Areas of investigation/research focus
We study how Alzheimer’s disease develops in the brain on the molecular and cellular level. The aim of our research is to better understand the disease causes and to develop new diagnostic, therapeutic and preventive approaches. Additionally, we want to predict possible side effects of Alzheimer-targeted drugs and, thus, make drug development safer.
For our interdisciplinary research we use a variety of modern methods from biochemistry, proteomics, molecular, cellular and neurobiology as well as in vitro and in vivo models of Alzheimer’s disease.
The focus of our research is on the molecular scissors (proteases) ADAM10 (alpha-secretase), BACE1 (beta-secretase) und gamma-secretase as well as microglia-dependent inflammatory processes in the brain. These molecules and processes have a central role in Alzheimer’s pathogenesis. We investigate their physiological function in the healthy brains and develop ways to specifically target them for a treatment of Alzheimer’s disease.
Additionally, we develop proteomic methods for a faster and more detailed study of these proteases, but also of the brain’s cerebrospinal fluid. This will not only allow a better understanding of the brain, but also help to develop new diagnostics for evaluating whether patients respond well to a drug.
In the following we demonstrate selected examples of our recent research.
ADAM10: We identified the metalloprotease ADAM10 as the Alzheimer alpha-secretase. This enzyme is able to prevent the molecular pathogenesis leading to Alzheimer’s disease. We also found that ADAM10 cleaves numerous additional proteins in neurons and, thus, has a fundamental function in development and function of the brain. An example is the cell adhesion protein NrCAM, which we identified as a novel ADAM10 substrate and for which cleavage is necessary for the correct outgrowth of axons.
BACE1: This protease has a major role in Alzheimer’s pathogenesis and is a main target for drug development. We discovered that BACE1 – similar to ADAM10 – cleaves numerous proteins in the nervous system and has a key role in the function of the brain. An example is seizure protein 6 (SEZ6). Its proteolytic cleavage is required for synapse formation and maintenance. Moreover, its cleavage product appears suitable as a companion diagnostic for BACE1 inhibitors, which are currently being developed.
Neuroproteomics: Three mass spectrometers are available in our group. The Q-Exactive HF and the Exploris 480, as well as the timsTOF Pro are applied for untargeted analyses (DDA: data-dependent analysis; DIA: data-independent analysis). One example of our work is the development of the proteomic hiSPECS method for secretome analyses and for the identification of protease substrates in primary neurons. Another example is the proteomic analysis of cerebrospinal fluid (CSF) which is now possible with only few microliters of CSF from different organisms.