Division of Psychiatry Research
Our group is interested in elucidating the cellular function of the amyloid precursor protein (APP) in health and disease. We are currently focusing on the nuclear signaling function of the APP intracellular domain (AICD). We are further developing novel mouse models and therapeutic approaches for Alzheimer’s disease, reducing the pathogenic APP-derived Aβ peptide by immunization, or by compounds increasing Aβ-degrading activity.
Keywords: Alzheimer’s disease, amyloid precursor protein, γ-secretase processing, nuclear signalling, immunization, arctic mutation, Aβ-oligomers
1 group leader, 3 PhD students, 3 technicians
The amyloid precursor protein (APP) plays a central role in Alzheimer’s disease (AD). Despite extensive research the physiological role of APP is still elusive. APP is a single-pass transmembrane protein undergoing complex proteolytic processing. After liberation of the large extracellular domain by α- or β-cleavage the remaining membrane-anchored stub is cleaved in the membrane by the γ-secretase complex. In the case of preceding β-cleavage this leads to the generation of the amyloid plaque-forming Aβ-peptide. In addition γ-secretase cleavage releases the APP intracellular domain (AICD) from the membrane. Proteolytic processing of the Notch receptor by similar secretases results in nuclear translocation of the Notch intracellular domain (NICD) and the activation of gene expression.
We have analyzed the nuclear translocation of AICD derived from the cleavage of APP in cultured cells with confocal microscopy. By co-transformation of APP and various AICD-binding proteins we could identify molecules involved in the nuclear translocation of AICD. The APP-adaptor FE65 bound to AICD and actively transported it to the nucleus. In the nucleus the AICD-Fe65-complex bound the histone-acetylase Tip60, forming multiple spherical spots. We hypothesize that these spots represent sites of active transcription and have identified several genes regulated by the overexpression of AICD. The identification of genes regulated by APP will lead to a better understanding of its cellular function and might enable the identification of new therapeutic targets for treating AD.
In the field of AD therapy the Division of Psychiatry Research was involved in the first immunization trial for AD. Our group has established a new assay to judge the quality of the patients immune response (TAPIR assay, see Publications).
We have created new mouse models that express mutant forms of APP, resulting in the increased production of Aβ-oligomers. These mice show behavioural deficits before the deposition of amyloid-plaques. We are currently analyzing the synaptic changes responsible for the changed behaviour.
We have performed microarray experiments with clonal cell lines that can be induced to express exogenous AICD. Candidate AICD-regulated genes are currently verified in different cellular systems at the RNA and protein level. In addition we are using a proteomic approach to identify novel APP-interacting proteins. Using AICD peptides as baits, the resulting isolates are analyzed by LC-MS-MS at the FGCZ. We are focussing on nuclear interaction partners, such as proteins involved in transcription, as well as peripheral binding proteins. Thereby we hope to better understand the molecular mechanism of AICD transport from the periphery to the nucleus. Besides analyzing the physiology of APP we are experimenting with FRET-based approaches, to enable high throughput screening for Aβ-degrading compounds. Ongoing efforts are to create novel AD mouse models that more closely resemble the human disease.
Recombinant DNA technology, in situ hybridization, cell culture, primary neuronal cultures, hippocampal progenitor culture, tissue fractionation, immunoprecipitation and Western blot analysis, immunohistochemistry, confocal microscopy, FRET analysis of fluorescent fusion proteins, laser dissection microscopy, real-time PCR, production of transgenic and knockout mice, behavioural analysis of mice.
Animal facility, fluorescence microscopes, confocal microscope, microinjection equipment, cell culture facility.
Forschungskredit der Universität Zürich, Deutsche Forschungsgemeinschaft, National Center for Competence in Research (NCCR) „Neural Plasticity and Repair", Sixth EU Framework Programme APOPIS (Abnormal proteins in the pathogenesis of neurodegenerative disorders).
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