QPS Austria GmbH

Grambach, Austria

QPS Austria GmbH

Grambach, Austria
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Izzo N.J.,Cognition Therapeutics, Inc. | Staniszewski A.,Columbia University | To L.,Stanford University | Fa M.,Columbia University | And 25 more authors.
PLoS ONE | Year: 2014

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics. ©2014 Izzo et al.


PubMed | University of Kentucky, Brown University, Cognition Therapeutics, Inc., Stanford University and 3 more.
Type: Journal Article | Journal: PloS one | Year: 2014

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimers disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimers disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimers therapeutics.


PubMed | NeuroScios GmbH, Academy of Sciences of the Czech Republic, University of Szeged, Masaryk University and QPS Austria GmbH
Type: | Journal: Journal of neurochemistry | Year: 2015

Diffusion kurtosis imaging (DKI) by measuring non-Gaussian diffusion allows an accurate estimation of the distribution of water molecule displacement and may correctly characterize microstructural brain changes caused by neurodegeneration. The aim of the present study was to evaluate the ability of DKI to detect changes induced by -synuclein (-Syn) accumulation in -Syn overexpressing transgenic mice (TNWT-61) in both gray matter (GM) and white matter (WM) using region of interest (ROI) and tract-based spatial statistics (TBSS) analyses respectively and to explore the relationship between -Syn accumulation and DKI metrics in our regions of interest. Fourteen-month-old TNWT-61 mice and wild-type (WT) littermates underwent in vivo DKI scanning using the Bruker Avance 9.4 Tesla MRI system. ROI analysis in the GM regions substantia nigra, striatum, hippocampus, sensorimotor cortex, and thalamus and TBSS analysis in WM were performed. Immunohistochemistry for -Syn was performed in TNWT-61 mice and correlated with DKI findings. We found increased kurtosis and decreased diffusivity values in GM regions such as the thalamus and sensorimotor cortex, and in WM regions such as the external and internal capsule, mamillothalamic tract, anterior commissure, cingulum, and corpus callosum in TNWT-61 mice as compared to WT mice. Furthermore, we report for the first time that -Syn accumulation is positively correlated with kurtosis and negatively correlated with diffusivity in the thalamus. The study provides evidence of an association between the amount of -Syn and the magnitude of DKI metric changes in the ROIs, with the potential of improving the clinical diagnosis of PD. This article is protected by copyright. All rights reserved.


PubMed | Academy of Sciences of the Czech Republic, University of Szeged, Masaryk University and QPS Austria GmbH
Type: | Journal: Brain, behavior, and immunity | Year: 2016

Diffusion kurtosis imaging (DKI) is sensitive in detecting -Synuclein (-Syn) accumulation-associated microstructural changes at late stages of the pathology in -Syn overexpressing TNWT-61 mice. The aim of this study was to perform DKI in young TNWT-61 mice when -Syn starts to accumulate and to compare the imaging results with an analysis of motor and memory impairment and -Syn levels. Three-month-old (3mo) and six-month-old (6mo) mice underwent DKI scanning using the Bruker Avance 9.4T magnetic resonance imaging system. Region of interest (ROI) analyses were performed in the gray matter; tract-based spatial statistics (TBSS) analyses were performed in the white matter. In the same mice, -Syn expression was evaluated using quantitative immunofluorescence. Mean kurtosis (MK) was the best differentiator between TNWT-61 mice and wildtype (WT) mice. We found increases in MK in 3mo TNWT-61 mice in the striatum and thalamus but not in the substantia nigra (SN), hippocampus, or sensorimotor cortex, even though the immunoreactivity of human -Syn was similar or even higher in the latter regions. Increases in MK in the SN were detected in 6mo mice. These findings indicate that -Syn accumulation-associated changes may start in areas with a high density of dopaminergic nerve terminals. We also found TBSS changes in white matter only at 6mo, suggesting -Syn accumulation-associated changes start in the gray matter and later progress to the white matter. MK is able to detect microstructural changes induced by -Syn overexpression in TNWT-61 mice and could be a useful clinical tool for detecting early-stage Parkinsons disease in human patients.


Rabl R.,QPS Austria GmbH | Horvath A.,QPS Austria GmbH | Breitschaedel C.,QPS Austria GmbH | Breitschaedel C.,University of Graz | And 3 more authors.
Journal of Neuroscience Methods | Year: 2016

Background Evaluation of motor deficits in rodents is mostly restricted to limb motor tests that are often high stressors for the animals. New method To test rodents for orofacial motor impairments in a stress-free environment, we established the pasta gnawing test by measuring the biting noise of mice that eat a piece of spaghetti. Two parameters were evaluated, the biting speed and the biting peaks per biting episode. To evaluate the power of this test compared to commonly used limb motor and muscle strength tests, three mouse models of Parkinson's disease, amyotrophic lateral sclerosis and Niemann-Pick disease were tested in the pasta gnawing test, RotaRod and wire suspension test. Results Our results show that the pasta gnawing test reliably displays orofacial motor deficits. Comparison with existing methods The test is especially useful as additional motor test in early onset disease models, since it shows first deficits later than the RotaRod or wire suspension test. The test depends on a voluntary eating behavior of the animal with only a short-time food deprivation and should thus be stress-free. Conclusions The pasta gnawing test represents a valuable tool to analyze orofacial motor deficits in different early onset disease models. © 2016 The Author(s)


PubMed | University of Graz and QPS Austria GmbH
Type: | Journal: Journal of neuroscience methods | Year: 2016

Evaluation of motor deficits in rodents is mostly restricted to limb motor tests that are often high stressors for the animals.To test rodents for orofacial motor impairments in a stress-free environment, we established the pasta gnawing test by measuring the biting noise of mice that eat a piece of spaghetti. Two parameters were evaluated, the biting speed and the biting peaks per biting episode. To evaluate the power of this test compared to commonly used limb motor and muscle strength tests, three mouse models of Parkinsons disease, amyotrophic lateral sclerosis and Niemann-Pick disease were tested in the pasta gnawing test, RotaRod and wire suspension test.Our results show that the pasta gnawing test reliably displays orofacial motor deficits.The test is especially useful as additional motor test in early onset disease models, since it shows first deficits later than the RotaRod or wire suspension test. The test depends on a voluntary eating behavior of the animal with only a short-time food deprivation and should thus be stress-free.The pasta gnawing test represents a valuable tool to analyze orofacial motor deficits in different early onset disease models.


Loffler T.,QPS Austria GmbH | Loffler T.,Medical University of Graz | Flunkert S.,QPS Austria GmbH | Havas D.,QPS Austria GmbH | And 5 more authors.
Journal of Neuroinflammation | Year: 2014

Background: Beyond cognitive decline, Alzheimer's disease (AD) is characterized by numerous neuropathological changes in the brain. Although animal models generally do not fully reflect the broad spectrum of disease-specific alterations, the APPSL mouse model is well known to display early plaque formation and to exhibit spatial learning and memory deficits. However, important neuropathological features, such as neuroinflammation and lipid peroxidation, and their progression over age, have not yet been described in this AD mouse model. Methods: Hippocampal and neocortical tissues of APPSL mice at different ages were evaluated. One hemisphere from each mouse was examined for micro- and astrogliosis as well as concomitant plaque load. The other hemisphere was evaluated for lipid peroxidation (quantified by a thiobarbituric acid reactive substances (TBARS) assay), changes in Aβ abundance (Aβ38, Aβ40 and Aβ42 analyses), as well as determination of aggregated Aβ content (Amorfix A4 assay). Finally, correlation analyses were performed to illustrate the time-dependent correlation between neuroinflammation and Aβ load (soluble, insoluble, fibrils), or lipid peroxidation, respectively. Results: As is consistent with previous findings, neuroinflammation starts early and shows strong progression over age in the APPSL mouse model. An analyses of concomitant Aβ load and plaque deposition revealed a similar progression, and high correlations between neuroinflammation markers and soluble or insoluble Aβ or fibrillar amyloid plaque loads were observed. Lipid peroxidation, as measured by TBARS levels, correlates well with neuroinflammation in the neocortex but not the hippocampus. The hippocampal lipid peroxidation correlated strongly with the increase of LOC positive fiber load, whereas neocortical TBARS levels were unrelated to amyloidosis.Conclusions: These data illustrate for the first time the progression of major AD related neuropathological features other than plaque load in the APPSL mouse model. Specifically, we demonstrate that microgliosis and astrocytosis are prominent aspects of this AD mouse model. The strong correlation of neuroinflammation with amyloid burden and lipid peroxidation underlines the importance of these pathological factors for the development of AD. The new finding of a different relation of lipid peroxidation in the hippocampus and neocortical regions show that the model might contribute to the understanding of complex pathological mechanisms and their interplay in AD. © 2014 Löffler et al.; licensee BioMed Central Ltd.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-2012-IAPP | Award Amount: 999.00K | Year: 2013

Huntington Disease (HD) is an autosomal dominantly inherited neurodegenerative disorder, which is caused by an expanded CAG repeat in the huntingtin gene. Mutant Huntingtin (mhtt) is expressed ubiquitously in the brain but the most affected region is the striatum. Marked atrophy also occurs in other brain regions such as the cortex and the hypothalamus. The latter has been linked to disturbances in sleep pattern, energy metabolism and emotion, all of them non-motor symptoms of HD that occur early in disease. In the project SWITCH-HD we will, for the first time, analyse, which mhtt containing brain area is causing which symptom in HD. We will investigate the role of mhtt in the striatum and in the hypothalamus by down-regulating mhtt in these brain regions at different disease stages using lentiviral delivery of Cre recombinase into a unique transgenic rat model of Huntington disease (BACHD rats). The effect of switching off mhtt in these brain regions on behaviour, metabolism, neuropathology, neuroimaging and potential biomarkers will be investigated. Translation of the results of this study to humans will allow to develop more specified treatments against HD. SWITCH-HD brings together the expertise of the SME JSW Life Sciences (JSW, Austria) and the University of Tbingen (EKUT, Germany). JSW will contribute and transfer its expertise regarding stereotactic applications, gene delivery by lentiviral vectors and behavioural studies. EKUT will contribute and transfer their expertise in regard to generation and comprehensive characterisation of transgenic rat models of HD. Co-operation and transfer of knowledge is dedicated to gaining new insights relevant to pathogenesis and treatment of HD as well as the establishment of new tools. Transfer of knowledge will be implemented through secondments, recruitments and meetings. There will be a structured exchange of researchers from both partners at project milestones facilitating the training of newly recruited team members


Lipsanen A.,University of Eastern Finland | Flunkert S.,QPS Austria GmbH | Kuptsova K.,University of Eastern Finland | Hiltunen M.,University of Eastern Finland | And 3 more authors.
PLoS ONE | Year: 2013

Experimental studies have identified a complex link between neurodegeneration, β-amyloid (Aβ) and calcium homeostasis. Here we asked whether early phase β-amyloid pathology in transgenic hAPPSL mice exaggerates the ischemic lesion and remote secondary pathology in the thalamus, and whether a non-selective calcium channel blocker reduces these pathologies. Transgenic hAPPSL (n = 33) and non-transgenic (n = 30) male mice (4-5 months) were subjected to unilateral cortical photothrombosis and treated with the non-selective calcium channel blocker bepridil (50 mg/kg, p.o., once a day) or vehicle for 28 days, starting administration 2 days after the operation. Animals were then perfused for histological analysis of infarct size, Aβ and calcium accumulation in the thalamus. Cortical photothrombosis resulted in a small infarct, which was associated with atypical Aβ and calcium accumulation in the ipsilateral thalamus. Transgenic mice had significantly smaller infarct volumes than non-transgenic littermates (P<0.05) and ischemia-induced rodent Aβ accumulation in the thalamus was lower in transgenic mice compared to non-transgenic mice (P<0.01). Bepridil decreased calcium load in the thalamus (P<0.01). The present data suggest less pronounced primary and secondary pathology in hAPPSL transgenic mice after ischemic cortical injury. Bepridil particularly decreased calcium pathology in the thalamus following ischemia. © 2013 Lipsanen et al.


Windisch M.,QPS Austria GmbH | Flunkert S.,QPS Austria GmbH | Havas D.,QPS Austria GmbH | Hutter-Paier B.,QPS Austria GmbH
Ageing Research Reviews | Year: 2013

Li and colleagues summarized the most frequently used Alzheimer's disease (AD) mouse models available for drug testing and the mediating effects of the different compounds. With almost 300 cited publications, authors present the research community's effort of the last 10 years in finding a new drug for the treatment of AD.Some of the transgenic mouse lines mentioned by Li and colleagues are discussed only very briefly. Since we are convinced that a couple of these models indeed have a great value for AD research and the development of new AD drugs we will subsequently describe a few of them in more detail.A suitable mouse model of AD does not only have to mimic major hallmarks of AD that are modifiable by different test substances as mentioned by the authors; they also have to be translational to clinical trials in humans. For the following discussion, we will therefore also include information on clinical trials of drugs previously tested in the different transgenic mice. © 2013 Elsevier B.V.

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