on the basis of a comparison between the mean log(10) CFU in kidneys in the groups treated with antifungal agents and that in control group. A single dose of FK463 at 0.5 mg/kg or higher significantly reduced the viable counts in kidneys compared with the numbers of yeast cells before treatment, and its efficacy was comparable to that of AMPH-B, while FLCZ at 4 mg/kg showed only a suppressive effect on the growth of C. albicans in the kidneys. In the disseminated aspergillosis model, FK463 given at doses of 0.5 mg/kg or higher significantly prolonged the survival of mice infected intravenously with Aspergillus fumigatus conidia. The efficacy of FK463 was about 2 times inferior to that of AMPH-B, with ED(50)s ranging from 0.25 to 0.50 mg/kg and 0.11 to 0.29 mg/kg, respectively. These results indicate that FK463 may be a potent parenterally administered therapeutic agent for disseminated candidiasis and aspergillosis.

Animals↗
PubMed1993

Modulating effect of dietary carbohydrate supplementation on Candida albicans colonization and invasion in a neutropenic mouse model.

We studied the effect of dietary carbohydrate supplementation on Candida albicans colonization and invasion of the gastrointestinal tract in a neutropenic mouse model. Mice inoculated with C. albicans were allowed free access to standard chow and drinking water supplemented with either glucose or xylitol or no carbohydrates (control). On days 33 through 36 postinoculation, the mean +/- standard error log10 CFU of C. albicans per gram on the mucosal surface, determined by quantitating CFU dislodged in the first wash of the gastric wall, was significantly higher in mice given the glucose supplement: 7.20 +/- 0.09 (glucose) versus 5.38 +/- 0.28 (xylitol) and 5.11 +/- 0.33 (control) CFU/g (P < or = 0.05 for each comparison by Fisher's protected least-significant-difference test). Fecal cultures also yielded the highest quantities of C. albicans in the glucose group. Invasion of the gastric wall by C. albicans correlated well with surface colonization in glucose-supplemented animals. Eight of 10 mice in this group, all with > 10(6) CFU/g, showed extensive invasive growth, as compared with only 2 of 26 mice in the remaining groups (P = 0.00006 by Fisher's exact test). These results indicate that dietary glucose intake is a key determinant of C. albicans growth in the gastrointestinal tract. The data provide an experimental rationale for clinical trials to decrease the intake of glucose or its utilization by C. albicans in immunocompromised patients.

Animals↗
PubMed2006

Quantitative correlation of optic nerve pathology with ocular pressure and corneal thickness in the DBA/2 mouse model of glaucoma.

PURPOSE: To investigate quantitatively the relationships between elevated intraocular pressure (IOP), axonal loss, and corneal thickness in the DBA/2 mouse model of glaucoma, to understand better how these factors contribute to disease progression. METHODS: IOP was measured with a handheld tonometer (Tono-Pen; Medtronic Solan, Jacksonville, FL) in 195 to 446 eyes of mice 2 to 10 months of age sampled from a colony of 400 DBA/2 mice. From a group of 24 eyes at 4, 9, and 10 months of age, correlations were determined between the density and number of RGC axons, corneal thickness, and IOP. RESULTS: Mean IOP levels in the colony were 15 to 16 mm Hg at 2 months of age and rose almost linearly at a rate of 0.9 mm Hg/mo before reaching 22 to 23 mm Hg at 10 months. Both the density and number of axons decreased with increasing average lifetime IOP. IOP variation within age groups strongly correlated with density. Age-matched mice with lower mean IOP had greater preservation of axons in the optic nerve. Elevated IOP was accompanied by increased corneal thickness at the limbus. Surprisingly, corneal thickness was a strong predictor of axonal density (r2 = -0.75), regardless of age. CONCLUSIONS: IOP increased with age in most, but not all, DBA/2 mice. In age-matched mice, differences in IOP corresponded to differences in axonal density and number. In young mice with elevated IOP, the loss of axons resembled that of older animals with similar IOP. Whether corneal thickness is a byproduct of elevated IOP remains unknown, but it may be useful as an index of optic nerve degeneration.

Aging↗
PubMed1988

Inflammatory response in enterocolitis in the piebald lethal mouse model of Hirschsprung's disease.

Mucosal immune defense responses in two clinical forms of enterocolitis complicating congenital megacolon in the piebald lethal mouse model of Hirschsprung's disease were investigated. Significant histological and immunocytochemical differences were seen in the ganglionic segment of colon between piebald mice with early clinical onset of acute illness and piebald mice with late onset enterocolitis. The number of IgA-containing plasma cells infiltrating the lamina propria of the gut in the former group were significantly increased (p less than 0.001) compared to the latter group of mice and healthy controls. This study suggests that the two forms of enterocolitis complicating congenital megacolon in piebald mice have different etiologies.

Animals↗
PubMed2006

Mouse models of induced otitis media.

The mouse has seen limited use as a model for experimental otitis media, due primarily to the small size of its middle ear. However, the genetic resources of this species offer substantial potential benefits. These include detailed genomic information, a wealth of genetic models, and gene arrays that represent virtually all mouse genes. This has led to the development of methods for inducing otitis in mice. These include surgical approaches to the middle ear, documentation of the murine middle ear response to various pathogens and inflammatory factors, as well as characterization of induced otitis media in several mouse strains. The results indicate that induced otitis media in the normal mouse is in most respects comparable to that observed in other animal models and in humans. They further suggest that the considerable genetic resources of this species can be harnessed to increase our understanding of this disease.

Animals↗