Nitsch
Fakultäten » Medizinische Fakultät » Psychiatrische Universitätsklinik » Psychiatrische Forschung, Abteilung für und Klinik für Alterspsychiatrie » Prof. Dr. Roger M. Nitsch » Nitsch
Completed research project
| Title / Titel | Molecular Pathophysiology, Genetics and the Treatment of Alzheimer’s Disease | ||
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| Abstract (PDF, 14 KB) | |||
| Summary / Zusammenfassung | We have a long-standing interest in the molecular and cellular biology of neurodegenerative diseases including Alzheimer’s disease in order to find clues for the development of novel avenues for the treatment and prevention of dementia. To achieve these research goals, we implemented in Zurich a truly integrated research operation with clinical units and neurobiological units working seamlessly together, coached and supervised by a joint clinical-basic leadership, and working in close collaboration with biotechnology companies and pharmaceutical partners to ensure that results of the academic research programs are translated into the development of useful products for unmet medical needs. We successfully completed the cycle from basic science discoveries to applications in clinical trials several times. As an example, we first described in 1992 the regulation of APP processing by neurotransmitter receptors (Nitsch et al., Science 1992; Nitsch et al. PNAS 1993) and led this approach all the way to clinical studies in which he demonstrated proof of concept in patients with Alzheimer’s disease (Nitsch et al., Ann. Neurol. 2000). The approach of using subtype selective muscarinic agonists to lower brain levels of beta amyloid for the treatment of Alzheimer’s disease is now pursued by several leading pharmaceutical companies. In order to understand better the pathophysiological relation of beta amyloid plaques and neurofibrillary tangles (NFT), we initiated experiments designed to express disease-causing tau mutations in brains of transgenic mice, thereby enabling the principle process of NFT formation, and then exposed these mice to intracerebral microinjection of beta amyloid plaques. Together with Jürgen Götz and Feng Chen in our lab, this approach let to the first experimental demonstration of NFT in the brains of mice, and it showed that beta amyloid can trigger, and accelerated, NFT formation in brain. (Götz et al., J. Biol Chem. 2001, Götz et al., Science 2001). A closely related focus is the use of mouse models generated in the lab in the characterization of novel treatment approaches. For example, together with Hasan Mohajeri, we showed that both Abeta cleaving proteases and antibodies against Abeta can lower brain levels of Abeta iin transgenic mice. In addition, the latter finding was the first to demonstrate neuroprotective effects of antibodies against beta amyloid in vivo (Mohajeri et al., J. Biol. Chem. 2002a, Mohajeri et al., J. Biol. Chem. 2002b). Together with Christoph Hock, we perform clinical therapy studies on Alzheimer’s disease. Here, we design and implement neurobiological proof of principle studies that are added on to regular early phase clinical trials. As an example, in the current ELAN trial of Abeta vaccination, we initiated experiments for the characterization of antibodies in human sera by using brain tissues sections from transgenic mice in the laboratory (Hock et al., Nat. Med. 2002). These finding let to the development of the tissue amyloid plaque immunoreactivity (TAPIR) assay that demonstrated for the first time, the clinical efficacy of antibodies against beta amyloid in patients with Alzheimer’s disease (Hock et al., Neuron 2003). Together with Andreas Papassotiropoulos we are intimately involved in several genetic projects designed to identify genes that modify the risk for Alzheimer’s disease. After identification of such genes in clinical studies, he initiated and supervises experiments designed to explore the normal neurobiological function as well as the possible role in the pathology of disease. (See, for example, Finck et al., Arch Neurol.2000; Steinhoff et al., Neurobiol. Dis. 2001; Deng et al., Am. J. Pathol. 2001). Another innovative approach is based upon the observation of selective vulnerability in the brains of patients with Alzheimer’s disease, where predominantly brain regions required for cognition, such as the inferior temporal cortex and the hippocampus degenerate, whereas others including the parietal cortex are relatively protected from degeneration. The neurobiological functions of individual examples of several interesting genes are being characterized in the lab (Greeve et al., J. Neurosci. 2000; von Rotz et al., submitted for publication). These results are now followed up to identify novel target candidates in drug development with leading pharmaceutical partners. |
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| Publications / Publikationen | Götz, J., Chen, F., Van Dorpe, J. and Nitsch, R.M. (2001) Abeta42 fibrils induce the formation of neurofibrillary tangles in P301L tau transgenic mice. Science, 293, 1491-1495Hock, C., Konietzko, U., Papassotiropoulos, A., Wollmer, A., Streffer, J., von Rotz, R.C., Davey, G., Moritz, E. and Nitsch, R.M. (2002) Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nature Med. 8, 1270-1275Hock, C., Konietzko, U., Streffer, J.R., Tracy, J., Signorell, A., Müller-Tillmanns, B., Lemke, U., Henke,K., Moritz, E., Garcia, E., Wollmer, M.A., Umbricht, D., de Quervain, D.J.F., Hofmann, M., Maddalena, A., Papassotiropoulos, A. and Nitsch, R.M. (2003) Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 38, 547-554 | ||
| Keywords / Suchbegriffe | Alzheimer, amyloid, Vaccination, Genetics, Therapy | ||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Universität Zürich (position pursuing an academic career), SNF (Personen- und Projektförderung), SNF (Programm NFS/NCCR), EU |
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| Duration of Project / Projektdauer | May 1999 to Dec 2004 |