Molecular Biology

The group studies mechanisms of neurodegeneration using molecular and cell biology techniques.

One part of our work concentrates on the processing and cellular function of the amyloid precursor protein (APP). APP is one of the major proteins involved in Alzheimer's disease (AD), but its physiological function remains elusive. Sequential cleavage of APP by β- and λ-secretase leads to generation of amyloid-beta (Aβ) peptides, the major components of amyloid plaques in the brain of patients with AD. We aim to find new pathways to decrease the amount of Aβ as a therapeutical strategy. Thereby we gained new insights into the mechanism of Gleevec, a known tyrosine kinase inhibitor, which may serve asa basis for potential Aβ lowering drugs (Eisele et al. 2007). Moreover we have found that the BRI2 protein involved in familial Danish Dementia (FDD) and familial British Dementia (FBD) might act as a receptor protein that regulates insulin degrading enzyme (IDE) levels which in turn influences APP metabolism (Kilger et al., 2011).

Uptake and internalization may be the first step required for spreading and amplification of Aβ and initial seeding active material. We aim to further analyze the cellular prerequisites for these events using fluorescently labeled Aβ and seeding analogs in combination with live cell imaging techniques. Spreading and transmission of amyloidogenic peptides from cell to cell have been reported already in vitro and in vivo with nanotubes and exosomes coming into focus. Mechanistic models have been discussed for the prion protein and might be conserved among other amyloids. Based on in house available mouse models we further investigate this topic using primary neuronal cultures and live cell imaging techniques.

Finally, we are interested in the toxic properties of Aβ. Apart from in extracellular deposits Aβ is found in several intracellular compartments and also in association with a variety of biological membranes. Yet it still remains elusive which key localizations are prerequisite for its neuro toxicity, i.e. the pathophysiological hallmarks such as neuronal loss and cognitive decline observed in AD patients. To this end, we have established new cell culture and mouse models to test a variety of hypotheses both in vivo and in vitro.

Contact: Dr. F. Baumann

Recent Publications
Eisele YS, Baumann M, Klebl B, Nordhammer C, Jucker M, Kilger E (2007) Gleevec increases levels of the amyloid precursor protein intracellular domain and of the amyloid-ß-degrading enzyme neprilysin, Molecular Biology of the Cell, 18:3591-3600 (Abstract)

Baumann F,Pahnke J, Radovanovic I, Rulicke T, Bremer J, Tolnay M, Aguzzi A (2009) Functionallyrelevant domains of the prion protein identified in vivo. PLoS One, 4e6707 (Abstract)

Kilger E, Buehler A, Woelfing H, Kumar S, Kaeser SA, Nagarathinam A, Walter J, Jucker M, Coomaraswamy J (2011) BRI2 protein regulates ß-Amyloid degradation by increasing levels of secreted Insulin-degrading enzyme (IDE). J Biol Chem 286:37446-57 (Abstract)