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At least 415 records · Page 23Linked to original sources
PubMed2002

Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis.

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.

Acetylcholinesterase↗
PubMed2003

Tissue-specific replicating capacity of a chimeric poliovirus that carries the internal ribosome entry site of hepatitis C virus in a new mouse model transgenic for the human poliovirus receptor.

Nucleotides (nt) 108 to 742 of an infectious cDNA clone of poliovirus (PV) Mahoney strain, including the corresponding region of the internal ribosome entry site (IRES), was replaced by nt 28 to 710 of hepatitis C virus (HCV) cDNA corresponding to the whole HCV IRES. A chimeric PV (2A-369) was generated by transfecting mammalian cells with an RNA transcribed in vitro from the cDNA. To examine replicating capacity of virus 2A-369 in the brain and liver of a mouse model for poliomyelitis, a new mouse model (MPVRTg25-61) that is transgenic for human PV receptor (hPVR; CD155) was generated in order to obtain a higher expression level of hPVR in the liver than those of hPVRTg mouse lines generated by us so far. The transgene used was constructed by combining a putative regulatory region of the mouse PVR homolog and the whole structural region of the hPVR gene. Virus 2A-369 replicated well in the liver of MPVRTg25-61 but not in the brain, whereas control Mahoney virus replicated well both in the liver and in the brain. The data suggest that the HCV IRES works more efficiently in the liver than in the brain and that PV IRES works well both in the liver and in the brain. The results support the notion that tissue-specific activity of IRES may be reflected in tissue tropism of a virus whose specific translation initiation is driven by IRES, that is, an IRES-dependent virus tropism.

Animals↗
PubMed2003

A transgenic mouse model of the ubiquitin/proteasome system.

Impairment of the ubiquitin/proteasome system has been proposed to play a role in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Although recent studies confirmed that some disease-related proteins block proteasomal degradation, and despite the existence of excellent animal models of both diseases, in vivo data about the system are lacking. We have developed a model for in vivo analysis of the ubiquitin/proteasome system by generating mouse strains transgenic for a green fluorescent protein (GFP) reporter carrying a constitutively active degradation signal. Administration of proteasome inhibitors to the transgenic animals resulted in a substantial accumulation of GFP in multiple tissues, confirming the in vivo functionality of the reporter. Moreover, accumulation of the reporter was induced in primary neurons by UBB+1, an aberrant ubiquitin found in Alzheimer disease. These transgenic animals provide a tool for monitoring the status of the ubiquitin/proteasome system in physiologic or pathologic conditions.

Alzheimer Disease↗
PubMed1998

Striatal transplantation in a transgenic mouse model of Huntington's disease.

Striatal grafts have been proposed as a potential strategy for striatal repair in Huntington's disease, but it is unknown whether the diseased brain will compromise graft survival. A transgenic mouse line has recently been described in which hemizygotes with an expanded CAG repeat in exon 1 of the HD gene exhibit a progressive neurological phenotype similar to the motor symptoms of Huntington's disease. We have therefore evaluated the effects of the transgenic brain environment on the survival, differentiation, and function of intrastriatal striatal grafts and undertaken a preliminary analysis of the effects of the grafts on the development of neurological deficits in the host mice. Hemizygote transgenic and wild-type littermate female mice received striatal grafts at 10 weeks of age and were allowed to survive 6 weeks. Normal healthy grafts were seen to survive and differentiate within the striatum of transgenic mice in a manner comparable to that seen in control mice. The transgenic mice exhibited a progressive decline in body weight from 9 weeks of age and a progressive hypoactivity in an open field test of general locomotor behavior. Although striatal grafts exerted a statistically significant influence on several indices of this impairment, all behavioral effects were small and did not exert any clinically relevant effect on the profound neurological deficiency of the transgenic mice.

Animals↗
PubMed2002

Pathways to motor neuron degeneration in transgenic mouse models.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disorder characterized by the selective loss of motor neurons. A pathological hallmark of both sporadic and familial ALS is the presence of abnormal accumulations of neurofilament and peripherin proteins in motor neurons. In the past decade, transgenic mouse approaches have been used to address the role of such cytoskeletal abnormalities in motor neuron disease and also to unravel the pathogenesis caused by mutations in the gene coding for superoxide dismutase 1 (SOD1) that account for ~20% of familial ALS cases. In mouse models, disparate effects could result from different types of intermediate filament (IF) aggregates. Perikaryal IF accumulations induced by the overexpression of any of the three wild-type neurofilament proteins were quite well tolerated by motor neurons. Indeed, perikaryal swellings provoked by NF-H overexpression can even confer protection against toxicity of mutant SOD1. Other types of IF aggregates seem neurotoxic, such as those found in transgenic mice overexpressing either peripherin or an assembly-disrupting NF-L mutant. Moreover, understanding the toxicity of SOD1 mutations has been surprisingly difficult. The analysis of transgenic mice expressing mutant SOD1 has yielded complex results, suggesting that multiple pathways may contribute to disease that include the involvement of non-neuronal cells.

Adult↗
PubMed2003

Insulators to improve expression of a 3(')IgH LCR-driven reporter gene in transgenic mouse models.

A locus control region (LCR) containing four transcriptional enhancers lies downstream of the IgH chain locus. We studied transgenes carrying a 3(')IgH LCR-driven GFP reporter gene for expression and B cell differentiation stage specificity. We also compared transgenes that were or were not flanked by two copies of the beta-globin HS4 insulator, an element defined by its ability to protect transgenes from the influences of surrounding genes at the insertion site. Results indicate that insulators are instrumental in sustaining GFP expression in GFP-3(')LCR transgenic mice when they were included. Flow cytometry experiments reported a strictly B cell specific GFP expression from pre-B cells in bone marrow to mature B cells in spleen. Despite addition of 5(')HS4 insulators to the GFP-3(')LCR construct, complete transgene silencing occurred in some transgenic lines and was systematically observed in ageing animals from all lines.

Animals↗
PubMed2000

Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model.

Arterial inflammatory responses are thought to be a significant component of atherosclerotic disease. We describe here, using a transgenic approach, the mutual perpetuation of immune-mediated arterial inflammation and cholesterol-induced atherosclerosis. Mice expressing the bacterial transgene beta-galactosidase exclusively in cardiomyocytes and in smooth muscle cells in lung arteries and the aorta (SM-LacZ), and hypercholesterolemic apolipoprotein E-deficient SM-LacZ mice (SM-LacZ/apoE(-/-)) developed myocarditis and arteritis after immunization with dendritic cells presenting a beta-galactosidase-derived immunogenic peptide. Hypercholesterolemia amplified acute arteritis and perpetuated chronic arterial inflammation in SM-LacZ/apoE(-/-) mice, but had no major impact on acute myocarditis or the subsequent development of dilated cardiomyopathy. Conversely, arteritis significantly accelerated cholesterol-induced atherosclerosis. Taken together, these data demonstrate that the linkage of immune-mediated arteritis and hypercholesterolemia favors initiation and maintenance of atherosclerotic lesion formation. Therapeutic strategies to prevent or disrupt such self-perpetuating vicious circles may be crucial for the successful treatment of atherosclerosis.

Animals↗
PubMed2006

Phototransduction in a transgenic mouse model of Nougaret night blindness.

The Nougaret form of dominant stationary night blindness is linked to a G38D mutation in the rod transducin-alpha subunit (Talpha). In this study, we have examined the mechanism of Nougaret night blindness using transgenic mice expressing TalphaG38D. The biochemical, electrophysiological, and vision-dependent behavioral analyses of the mouse model revealed a unique phenotype of reduced rod sensitivity, impaired activation, and slowed recovery of the phototransduction cascade. Two key deficiencies in TalphaG38D function, its poor ability to activate PDE6 (cGMP phosphodiesterase) and decreased GTPase activity, are found to be the major mechanisms altering visual signaling in transgenic mice. Despite these defects, rod-mediated sensitivity in heterozygous mice is not decreased to the extent seen in heterozygous Nougaret patients.

Animals↗
PubMed2000

Transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) pathology is characterized by A beta peptide-containing plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, extensive neuritic degeneration, and distinct neuron loss. We generated several transgenic mouse lines expressing the human amyloid precursor protein (APP751) containing the AD-linked KM670/671NL double mutation (Swedish mutation) under the control of a neuron-specific Thy-1 promoter fragment. In the best APP-expressing line (APP23), compact A beta deposits can be detected at 6 months of age. These plaques dramatically increase with age, are mostly Congo Red positive, and accumulate typical plaque-associated proteins such as heparansulfate proteoglycan and apolipoprotein E. Activated astrocytes and microglia indicative of inflammatory processes reminiscent of AD accumulate around the deposits. Furthermore, plaques are surrounded by enlarged dystrophic neurites as visualized by neurofilament or Holmes-Luxol staining. Strong staining for acetylcholinesterase activity is found throughout the plaques and is accompanied by local distortion of the cholinergic fiber network. All congophilic plaques contain hyperphosphorylated tau reminiscent of early tau pathology. Modern stereologic methods demonstrate a significant loss of neurons in the hippocampal CA1 region, correlating with an increasing A beta plaque load. Interestingly, APP23 mice develop cerebral amyloid angiopathy in addition to amyloid plaques even though the APP transgene is only expressed in neurons. Crossbreeding of APP23 mice with transgenic mice carrying AD-linked presenilin mutations but not wild-type presenilin resulted in enhanced formation of pathology. In conclusion, our APP transgenic mice present many pathologic features, similar to those observed in AD and therefore offer excellent tools for studying the contribution of A beta to AD pathogenesis.

Alzheimer Disease↗
PubMed2004

The metabotropic glutamate receptor 5 antagonist MPEP and the mGluR2 agonist LY379268 modify disease progression in a transgenic mouse model of Huntington's disease.

Chronic glutamate mediated excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Both, inhibition of glutamate release through stimulation of presynaptic metabotropic glutamate receptor (mGluR) 2 and blockade of postsynaptic mGluR5 have been demonstrated to be neuroprotective against excitotoxicity. R6/2 HD transgenic mice which express an expanded CAG triplet repeat serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with either the mGluR2 agonist LY379268 (1.2 mg/kg) or with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (100 mg/kg) orally from a presymptomatic stage until death to investigate their potential disease modifying effects. We found that survival time in both the MPEP treated mice and the LY379268 treated mice was significantly increased in comparison to placebo treated transgenic controls (14.87+/-0.14 and 14.22+/-0.11 weeks versus 12.87+/-0.11 weeks, respectively). Additionally, the progressive decline in motor coordination of HD transgenic mice as tested with the rotarod test was significantly attenuated in MPEP- but not in LY379268-treated mice. Early pathological hyperactivity, which can be found in placebo treated HD transgenic mice, was significantly attenuated by both MPEP and LY379268 treatment. Immunohistologial examination of HD characteristic neuronal intranuclear inclusion (NII), however, demonstrated no effect on NII formation by either of the treatments applied. These data suggest that inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment in HD.

Amino Acids↗
PubMed2001

Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation.

To facilitate the elucidation of the genetic events that may play an important role in the development or tumorigenesis of the prostate gland, we have generated a transgenic mouse line with prostate-specific expression of Cre recombinase. This line, named PB-Cre4, carries the Cre gene under the control of a composite promoter, ARR2PB which is a derivative of the rat prostate-specific probasin (PB) promoter. Based on RT-PCR detection of Cre mRNA in PB-Cre4 mice or Cre-mediated activation of LacZ activity in PB-Cre4/R26R double transgenic mice, it is conclusively demonstrated that Cre expression is post-natal and prostatic epithelium-specific. Although the Cre recombination is detected in all lobes of the mouse prostate, there is a significant difference in expression levels between the lobes, being highest in the lateral lobe, followed by the ventral, and then the dorsal and anterior lobes. Besides the prostate gland, no other tissues of the adult PB-Cre4 mice demonstrate significant Cre expression, except for a few scattered areas in the gonads and the stroma of the seminal vesicle. By crossing the PB-Cre4 animals with floxed RXRalpha allelic mice, we demonstrate that mice, whose conventional knockout of this gene is lethal in embryogenesis, could be propagated with selective inactivation of RXRalpha in the prostate. Taken together, the results show that the PB-Cre4 mice have high levels of Cre expression and a high penetrance in the prostatic epithelium. The PB-Cre4 mice will be a useful resource for genetic-based studies on prostate development and prostatic disease.

Alleles↗
PubMed2006

Distribution and cellular localization of high mobility group box protein 1 (HMGB1) in the spinal cord of a transgenic mouse model of ALS.

Although the aetiology of amyotrophic lateral sclerosis (ALS) is still elusive, increased attention has been put forward on events related to neuroinflammation and an active participation of glial cells in the ALS pathogenesis has been suggested. However, the specific role of many proinflammatory mediators that usually accompany the inflammatory changes is still largely unknown. High mobility group box protein 1 (HMGB1) is an ubiquitous nuclear protein that exerts numerous extranuclear and extracellular functions, including a proinflammatory activity, able to induce cytokines expression and activate inflammatory cells. To investigate whether this protein may play a role in the inflammatory events in ALS, we examined both expression and localization of HMGB1 in the lumbar spinal cord of SOD1G93A transgenic mice, a well established mouse model of familial ALS, at different stages of the disease. Intense HMGB1 reactivity was detected in ventral horn motor neurons of both non-transgenic and SOD1G93A mice and there was no difference in its expression between presymptomatic SOD1G93A mice and controls. With the progression of the disease, degenerating neurons showed a reduction of HMGB1 immunoreactivity which could reflect an extracellular release of this protein. By contrast, in the reactive glial cells HMGB1 was remarkably expressed in the nucleus, but not in the cytosol, likely contributing to the proliferation and/or hypertrophy of these cells. These results suggest that HMGB1 may have a different involvement in the motor neurons and glial cells in response to the neurotoxic environment in the spinal cord of SOD1G93A mice, and it may contribute to the progression of inflammatory and neurodegenerative processes.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model.

Tau protein hyperphosphorylation and aggregation into neurofibrillary tangles are characteristic features of several neurodegenerative disorders referred to as tauopathies. Among them, frontotemporal dementia and Parkinsonism linked to chromosome 17 may be caused by dominant missense mutations in the tau gene. Transgenic mice expressing mutant tau serve as valid model systems to study the ethiopathogenesis of these diseases and assay possible therapeutic interventions. Here we report that chronic lithium treatment of a transgenic mouse strain expressing human tau with three missense mutations results in decreased glycogen synthase kinase-3-dependent-tau phosphorylation and a reduction of filamentous aggregates. These data indicate that lithium, presumably acting through the inhibition of glycogen synthase kinase 3, may be useful to curb neurodegeneration in tauopathies.

Animals↗
PubMed2001

Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy.

The deposition of amyloid Abeta peptide in the wall of cerebral vessels (cerebral amyloid angiopathy), can lead to weakness and rupture of the vessel wall, resulting in hemorrhagic stroke. The Tg2576 transgenic mouse line, overexpressing mutant amyloid precursor protein in an age-dependent manner, forms amyloid angiopathy morphologically similar to that seen in the human. We report here the structural and functional disruption of smooth muscle cells (SMCs) in the walls of pial vessels affected by amyloid deposition in the Tg2576 mouse. We demonstrate, using multiphoton imaging, that the arrangement of SMCs becomes disorganized before the onset of cell death, and that these disorganized SMCs are unable to respond appropriately to application of endothelial-dependent and endothelial-independent vasodilators in a closed-cranial window preparation.

Acetylcholine↗
PubMed2005

Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized behaviorally by chorea, incoordination, and shortened lifespan and neuropathologically by huntingtin inclusions and neuronal degeneration. In order to facilitate studies of pathogenesis and therapeutics, we have generated a new inducible mouse model of HD expressing full-length huntingtin (Htt) using a tetracycline-regulated promoter. In double transgenic mice Htt was expressed widely in the brain under the control of the tet-transactivator (tTA) driven by the prion promoter PrP (in the absence of doxycycline). Mice expressing full-length mutant Htt, but not full-length normal Htt, displayed a progressive behavioral phenotype, consisting of slowed and irregular voluntary movements, gait ataxia, tremor and jerky movements, incoordination, and weight loss, with a shortened lifespan. Neuropathology included prominent intranuclear inclusions in cortex and striatum as well as cytoplasmic aggregates. This phenotype is very similar to the phenotypes of previous transgenic mice expressing N-terminal fragments of mutant Htt. The current HD-transgenic mice had nuclear accumulation of Htt, particularly an approximately 60-kDa fragment, which appears to represent an N-terminal cleavage product. This fragment is smaller than calpain or caspase-derived cleavage products of Htt, but it is comparable to a product, termed cp-A, which accumulates in nuclei of cells in a previously described cell model. This new mouse model may be useful in the future for pathogenic and preclinical therapeutic studies related to HD. The data suggest that proteolytic processing could be a part of the pathogenesis of HD, potentially representing an attractive therapeutic target.

Animals↗
PubMed1993

[Transgenic mouse model for hepatocellular carcinoma in human hepatitis B virus infection].

The exact role of hepatitis B virus (HBV) in hepatocarcinogenesis is not known. We generated HBV x gene transgenic mice under the hypothesis that the viral transactivator may alter the host gene expression and lead to the development of hepatocellular carcinoma. The x gene under its own regulatory element caused progressive histopathological changes specifically in the transgenic mouse liver, beginning with multifocal foci of altered hepatocytes, followed by the appearance of neoplasia. This finding shows, for the first time, the direct involvement of HBV in the development of liver cancer. Analyses of events that follow the expression of the x gene suggest that the x gene acts at the early stage of carcinogenesis in the liver.

Animals↗