Lichtenthaler, Stefan

Molecular mechanisms of Alzheimer’s disease I Biochemistry of the nervous system I Proteases in neurodegenerative diseases

We study how Alzheimer’s disease develops in the brain on the molecular and cellular level and develop new diagnostic, therapeutic and preventive approaches. Additionally, using proteomics we try to predict possible side effects of Alzheimer-targeted drugs, thus making drug development safer. For our interdisciplinary research we use a variety of modern methods from biochemistry, proteomics, molecular, cellular, neurobiology, in vitro and in vivo models of Alzheimer’s disease. The focus of our research is on proteases of the ADAM (alpha-secretase) and BACE (beta-secretase) families as well as on microglia-dependent inflammatory processes, which have a central role in Alzheimer’s pathogenesis.
Selected examples of our recent research:
ADAM10: We identified this metalloprotease as the Alzheimer’s alpha-secretase, which is able to prevent the molecular pathogenesis leading to Alzheimer’s disease. We found that ADAM10 cleaves numerous additional proteins in neurons. An example is the cell adhesion protein NrCAM, for which we established that cleavage is necessary for the correct outgrowth of axons.
BACE1: We discovered that this major Alzheimer’s drug target 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), where the proteolytic cleavage is required for synapse formation/maintenance.
Neuroproteomics: We have two Orbitrap mass spectrometers. One example of our work is the development of the proteomic hiSPECS method for secretome analyses. Another example is the proteomic analysis of cerebrospinal fluid (CSF), which is now possible with only few microliters of CSF from different organisms.

Selected publications:

Pigoni, M., et al. (2020). Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3.
EMBO J, in press.

Rudan Njavro, J., et al. (2020). Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1.
FASEB J, in press.

Fecher, C., et al. (2019). Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity.
Nat Neurosci 22, 1731-1742.

Lichtenthaler, S.F., and Guner, G. (2019). Pathology-linked protease caught in action.
Science 363, 690-691.

Brummer, T., et al. (2019). NrCAM is a marker for substrate-selective activation of ADAM10 in Alzheimer's disease.
EMBO Mol Med 11.

Parhizkar, S., et al. (2019). Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.
Nat Neurosci 22, 191-204.

Lichtenthaler, S.F., et al. (2018). Proteolytic ectodomain shedding of membrane proteins in mammals - hardware, concepts, and recent developments.
EMBO J 37.

Colombo, A., et al (2018). Non-cell-autonomous function of DR6 in Schwann cell proliferation.
EMBO J 37.

Kuhn, P.H., et al. (2012). Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons.
EMBO J 31, 3157-3168.