Prof. Dr. Stefan Lichtenthaler

Areas of investigation/research focus

We study how Alzheimer’s disease (AD) develops in the brain at 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, molecular, cellular and neurobiology as well as in vitro and in vivo models of AD. 

In our research, we focus on proteolytic processes in the brain. We are specifically interested in the molecular scissors (proteases) ADAM10 (alpha-secretase) and BACE1 (beta-secretase) as well as in newly identified genetic risk factors for AD, that may modulate proteolysis in the brain. Many of them are strongly expressed in microglia, the brain-resident immune cells, and may directly control the microglia-dependent inflammatory processes in an AD brain. We investigate the physiological function of the proteases and their modulators in the healthy brain, study the mechanisms through which they contribute to AD and develop ways to specifically target them for the treatment of AD.

Additionally, we develop proteomic methods for a faster and more detailed study of the proteases and their modulators, 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 give selected examples of our recent and ongoing research.

ADAM protease-mediated microglia functions: Metalloproteases of the ADAM family, in particular ADAM10 and ADAM17, have central roles in controlling membrane protein homeostasis. Both proteases also contribute to AD pathogenesis, for example by controlling the function of the surface receptor TREM2 in microglia and the generation of the amyloid ß peptide in neurons. Several recently identified genetic risk factors for AD, such as RHBDF2/iRhom2 and MS4A4A, are expressed in microglia, the brain-resident immune cells, but little is known about their function, how they modulate AD risk and whether they are suitable as new AD drug targets. We study the physiological function of these new risk genes, including during embryonic development, and their pathophysiological functions in AD. As experimental systems, we use mice, iPSC-derived human cells, primary murine cells and cell lines.

BACE1: This protease has a major role in Alzheimer’s pathogenesis and is a main target for drug development. We discovered that BACE1 cleaves numerous proteins in the nervous system and has a key role in the function of the brain. BACE1-targeted inhibitors efficiently lower Aß in the human brain, but are associated with side effects. To understand the cause of the side effects, we determined how the CSF proteome changes after BACE1 inhibition in clinical trials. To prevent the side effects, we proposed changes in drug dosing, which are the basis for new clinical trials with BACE1 inhibitors.

Neuroproteomics: An Exploris 480 Orbitrap, as well as a timsTOF Pro mass spectrometer are used in our group, in particular for discovery proteomics. One example of our work is the development of the proteomic hiSPECS method for secretome analyses and for the identification of protease substrates from primary cells. Another example is the proteomic analysis of cerebrospinal fluid (CSF) which is now possible with only few microliters of CSF from different organisms. We often use proteomic analyses at the beginning of a project and then characterize the hits functionally and mechanistically, both in vitro and in vivo.

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