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Rennweg, Austria

Marosova L.,Slovak Academy of Sciences | Neradil P.,Slovak Academy of Sciences | Zilka N.,Slovak Academy of Sciences | Zilka N.,Axon Neuroscience GmbH
Acta Virologica | Year: 2013

Age is one of the key risk factors of several human neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. During aging the immune system of the brain undergoes multiple structural and functional changes. The major immune cells of the brain-microglia and astrocytes-significantly change their morphology and functional state during aging. Similarly, the blood brain barrier (BBB), that is considered to be the iron curtain protecting the brain parenchyma against invasion of the pathogens, can be influenced by aging. This state of altered brain immunity may lead to the increased brain vulnerability to viral infections, primoinfection as well as reactivation. We hypothesize that impairment of the brain immunity and BBB integrity can create the optimal condition for viral infection that can further amplify the neuroinflammation mediated by glial cells and neurodegeneration induced and driven by disease modified proteins. Source

Skrabana R.,Slovak Academy of Sciences | Skrabana R.,Axon Neuroscience GmbH | Dvorsky R.,Max Planck Institute of Molecular Physiology | Sevcik J.,Slovak Academy of Sciences | And 2 more authors.
Journal of Structural Biology | Year: 2010

Flexibility of intrinsically disordered tau protein is important for performing its functions. It is believed that alteration of the flexibility is instrumental to the assembly of tau protein into paired helical filaments (PHF) in tauopathies. Tau flexibility represents the main obstacle for structure determination of its conformation in physiology and/or pathology. We have alleviated this inherited difficulty by using specific monoclonal antibodies as tau protein surrogate binding partners. In this work we compare two " antibody mold structures": (1) X-ray structure of the free form of the Alzheimer's disease PHF core-specific antibody MN423 and (2) previously solved structure of the complex of MN423 with the PHF core C-terminal tau peptide. We found that MN423 combining site is in both structures identical. As a consequence, recombinant tau assumes in the complex a fold determined by the antibody combining site. Obtained results show that MN423 functions as a molecular mold for the PHF core segment, and opens the way for structure determination of other PHF core segments providing that other conformation-specific antibodies are available. Data from in silico docking of tau peptide into antibody mold, obtained in this study, show that biochemical data and computational approaches provide results comparable to X-ray crystallography. © 2010 Elsevier Inc. Source

Kovacech B.,Slovak Academy of Sciences | Kovacech B.,Axon Neuroscience GmbH | Skrabana R.,Slovak Academy of Sciences | Skrabana R.,Axon Neuroscience GmbH | Novak M.,Slovak Academy of Sciences
Neurodegenerative Diseases | Year: 2010

The neuronal protein tau, a member of the class of intrinsically disordered proteins, is characterized by the absence of any firm 3-D structure and high solubility when free in solution. The tau protein forms insoluble fibrils in the brain of people suffering from Alzheimer's disease (AD) and other tauopathies and plays a key role in the neurodegenerative process. Posttranslational events leading to the transition of tau from a disordered highly soluble protein to the insoluble aggregate seem to be associated with hyperphosphorylation, truncation or a combination of both. These modifications are assumed to change the native disorder of tau into a preaggregation state, which then directly initiates the fibrillization process. Conformation-specific anti-tau antibody DC11 detects pathological truncated tau forms present in AD brains but not in the normal human brain. A truncated tau protein selected from this pool of DC11-positive molecules was sufficient to initiate and drive the complete tau cascade of neurofibrillary pathology in a rat model of tauopathy. Thus, DC11 antibody recognizes the AD-specific conformation of tau not found in the normal human brain. We propose the term 'misdisordered' for this distinct conformational state of tau, which is the first step in the transition of tau from a soluble disordered protein to its insoluble, misordered aggregated form. Copyright © 2010 S. Karger AG, Basel. Source

Zilka N.,Slovak Academy of Sciences | Zilka N.,Axon Neuroscience GmbH | Korenova M.,Slovak Academy of Sciences | Kovacech B.,Slovak Academy of Sciences | And 4 more authors.
Acta Neuropathologica | Year: 2010

The aim of the present study was to identify the relationship between progressive neurobehavioural decline and phospho-tau levels (p-tau 181) in the cerebrospinal fluid (CSF) and the brain in transgenic rats expressing human truncated tau protein. Behavioural analyses, as quantified using the NeuroScale scoring method, revealed that the transgenic rats fell into two main groups based on the baseline behavioural functioning: (1) mild neurobehavioural impairment (MNI, score 3.3-26) and (2) severe neurobehavioural impairment (SNI, score 36-44). SNI transgenic rats showed a significant increase in brain sarkosyl insoluble p-tau181 when compared to their MNI counterparts. In order to determine whether CSF phosphotau reflects the behavioural decline and increase in sarkosyl insoluble tau in the brain, p-tau181 was measured in the CSF in a longitudinal study. The study showed a significant increase in CSF p-tau181 during the progression of the disease from MNI to SNI. Moreover, increased levels of p-tau 181 in CSF correlated with an increase in the sarkosyl insoluble p-tau181 levels in the brain. The increase in the CSF level of p-tau181 during progressive behavioural decline suggests that it may represent a useful surrogate biomarker for preclinical drug development and a potential surrogate endpoint for clinical trials of disease-modifying therapy for Alzheimer's disease and related human tauopathies. © Springer-Verlag 2010. Source

Filipcik P.,Slovak Academy of Sciences | Filipcik P.,Axon Neuroscience GmbH | Zilka N.,Slovak Academy of Sciences | Zilka N.,Axon Neuroscience GmbH | And 6 more authors.
Neurobiology of Aging | Year: 2012

Neurofibrillary degeneration induced by misfolded protein tau is considered to be one of the key pathological hallmarks of Alzheimer's disease (AD). In the present study, we have introduced a novel transgenic rat model expressing a human truncated tau that encompasses 3 microtubule binding domains (3R) and a proline-rich region (3R tau151-391). The transgenic rats developed progressive age-dependent neurofibrillary degeneration in the cortical brain areas. Neurofibrillary tangles (NFTs) satisfied several key histological criteria used to identify neurofibrillary degeneration in human Alzheimer's disease including argyrophilia, Congo red birefringence, and Thioflavin S reactivity. Neurofibrillary tangles were also identified with antibodies used to detect pathologic tau in the human brain, including DC11, recognizing an abnormal tau conformation and antibodies that are specific for hyperphosphorylated forms of tau protein. Moreover, neurofibrillary degeneration was characterized by extensive formation of sarkosyl insoluble tau protein complexes consisting of rat endogenous and truncated tau species. Interestingly, the transgenic rats did not show neuronal loss either in the cortex or in the hippocampus. We suggest that novel transgenic rat model for human tauopathy represents a valuable tool in preclinical drug discovery targeting neurofibrillary degeneration of Alzheimer's type. © 2012 Elsevier Inc. Source

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