Prof. Dr. Roger Nitsch

 

Main Goals, Keywords

Molecular pathophysiology, genetics and markers of Alzheimer’s disease and related disorders. Transgenic mouse models of these diseases. Regulation of APP processing. Neurobiology of genes involved in neurodegeneration and neuroprotection. Therapies designed to prevent amyloid formation and neuronal atrophy. Immunotherapy and b-amyloid vaccination.

Group Members

The Division of Psychiatry Research comprises 4 professors, 7 group leaders, 1 research scientist, 6 postdoctoral fellows, 12 graduate students, 3 medical students, 3 diploma students, 9 technical assistants, 3 study nurses, 3 ICT team members, 4 lab support and animal care assistants, 3 secretaries, and 20 inpatient unit nursing staff.

Previous and Current Research

The scientific analysis of tissues, cells and fluids derived from patients with dementia provided an important starting point for many of the most important discoveries that led to a detailed understanding of the genes and proteins involved in the disease first described in 1907 by the Neuropathologist and Psychiatrist Alois Alzheimer. At the Division of Psychiatry Research of the University of Zurich, we follow this tradition by integrating clinical and basic scientific research programs designed to better understand the normal functions of genes and proteins involved in Alzheimer’s disease (AD) and related disorders, to characterize their role in the pathophysiology of the disease, and to identify novel avenues for diagnosing, treating and preventing dementia. A multidisciplinary team of investigators with backgrounds ranging from molecular and cell biology, neurobiology and genetics, to medicine, neurology, psy­chiatry and neuropsychology is required to do this work. Our strategy is simple: Careful clinical observation of our patients in the clinical research units leads to the characterization of disease-related phenotypes, and is accompanied by the sampling of biological material including leukocyte DNA, plasma, cerebrospinal fluid, and – after death – brain tissues. We use molecular genetic analyses to identify disease-related mutations and polymorphisms that increase the risk for AD, characterize disease-related protein profiles by recent proteomics technologies, and determine disease-related gene expression profiles in brain tissues. In parallel, we analyze the functional status of cognition and memory by using fMRI and PET, and correlate the resulting phenotypes with genetic and biochemical abnormalities. To understand better the pathophysiological implications of specific mutations and genetic variations, we express them in tissue culture, neural progenitor cells and in transgenic mice, analyze their cell biology and functions, and characterize their impact on the formation of amyloid plaques, neurofibrillary tangles, and cell death and – in some cases – on the behavior of the animals. In parallel, we use some of these tissue cultures and mice for testing novel therapeutic approaches designed to reduce the pathological abnormalities – before they enter the clinical trials, and thus close the scientific loop from the patients to the laboratory and back again. These studies are supplemented by the first electrophysiol­ogi­cal recordings of disease-related evoked potentials in awake and genetically modified mice, and by an Internet-based E-learning program designed to relate the knowledge on dementia to our students who may be able – within their lifetime – to prevent this dreadful disease.
Current clinical studies are testing the first immunization strategy for the treatment of Alzheimer’s disease.

Future Projects

Abnormal protein processing and protein aggregation are central events in the patho­physio­logies of many neurodegenerative diseases. Some of these structures may be related by meaningful interactions: Investigators in our laboratory showed recently that b-amyloid fibrils can cause the formation of neurofibrillary tangles in transgenic mice (Götz et al., 2001). Current studies aim at understanding the biological mechanisms involved in amyloid-induced tangle formation, their relation to functional impairment and cell death, the identification of similarities and distinctive differences among various species of tangles, and their role in ‘sporadic’ forms of the diseases. We hope that these studies will lead to novel targets for the design of treatments that can prevent the formation of neurofibrillary tangles in AD and related disorders. Such treatments include immunotherapeutic approaches and vaccination against b-amyloid. These studies are integrated in the newly established “National Center of Competence in Research (NCCR) on Neural Plasticity and Repair“. The fundamental goal of the NCCR is the restoration of function after damage or disease of the nervous system.

Techniques and Equipment

Differential cloning. Transgenic and knock-out techniques. In situ hybridization and immunohistochemistry. Viral expression vectors. Tissue culture including neural progenitor cells. Neuronal cell transplantation. Genetic analyses including SNP analyses and Pyrosequencing, Automated DNA sequencing, Cyphergen protein chip technology. ELISA. Immunofluorescence and laser confocal microscopy. Mouse behavior. Mouse EEG. Stereotaxic injection.

Selected Publications

• Bengtsson SK, Johansson M, Backstrom T, Nitsch RM, Wang M. Brief but chronic increase in allopregnanolone cause accelerated AD pathology differently in two mouse models. Curr Alzheimer Res. 2013 Jan;10(1):38-47.
• Biscaro B, Lindvall O, Tesco G, Ekdahl CT, Nitsch RM. Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer's disease. Neurodegener Dis. 2012;9(4):187-98. doi: 10.1159/000330363. Epub 2012 May 8.
• Klohs J, Baltes C, Princz-Kranz F, Ratering D, Nitsch RM, Knuesel I, Rudin M. Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAβ mice. J Neurosci. 2012 Feb 1;32(5):1705-13. doi: 10.1523/JNEUROSCI.5626-11.2012.
• Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM. Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. Acta Neuropathol. 2011 Sep;122(3):293-311. doi: 10.1007/s00401-011-0834-y. Epub 2011 Jun 19.

Selected Lectures, Seminars, Colloquia

• Psychiatry Clinic I
• Psychiatry Clinic II
• Biochemistry and Cell Biology of the Nervous System
• Molecular Pathophysiology of Neuropsychiatric Diseases
• Journal Club Neurodegeneration

Funding

NCCR Neural Plasticity and Repair, Swiss National Science Foundation, European Union - DIADEM / Diagnosis of Dementia and Related Disorders, BMBF, Alzheimer Forschung Initiative, Stammbach Foundation, Baugarten Foundation, Vontobel Foundation, Evotec NeuroSciences, AHP-Wyeth-Elan