A5045030952- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Cell death mechanisms and regulation
- Cholinesterase and Neurodegenerative Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Mitochondrial Function and Pathology
- Computational Drug Discovery Methods
- Cellular transport and secretion
- Glycosylation and Glycoproteins Research
- 14-3-3 protein interactions
- Advanced Proteomics Techniques and Applications
- Metabolomics and Mass Spectrometry Studies
- Calpain Protease Function and Regulation
- Ion channel regulation and function
- Autophagy in Disease and Therapy
- Microtubule and mitosis dynamics
- Lysosomal Storage Disorders Research
- Carbohydrate Chemistry and Synthesis
- Prion Diseases and Protein Misfolding
- Memory and Neural Mechanisms
- Venomous Animal Envenomation and Studies
- RNA regulation and disease
- Retinal Development and Disorders
- Bioinformatics and Genomic Networks
- Free Radicals and Antioxidants
Lundbeck (Denmark)
2012-2023
University of Konstanz
1997-2007
In-Q-Tel
2007
University Hospital of Zurich
2007
Institute of Molecular and Cell Biology
2001-2005
École Polytechnique Fédérale de Lausanne
1999
The pathogenesis of stroke, trauma and chronic degenerative diseases, such as Alzheimer's disease (AD), has been linked to excitotoxic processes due inappropriate stimulation the N-methyl-D-aspartate receptor (NMDA-R). Attempts use potent competitive NMDA-R antagonists neuroprotectants have shown serious side-effects in patients. As an alternative approach, we were interested anti-excitotoxic properties memantine, a well-tolerated low affinity uncompetitive antagonist presently used...
The pathogenesis of several neurodegenerative diseases may involve indirect excitotoxic mechanisms, where glutamate receptor overstimulation is a secondary consequence initial functional defects neurons (e.g., impairment mitochondrial energy generation). neurotoxin 1-methyl-4-phenylpyridinium (MPP<sup>+</sup>) and other inhibitors rotenone or 3-nitropropionic acid) elicited apoptosis in cerebellar granule cell cultures via stimulation autocrine excitotoxicity. Cell death, increase...
Alzheimer's disease (AD) represents the most common age-related neurodegenerative disorder. It is characterized by invariant accumulation of β-amyloid peptide (Aβ), which mediates synapse loss and cognitive impairment in AD. Current therapeutic approaches concentrate on reducing Aβ levels amyloid plaque load via modifying or inhibiting generation Aβ. Based vivo two-photon imaging, we present evidence that side effects level dendritic spines may counteract beneficial potential these...
Conditional overexpression of four-repeat human tau containing the P301L missense mutation in rTg4510 mouse model tauopathy leads to progressive accumulation neurofibrillary tangles and hyperphosphorylated, sarkosyl-insoluble species, w
Plasma membrane Ca2+ ATPase (PMCA) pump isoforms 2, 3, and 1CII are expressed in large amounts the cerebellum of adult rats but only minimally neonatal cerebellum. These were almost undetectable rat cerebellar granule cells 1–3 days after plating, they became highly 7–9 culturing under depolarizing conditions (25 mm KCl). The behavior isoform 4 was different: it clearly detectable down-regulated by cultured cells. 25 mmKCl-activated l-type channels, significantly increasing cytosolic Ca2+....
There is growing evidence of apoptosis in neurodegenerative disease. However, it still unclear whether the pathological manifestations observed slow diseases are due to neuronal loss or they related independent degenerative events axodendritic network. It also remains elusive a single, caspase-based executing system involving caspases responsible for by apoptosis. Long-term exposure microtubule-disassembling agent, colchicine, was used disrupt network and eventually trigger...
Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms agitation, aggression, depression, insomnia. We explored the phenotype a mouse model (rTg4510) carrying human tau P301L mutation found in familial form FTD. tested these mice locomotor activity assays well Morris water maze access spatial memory....
Abstract Introduction The abnormal hyperphosphorylation of the microtubule‐associated protein tau plays a crucial role in neurodegeneration Alzheimer's disease (AD) and other tauopathies. Methods Highly specific selective anti‐pS396‐tau antibodies have been generated using peptide immunization with screening against pathologic hyperphosphorylated from rTg4510 mouse AD brains selection vitro vivo seeding assays. Results antibody C10.2 bound specifically to pS396‐tau an IC 50 104 pM detected...
Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently.To characterize proteomic profile SPs surrounding tissue in a mouse model AD 10-month-old tgAPPPS1-21 mice after chronic treatment for four months weekly dosing (10 mg/kg).After observing significant reduction SP numbers hippocampi aducanumab-treated mice, we applied localized analysis...
The pathogenesis of various acute and chronic neurodegenerative disorders has been linked to excitotoxic processes excess generation nitric oxide. We investigated the deleterious effects calpain activation in oxide-elicited neuronal apoptosis. In this model, oxide triggers apoptosis murine cerebellar granule cells by an mechanism requiring glutamate exocytosis receptor-mediated intracellular calcium overload. Here, we found that calcium-dependent cysteine proteases, calpains, were activated...
Aggregation of the amyloid-beta (Abeta) peptide into amyloid plaques is a characteristic feature Alzheimer's disease neuropathogenesis. We and others have previously demonstrated delayed Abeta aggregation as consequence oxidizing single methionine residue at position 35 (Met-35). Here, we examined consequences Met-35 oxidation on extremely aggregation-prone peptides Abeta1-42 Abeta1-40Arctic with respect to protofibril oligomer formation well neurotoxicity. Size exclusion chromatography mass...
Abstract Deposition of extensively hyperphosphorylated tau in specific brain cells is a clear pathological hallmark Alzheimer's disease and number other neurodegenerative disorders, collectively termed the tauopathies. Furthermore, hyperphosphorylation prevents it from fulfilling its physiological role as microtubule‐stabilizing protein leaves increasingly vulnerable to self‐assembly, suggestive central underlying contributing factor etiology these diseases. Via vitro phosphorylation...
Agonistic engagement of the cytokine receptor CD95 in mice leads to activation hepatic caspases, followed by massive hepatocyte apoptosis, acute liver failure, and death. This mechanism cell death is thought be associated with several human disorders. Because glutathione represents major defense against toxic injury, we investigated its role CD95-mediated which a model for hyperinflammatory organ destruction. As tool modulating status vivo , used GSH transferase substrate, phorone, rapidly...
Tau antibodies have shown therapeutic potential for Alzheimer's disease and several are in clinical trials. As a microtubule-associated protein, tau relies on dynamic phosphorylation its normal functions. In tauopathies, it becomes hyperphosphorylated aggregates into toxic assemblies, which collectively lead to neurodegeneration. Of the phospho-epitopes, region around Ser396 has received particular attention because of prominence stability tauopathies. Here we report first structure...
Background: Tauopathies such as Alzheimer’s disease (AD) are characterized by abnormal hyperphosphorylation of the microtubule-associated protein tau (MAPT) aggregating into neurofibrillary tangles (NFTs). O-linked β-N-acetylglucosamine (O-GlcNAc) modifications have been suggested to regulate phosphorylation and aggregation N-acetylglucosaminidase (OGA) removes GlcNAc moieties from proteins. Methods: We investigated effects OGA inhibitor Thiamet G in rTg4510 primary neuronal cultures mice....