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At least 775 records · Page 43Linked to original sources
PubMed2004

Massive liver necrosis after provocation of imbalance between Th1 and Th2 immune reactions in osteopontin transgenic mice.

BACKGROUND: Massive liver necrosis can develop as a consequence of imbalance between T-helper (Th)1 and Th2 immune reactions in the liver. Osteopontin is a glycoprotein secreted for the initiation of the Th1 immune reaction, as well as for extracellular matrix formation and calcium deposition in the bone and kidney. Osteopontin is overexpressed in Kupffer cells, macrophages, and stellate cells activated in injured livers. We established transgenic mice expressing osteopontin exclusively in hepatocytes, using a vector containing human serum amyloid P component promoter. The relation of Th1/Th2 immune imbalance to massive liver necrosis was studied using these transgenic mice. METHODS: Transgenic mice and C27BL/6 mice, wild-type controls of the transgenic mice, were given an intravenous injection of concanavalin-A, and the histological extent of liver injuries and plasma cytokine levels were evaluated. RESULTS: When the transgenic mice received concanavalin-A, massive necrosis and mononuclear cell infiltration developed in the liver, the extent of which was greater in the female mice than in the male mice. This treatment produced minimal liver injury and focal liver necrosis in male and female C57BL/6 mice. In these transgenic and control mice, plasma concentrations of interleukin (IL)-10 and interferon (IFN)-gamma were increased after concanavalin-A treatment. However, the upregulation of plasma IL-10 concentration was smaller in the male and female transgenic mice than in the control mice, and the upregulation of the IFN-gamma concentration was greater in the female transgenic mice than in the female control mice. CONCLUSIONS: Th1 and Th2 immune reactions were deranged after concanavalin-A treatment, with Th1 immunity predominating in transgenic mice expressing osteopontin in hepatocytes; this immunological imbalance may contribute to massive liver necrosis.

Animals↗
PubMed2005

Non-invasive imaging of a transgenic mouse model using a prostate-specific two-step transcriptional amplification strategy.

Non-invasive assessment of transgenic animals using bioluminescence imaging offers a rapid means of evaluating disease progression in animal models of disease. One of the challenges in the field is to develop models with robust expression to image repetitively live intact animals through solid tissues. The prostate-specific antigen (PSA) promoter is an attractive model for studying gene regulation due to its hormonal response and tissue-specificity permitting us to measure signaling events that occur within the native tissues. The use of the GAL4-VP16 activator offers a powerful means to augment gene expression levels driven by a weak promoter. We have used a two-step transcriptional amplification (TSTA) system to develop a transgenic mouse model to investigate the tissue-specificity and developmental regulation of firefly luciferase (fl) gene expression in living mice using bioluminescence imaging. We employed an enhanced prostate-specific promoter to drive the yeast transcriptional activator, GAL4-VP16 (effector). The reporter construct carries five Gal4 binding sites upstream of the fl gene. We generated a transgenic mouse model using a single vector carrying the effector and reporter constructs. The transgenic mice show prostate-specific expression as early as three weeks of age. The bioluminescence signal in the prostate is significantly higher than in other organs. We also demonstrate that blocking androgen availability can downregulate the fl expression in the prostate. The transgenic mice display normal physical characteristics and developmental behavior, indicating that the high level of GAL4 driven expression is well tolerated. These findings suggest that the GAL4-VP16 transactivator can be used to amplify reporter gene expression from a relatively weak promoter in a transgenic mouse model. The transgenic TSTA model in conjunction with other transgenic cancer models should also help to detect and track malignancies. The strategies developed will be useful for transgenic research in general by allowing for amplified tissue specific gene expression.

Animals↗
PubMed2006

Chromosomal localization of a proinsulin transgene in Japanese quail by laser pressure catapulting.

Transgenic avian bioreactors produce therapeutic recombinant proteins in egg white. To date, however, methods for transgenic modification of the avian genome or determining transgenic status of individual birds are scarce. The dual, but interrelated, goals of this research were to: (1) develop a method of detecting stable DNA insertion into Japanese quail; and (2) provide a method for gene location on avian chromosomes. We created Teflon-coated coverslip slides to facilitate laser pressure catapulting of avian chromosomes for DNA amplification and nucleotide sequencing. Transgenic G2 Japanese quail, containing germline incorporation of proinsulin, were identified by isolation of chromosomes using laser microdissection and laser pressure catapulting. Subsequent amplification of each chromosome identified 2-5 chromosomes with the proinsulin transgene inserted. Nucleotide sequencing of each chromosomal insertion was identical to the proinsulin portion of the original vector. By applying laser pressure catapulting and PCR of individual chromosomes, we were able to determine that the transgene correctly inserted into avian chromosomes and that the majority of the insertions occurred within microchromosomes. Because many potential therapeutic transgenes have similar or nearly identical nucleotide sequence to the host's native gene, laser microdissection and subsequent analysis may be required for detailed documentation of transgene expression before proceeding with transgenic protein production.

Animals↗
PubMed2006

Transgene constructs in coho salmon (Oncorhynchus kisutch) are repeated in a head-to-tail fashion and can be integrated adjacent to horizontally-transmitted parasite DNA.

Currently, little information is available regarding the molecular organization of integrated transgenes in genetically-engineered fish. We performed a detailed structural analysis of an inserted transgene in one strain (M77) of transgenic coho salmon (Oncorhynchus kisutch) containing a salmon growth hormone gene construct (OnMTGH1). Microinjected DNA was found to have inserted into a single site in the coho salmon genome, and was organized with four complete internal copies and two partial terminal copies of the OnMTGH1 construct. All construct copies were organized in a direct-tandem (head-to-tail) repeat fashion in strain M77 and five additional strains (one also possessed a second recombinant junction fragment). For strain M77, the junctions between the transgene insert and the insertion point within the wild-type genome were cloned from strain-specific cosmid libraries and sequenced, revealing that the transgene insertion was accompanied by a deletion of 587 bp of wild-type DNA as well as a small insertion (19 bp) of unknown DNA upstream and a 14 bp direct- tandem duplication of sequence downstream. Upstream and downstream wild-type DNA sequence contained several repetitive sequence elements based on Southern blot analysis and homology to repetitive sequences in GenBank. In the downstream flank, a pseudogene sequence was also identified which has high homology to the CA membrane protein gene from Schistosoma japonicum, a parasite closely related to Sanguinicola sp. parasites which infect salmonids. Whether the presence of an inserted transgene and the presence of potentially horizontally-transmitted DNA are indicative of a genomic region with a predisposition for insertion of foreign DNA requires further study. The information derived from this transgene structure provides information useful for comparison to other transgenic organisms and for determination of the mechanism of transgene integration in lower vertebrates.

Animals↗
PubMed1990

Isotype switching of an immunoglobulin heavy chain transgene occurs by DNA recombination between different chromosomes.

Transgenic mice carrying an immunoglobulin mu heavy chain transgene exhibit isotype switching of the transgene. We have now characterized the mechanism of transgene switching in these mice. The site of mu transgene insertion in one transgenic line has been localized to chromosome 5 using a series of polymorphic endogenous retroviruses as genetic markers in backcross mice. The endogenous immunoglobulin heavy chain locus resides on mouse chromosome 12, which shows that transgene isotype switching can occur between two different chromosomes even though normal antibody gene switching has generally been thought to occur within one chromosome. We find that transgene isotype switching involves interchromosomal DNA recombination, and our data suggest that the same enzymatic mechanisms mediate both normal isotype switch recombination and interchromosomal transgene switching. Our findings also support the notion that the isotype switching mechanism can induce chromosomal translocations such as observed for the c-myc gene in some B cell tumors.

Animals↗
PubMed1992

Tissue-specific expression of the human neuropeptide Y gene in transgenic mice.

Neuropeptide Y (NPY) is the most abundant neuropeptide detected in the mammalian brain, and is found throughout the central and peripheral nervous system. This peptide is a proposed regulator of appetite, blood pressure, and pituitary hormone release. Previous experiments have demonstrated the ability of 5' sequences within the human NPY gene to promote transcription in cultured neuronal cells. To identify sequences in this gene that regulate tissue-specific expression, a NPY/CAT fusion gene, containing approximately 850 bp of NPY sequences, was microinjected into fertilized mouse ova. Five lines of transgenic mice were derived from these ova and several tissues from mice of each line were tested for transgene expression using the CAT assay. One line demonstrated X-chromosome-linked transmission of the transgene while the other lines demonstrated autosomally-linked transmission. Three lines demonstrated transgene expression with significant levels of CAT activity detectable only in tissues which have been shown to express endogenous NPY. One autosomally-linked line did not demonstrate significant levels of transgene activity because the transgene appeared to have undergone structural alteration during genomic integration. No transgene activity was detected in either male of female mice from the X-linked line, suggesting a positional regulation of the transgene locus other than X-inactivation in this line. The present research demonstrated the NPY regulatory sequences included in pCATNPY delta 796 sufficiently directed tissue-appropriate gene expression in transgenic mice.

Animals↗
PubMed1994

Targeted pituitary tumorigenesis using the human thyrotropin beta-subunit chain promoter in transgenic mice.

We have generated transgenic mice that express the simian virus 40 (SV40) large T antigen under the control of a 1109 bp 5'-flanking sequence of the human thyrotropin beta-subunit (TSH beta) gene. The hybrid gene, termed TTP-1, was microinjected into fertilized mouse eggs and 11 transgenic mice were obtained. One of the transgenic mice, a female, a phenotypical dwarf, developed a pituitary tumor and wasted away from 7 to 9 weeks after birth. To establish the transgenic mouse line, her ovaries were transferred to a normal female, whose ovaries were removed beforehand. To examine the tissue specificity of transgene expression, mRNA of SV40 large T antigen was monitored in various tissues from the transgenic mice by the reverse transcriptase-polymerase chain reaction analysis, and was detected only in the pituitary. Histological and immunohistochemical analyses showed that the pituitary tumors of the transgenic mice were composed of poorly differentiated pituitary cells expressing SV40 large T antigen. These results indicated that the 1109 bp sequence of the human TSH beta 5'-flanking region is essential for pituitary-specific expression of SV40 large T antigen in transgenic mice, which exhibited a dwarf phenotype and developed pituitary tumors. The tumors were composed of undifferentiated cells and did not produce thyrotropin. These transgenic mice should provide a valuable animal model for studying the pathogenesis of anterior pituitary tumors.

Animals↗
PubMed1995

Abnormal perikaryal accumulation of neurofilament light protein in the brain of mice transgenic for the human protein: sequence of postnatal development.

Adult mice transgenic for the human form of neurofilament light protein display abnormal perikaryal immunoreactivity for this protein in many regions of the CNS and notably the thalamus. To determine the sequence of development of these anomalies, we have compared normal and transgenic mice of different postnatal ages (P0-P70), using immunocytochemistry with primary antibodies recognizing both murine and human sequence of neurofilament light protein (NR-4) or the human form only (DP5-1-12). In normal mouse brainstem, several nuclei displayed immunoreactive perikarya at P0. The number of these perikarya culminated at P10, followed by a general decrease, some nuclei having lost all perikaryal immunostaining in adults. In transgenic mouse brainstem, the distribution of perikaryal immunoreactivity already resembled at P0 that of P10 in normal mouse, and remained unchanged in adults. Differences between normal and transgenic mice were even more pronounced in the forebrain. Some nuclei of normal mouse basal forebrain that were weakly immunopositive at P10 or P20, but no longer in adults, were already labeled at P0 and remained so or became more intense at later stages in transgenic mice. In the thalamus of normal mouse, perikaryal labeling was faint, confined to a few nuclei, and detected only transiently at P10, whereas in transgenics, it was already observed in some nuclei at P0, increased in intensity and extended to other nuclei at P10, and persisted thereafter. Strongly immunoreactive, inflated perikarya with excentric nuclei were prominent in these thalamic nuclei at P20, and even larger in size at P70. In the cerebral cortex of normal mice, layers II-III and layer V of many cytoarchitectonic areas showed immunoreactive cell bodies at P10, a distribution which became gradually restricted to the parietal cortex in adults. In transgenic mice, immunopositive cortical cell bodies were first detected at P3, filled layers II-III of numerous cortical areas at P10, and then rapidly decreased in number to approach the adult pattern at P20. In the cortex as well as thalamus of P10 transgenic mice, differences between the patterns of cellular staining with clones NR4 and DP5-1-12 antibodies indicated that both the murine and human proteins were accumulated in these neurons. Thus, neurofilament light protein accumulation in the transgenic mouse brain generally involved neurons displaying perikaryal immunoreactivity for the protein at least at some point during normal postnatal development.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Desmin-lacZ transgene, a marker of regenerating skeletal muscle.

Transgenic C57 mice bearing a transgene of the desmin gene linked to the lacZ reporter gene which encoded for the enzyme beta-galactosidase were used. In the muscle cell, a blue nuclear product appearing in the presence of the X-gal substrate for the enzyme provided evidence of the expression of the desmin gene. However, no transgene expression was observed 2 weeks postnatal in skeletal muscles, even though endogenous desmin was present. In order to investigate the regulatory mechanisms of the desmin gene during regeneration, adult pectoralis fragments (without expression of the desmin transgene) from transgenic mice were implanted into the tibialis anterior of 4 day or 6 week old Swiss mice. Adult pectoralis transplants reexpressed the transgene from day 4 to 10 after implantation. In addition, lesions were performed in adult transgenic pectoralis and transgenic expression in injured muscles was observed 2 days later. This new transgenic mouse is a powerful tool for the study of the various steps of skeletal muscle regeneration.

Aging↗
PubMed1994

T cell receptor (beta chain) transgenic mice have selective deficits in gamma delta T cell subpopulations.

TCR-beta (T cell receptor-beta chain) transgenic mice have altered lymphocyte development. TCR-beta transgenic mice are hyporesponsive to alloantigens in vivo and are deficient in gamma delta T cells. In order to begin a study of the relationship between a deficiency of alloreactive gamma delta cells and the defective function of in vivo alloantigen recognition, we analysed the gamma delta T cell development in TCR-beta mice. The presence of the TCR-V beta 8.2 chain transgene is associated with inhibition of gamma chain gene rearrangement. In order to determine how the presence of the TCR-beta transgene affects gamma delta T cell development, gamma delta T cells were studied in the skin, intestine and spleen. TCR-beta mice have dramatically reduced numbers of gamma delta T cells in the spleen and moderately reduced numbers of gamma delta T cells among intestinal intraepithelial lymphocytes. In contrast, these mice have normal numbers of gamma delta dendritic epidermal cells (DEC). These selective deficits could be due to the developmental regulation of transgene transcription during fetal life. We examined transcription of the TCR-beta transgene in the fetal thymus and found that the TCR-beta transgene is first transcribed at high levels on day 16 of fetal life, after DEC have already migrated from the thymus to the epidermis. Furthermore, mRNA from the transgene was detected in DEC, ruling out the formal possibility that DEC bear a gamma delta receptor only because they are incapable of expressing the transgene.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2007

Transgenic overexpression of connexin50 induces cataracts.

To examine the effects of increased expression of Cx50 in the mouse lens, transgenic mice were generated using a DNA construct containing the human Cx50 coding region and a C-terminal FLAG epitope driven by the chicken betaB1-crystallin promoter. Expression of this protein in paired Xenopus oocytes induced gap junctional currents of similar magnitude to wild type human Cx50. Three lines of transgenic mice expressing the transgenic protein were analyzed. Lenses from transgenic mice were smaller than those from non-transgenic littermates, and had cataracts that were already visible at postnatal day 1. Expression of the transgene resulted in a 3- to 13-fold increase in Cx50 protein levels above those of non-transgenic animals. Light microscopy revealed alterations in epithelial cell differentiation, fiber cell structure, interactions between fiber cells and areas of liquefaction. Scanning electron microscopy showed fiber cells of varying widths with bulging areas along single fibers. Anti-Cx50 and anti-FLAG immunoreactivities were detected at appositional membranes and in intracellular vesicles in transgenic lenses. N-cadherin, Cx46, ZO-1 and aquaporin 0 localized mainly at the plasma membrane, although some N-cadherin and aquaporin 0 was associated with the intracellular vesicles. The abundance and solubility/integrity of alphaA-, alphaB-, beta- and gamma-crystallin were unaffected. These results demonstrate that transgenic expression of Cx50 in mice leads to cataracts associated with formation of cytoplasmic vesicles containing Cx50 and decreased or slowed epithelial differentiation without major alterations in the distribution of other integral membrane or membrane-associated proteins or the integrity/solubility of crystallins.

Animals↗
PubMed2004

CpG methylation of a plasmid vector results in extended transgene product expression by circumventing induction of immune responses.

Gene therapy has the potential to cure inherited diseases if the delivered genes achieve long-term expression at therapeutic levels in the targeted tissues. Expression is commonly short-lived due to induction of cell-mediated immune responses to the gene therapy vehicle and/or the transgene product, which can be perceived as "foreign" by the host's immune system. Plasmid expression vectors have been used to deliver genes. Bacterial DNA carries immunostimulatory sequences in the form of unmethylated CpG motifs, which induce an inflammatory reaction that in turn promotes activation of transgene product-specific B and T cells. Elimination or methylation of immunostimulatory CpG sequences in plasmid expression vectors prevents the stimulation of transgene product-specific immune responses without necessarily reducing transgene expression. In this study, we tested if a CpG-methylated plasmid expression vector expressing the highly immunogenic glycoprotein of rabies virus can achieve prolonged transgene product expression by circumventing immune recognition. Our data show that mice inoculated with a CpG-methylated plasmid expression vector show delayed clearance of transfected cells and fail to mount a strong immune response to the transgene product. Gene transfer with a CpG-methylated plasmid results in a state of immunological low responsiveness to the transgene product, which may facilitate readministration of the transgene. Nevertheless, mice remain responsive to the transgene product delivered by a viral vector.

Adenoviridae↗
PubMed1998

The use of human leucocyte antigen class I transgenic mice to investigate human immune function.

HLA class I transgenic mice are a powerful research tool which have been used as models for human immune responses. This review describes the generation of the different HLA class I transgenic mice, the techniques used to improve expression of the transgene and use of the transgene product in immune responses. It also illustrates how HLA class I transgenic mice have provided insights into the nature of the allogeneic and xenogeneic response, the generation of CTL responses, the development of autoimmune diseases, and their use for the generation of anti-HLA class I antibodies. Despite these advances, the use of available HLA class I transgenic mice as models for human disease and immune responses has been limited. The development of new transgenic strains incorporating multiple human transgenes may allow the potential of HLA class I transgenic mice to be realised.

Alleles↗
PubMed1997

Sex-linked behavioural differences in mice expressing a human insulin transgene in the medial habenula.

We previously reported that a human insulin transgene was specifically expressed in the medial habenula of the adult mouse brain, and that this expression was ascribed to the delta-168 transgene. The present study analyses the possible behavioural consequences of this insulin transgene expression using measures of food intake, spontaneous activity, emotional reactivity, learning and extinction performance of an operant task. The delta-168 transgenic mice did not differ from the C57BL/6 control mice as concerns food intake, behaviour in the open field, or emotional response in an elevated plus maze. On the other hand, measures of locomotor activity in a circular corridor revealed a significantly faster decline of spontaneous locomotor activity in male as compared to female delta-168 transgenic mice. Moreover, as compared to female transgenic mice, male transgenic mice exhibited a deficit in the rate of acquisition and an acceleration of the rate of extinction of a bar press response in a Skinner box. In contrast, the behaviour of female transgenic mice did not differ from either male or female C57BL/6 control mice. The results of the present study demonstrate that the behavioural modifications observed in delta-168 transgenic mice are sex-linked and suggest that these behavioural differences result from changes in the interaction (interface) between motivational and motor mechanisms mediated via the striato-habenulo-mesencephalic system.

Animals↗
PubMed1997

Placebo-controlled trial of vaccination with hepatitis B virus surface antigen in hepatitis B virus transgenic mice.

BACKGROUND/AIMS: Treatment of hepatitis B virus carriers by vaccine containing hepatitis B surface antigen with Pre-S protein and HBsAg/ anti-HBs complex has been reported and these studies have constituted a new and promising concept for the treatment of HBV-carriers. The present communication, a placebo-controlled trial of vaccination in HBV-transgenic mice, was designed to examine the impact of vaccination using a high dose of HBsAg for a duration of 12 months to achieve further insights about the dose, duration and effectiveness of vaccine therapy. Another aim of this study was to analyse the mechanism underlying the antiviral and immunomodulatory potentiality of vaccine therapy in HBV-transgenic mice. METHODS: HBV-transgenic mice positive for HBV DNA, hepatitis B surface antigen and hepatitis B e antigen in sera received either HBV-vaccine containing HBsAg in complete Freund's adjuvant (CFA), intraperitoneally, once a month for 12 consecutive months (vaccine recipients), or only CFA, intraperitoneally once in a month for 12 consecutive months (placebo recipients). Thirty-two vaccine-recipient and 16 placebo-recipient HBV-transgenic mice were injected, checked and followed on a monthly basis for the entire duration of 12 months. RESULTS: Of the 32 transgenic mice from the vaccine-recipient group, 25 became completely negative for HBsAg and 30 for HBeAg. Five mice developed anti-HBs in sera after the observation period of 12 months. Semiquantitative estimation of HBV DNA by polymerase chain reaction showed that vaccination resulted in a decrease of HBV DNA in sera. Placebo-recipient transgenic mice did not show any significant change in the titres of HBV markers after receiving 12 monthly injections of CFA. Interleukin-2 could be detected in sera from vaccine-recipient transgenic mice, but not in placebo-recipient transgenic mice. CONCLUSIONS: Vaccination with a high dose of HBsAg in adjuvant over a long period had a significant antiviral as well as immunomodulatory potential in HBV-transgenic mice. This inspires optimism that vaccine alone or in combination with antiviral agents can be used successfully for the treatment of human HBV-carriers.

Adjuvants, Immunologic↗
PubMed2000

Development of spontaneous hyperplastic skin lesions and chemically induced skin papillomas in transgenic mice expressing human papillomavirus type 16 E6/E7 genes.

Human papillomavirus type 16 (HPV16) has been known to be the major factor for the development of uterine cervical carcinomas. We have developed a line of transgenic mice that express the HPV16 E6 and E7 genes in certain organs using a fusion gene which consists of the tyrosinase promoter and E6/E7 of HPV16, and have chosen the tyrosinase minigene as a co-injected visual marker for the identification of transgenic mice. Our transgenic mice (1) expressed E6/E7 transgene mainly in skin and heart, and (2) showed skin and eye pigmentation profiles, and (3) raised incidence of hyperplastic skin lesions. We had performed two-stage skin carcinogenesis experiment to detect the susceptibility of skin papilloma development in our transgenic mice, using dimethylbenz-anthracene (DMBA) as a initiating agent and 12-O-tetradecanoyl-phorbol-13-acetate (TPA). After 1 week of DMBA treatment (25 microg dissolved in 0.2 ml acetone) and 15 consecutive weeks of TPA treatment (2.5 microg dissolved in 0.2 ml acetone) on the back of transgenic and non-transgenic control mice (Fv-1(b) strain mice which are Friend virus B-type susceptible (FVB)/N), papilloma incidence was increased in our transgenic mice approximately 2-fold higher than in control (in female mice, 69.2 vs. 30%, respectively). Thus our transgenic mice may be useful for the development of immunological or other therapies for HPV-associated cancers.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Dopaminergic activity in transgenic mice underexpressing glucocorticoid receptors: effect of antidepressants.

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used to investigate the long-term effect of hypothalamic-pituitary-adrenal axis dysfunction on brain dopamine transmission. Compared to control mice, the transgenic animals showed increased amphetamine-induced locomotor activity and increased concentrations of striatal dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Binding of [3H]SCH 23390 and [3H]spiperone to, respectively, D1 and D2 dopamine receptors was increased in transgenic mice. In contrast, autoradiography of striatal [3H]GBR 12935 binding to the dopamine transporter was decreased and the mRNA levels of this transporter, measured by in situ hybridization, remained unchanged in the substantia nigra pars compacta. The effect of chronic treatment for two weeks with amitriptyline or fluoxetine was compared in control and transgenic mice. No significant changes were observed in control mice following antidepressant treatment, whereas in transgenic mice both antidepressants reduced striatal [3H]SCH 23390 and [3H]raclopride specific binding to D1 and D2 receptors. Amitriptyline, but not fluoxetine, increased striatal [3H]GBR 12935 binding to the dopamine transporter, whereas its mRNA level in the substantia nigra pars compacta was decreased in fluoxetine, compared to vehicle- or amitriptyline-treated transgenic mice. From these results we suggest that hyperactive dopaminergic activity of the nigrostriatal pathway controls motor activity in the transgenic mice. Furthermore, antidepressant treatment corrected the increased striatal D1 and D2 receptors and decreased dopamine transporter levels in the transgenic mice.

Amitriptyline↗
PubMed2003

The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in alzheimer's disease-like transgenic mice.

A previous study in our laboratory, involving early stage, amyloid pathology in 8-month-old transgenic mice, demonstrated a selective loss of cholinergic terminals in the cerebral and hippocampal cortices of doubly transgenic (APP(K670N,M671L)+PSl(M146L)) mice, an up-regulation in the single mutant APP(K670N,M671L) mice and no detectable change in the PSl(M146L) transgenics [J Neurosci 19 (1999) 2706]. The present study investigates the impact of amyloid plaques on synaptophysin and vesicular acetylcholine transporter (VAChT) immunoreactive bouton numbers in the frontal cortex of the three transgenic mouse models previously described. When compared as a whole, the frontal cortices of transgenic and control mice show no observable differences in the densities of synaptophysin-immunoreactive boutons. An individual comparison of layer V of the frontal cortex, however, shows a significant increase in density in transgenic models. Analysis of the cholinergic system alone shows significant alterations in the VAChT-immunoreactive bouton densities as evidenced by an increased density in the single (APP(K670N,M671L)) transgenics and a decreased density in the doubly transgenics (APP(K670N,M671L)+PSl(M146L)). In investigating the impact of plaque proximity on bouton density at early stages of the amyloid pathology in our doubly (APP(K670N,M671L)+PSl(M146L)) transgenic mouse line, we observed that plaque proximity reduced cholinergic pre-synaptic bouton density by 40%, and yet increased synaptophysin-immunoreactive pre-synaptic bouton density by 9.5%. Distance from plaques (up to 60 microm) seemed to have no effect on bouton density; however a significant inverse relationship was visible between plaque size and cholinergic pre-synaptic bouton density. Finally, the number of cholinergic dystrophic neurites surrounding the truly amyloid, Thioflavin-S(+) plaque core, was disproportionately large with respect to the incidence of cholinergic boutons within the total pre-synaptic bouton population. Confocal and electron microscopic observations confirmed the preferential infiltration of dystrophic cholinergic boutons into fibrillar amyloid aggregates. We therefore hypothesize that extracellular Abeta aggregation preferentially affects cholinergic terminations prior to progression onto other neurotransmitter systems. This is supported by the observable presence of non-cholinergic sprouting, which may be representative of impending neuritic degeneration.

Acetylcholine↗