Hock Nitsch
Fakultäten » Medizinische Fakultät » Psychiatrische Universitätsklinik » Psychiatrische Forschung, Abteilung für und Klinik für Alterspsychiatrie » Prof. Dr. Christoph Hock » Hock Nitsch
Completed research project
| Title / Titel | Alzheimer’s Disease | ||||
|---|---|---|---|---|---|
| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | Alzheimer's disease (AD) is a progressive, neurodegenerative disease. Major pathological hallmarks are the abnormal deposition in brain of aggregated beta-amyloid (Abeta) peptides and neurofibrillary tangles. The major goals in this project are (I) to better understand the molecular mechanisms leading to Alzheimer's disease and (II) to develop innovative approaches for the treatment and prevention. We use transgenic mouse models to study the molecular and cellular mechanisms leading to Alzheimer pathology and to identify strategies to accelerate the removal of Abeta from the brain or to prevent Abeta accumulation. In ArcAbeta mice the familial AD-causing Arctic and Swedish mutations in the amyloid precursor protein (APP) are expressed leading to enhanced Abeta aggregation and protofibril formation. We analyze brain pathology; in particular we determine the temporal sequence of intracellular Abeta aggregates in relation to neurodegeneration and to the formation of extracellular beta-amyloid in plaques and cerebrovascular deposits. We also analyze the functional consequences of Abeta protofibrils formation by electrophysiology and by behavioral and neurological tests. The physiological and pathophysiological functions of the amyloid precursor protein (APP) are examined in vitro and in vivo. Despite extensive research the physiological role of APP is still under debate. We have shown that after proteolytic intramembraneous cleavage the APP intracellular domain (AICD) translocates to the nucleus to regulate transcription. We are currently characterizing which proteolytic cleavage pathways lead to nuclear signaling, the function of the nuclear spots where AICD localizes and the target genes regulated by AICD. Furthermore, we isolate and analyze APP-associated protein complexes directly from brain. One part of the project is focused on the characterization of therapeutically active antibodies. Therefore, specific antibodies are isolated from both patients and healthy individuals. A major focus is on the development of methods for the isolation and characterization of antibodies. Subsequently, we will characterize these antibodies in animal models of the disease. |
||||
| Publications / Publikationen | • Knobloch M, Konietzko U, Krebs DC,Nitsch RM. (2006) Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol. Aging in press. • Kohli BM, Eng JK, Nitsch RM, Konietzko, U. (2005) An alternative sampling algorithm for use in liquid chromatography/tandem mass spectroscopy experiments. Rapid Commun. Mass Spectrom. 19, 589-96. • von Rotz RC, Kohli BM, Bosset J, Meier M, Suzuki T, Nitsch RM, Konietzko U. (2004) The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. J. Cell Sci. 117, 4435-4448. • Nitsch, R.M. (2004) Immunotherapy of Alzheimer disease. Alzheimer Dis. Assoc. Disord. 18, 185-189. • Hock, C. et al. (2003) Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron 38, 547-554. • Mohajeri, M.H. et al. (2002) Passive immunization against beta-amyloid peptide protects central nervous system (CNS) neurons from increased vulnerability associated with an Alzheimer's disease-causing mutation. J. Biol. Chem. 277, 33012-33017. • Hock, C. et al. (2002) Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat. Med. 8, 1270-1275. |
||||
| Keywords / Suchbegriffe | Alzheimer, beta-amyloid, therapy, antibody, transgenic mouse models, behavioral testing, amyloid precursor protein (APP), nuclear signaling, APP target genes | ||||
| Project leadership and contacts / Projektleitung und Kontakte |
|
||||
| Funding source(s) / Unterstützt durch |
Universität Zürich (position pursuing an academic career), SNF (Personen- und Projektförderung), SNF (Programm NFS/NCCR), EU |
||||
| Duration of Project / Projektdauer | Jan 2005 to Dec 2009 |