Prof. Dr. Sascha Weggen

Research Interest

Our laboratory is primarily interested in the molecular neuropathology of and therapeutic strategies for Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder. Aβ peptides and in particular the longer Aβ42 isoform are thought to be the disease-causing agents in AD. We have discovered a new class of small molecules called γ-secretase modulators (GSMs) that selectively lower Aβ42 production by direct interaction with γ-secretase, a crucial protease activity in the generation of Aβ peptides. Ongoing efforts in our laboratory concentrate on full understanding of the molecular mechanism of GSMs, and chemical development and preclinical testing of improved GSMs. We are further interested in cellular pathways controlling Aβ production, the mechanism of presenilin mutations in familial Alzheimer’s disease, the role of inflammation and microglia cells in the disease, and the pathogenesis of frontotemporal dementia. The group uses techniques of cell and molecular biology and protein biochemistry. Synthetic chemistry is performed in collaboration with medicinal chemists. The laboratory harbors a robotic workstation, which allows us to conduct high-throughput chemical and genetic (RNAi) screens.

Selected Publications

1. Zettl H, Ness J, Hähnke V, Beher D, Jumpertz T, Saric A, Baumann K, Pietrzik CU, Bulic B, Schneider G, Weggen S (2012) Discovery of gamma-secretase modulators with a novel activity profile by text-based virtual screening. ACS Chemical Biology; 7:1488-95. undefinedPubMed

2. Jumpertz T, Rennhack A, Ness J, Baches S, Pietrzik CU, Bulic B, Weggen S (2012) Presenilin is the molecular target of acidic gamma-secretase modulators in living cells. PLoS ONE; 7:e30484. undefinedPubMed

3. Hahn, S., Brüning, T., Ness, J., Czirr, E., Baches, S., Gijsen, H., Korth, C., Pietrzik, C.U., Bulic, B., Weggen, S. (2011) Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer’s disease attenuate the response of cultured cells to gamma-secretase modulators regardless of their potency and structure. J. Neurochem. 116:385-95. undefinedPubMed

4. Hieke, M., Ness, J., Steri, R., Dittrich, M., Greiner, C., Werz, O., Baumann, K., Schubert-Zsilavecz, M., Weggen, S*., Zettl, H*. (2010) Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity. J. Med. Chem. 53:4691-4700. (*corresponding authors) undefinedPubMed

5. Czirr, E:, Cottrell, B. A., Leuchtenberger, S., Kukar, T., Ladd, T. V., Esselmann, H., Paul, S., Schubenel, R., Torpey, J. W., Pietrzik, C. U., Golde, T. E., Wiltfang, J., Baumann, K. H., Koo, E. H., Weggen, S. (2008) Independent generation of Abeta42 and Abeta38 peptide species by gamma-secretase. J. Biol. Chem. 283:17049-17054. undefinedPubMed

6. Czirr, E., Leuchtenberger, S., Dorner-Ciossek, C., Schneider, A., Jucker, M., Koo, E. H., Pietrzik, C. U., Baumann,  K. H., Weggen, S. (2007) Insensitivity to Abeta42-lowering non-steroidal anti-inflammatory drugs (NSAIDs) and gamma-secretase inhibitors is common among aggressive presenilin-1 (PS1) mutations. J. Biol. Chem. 282:24504-24513. undefinedPubMed

7. Kukar, T., Murphy, M. P., Eriksen, J. L., Sagi, S. A., Weggen, S., Smith, T. E., Ladd,  T., Khan, M. A., Beard, J., Dodson, M., Merit, S., Ozols, V. V., Anastasiadis, P. Z., Das, P., Fauq, A., Koo, E. H., Golde, T. E. (2005) Diverse compounds mimic Alzheimer’s disease causing mutations by augmenting Abeta42 production. Nat. Med. 11:545-550. undefinedPubMed

8. Weggen, S., Eriksen, J., Sagi, S. A., Pietrzik, C. U., Ozols, V., Fauq, A., Golde, T. E., Koo, E. H. (2003) Evidence that nonsteroidal anti-inflammatory drugs decrease Abeta42 production by direct modulation of gamma-secretase activity. J. Biol. Chem. 278:31831-31837. undefinedPubMed

9. Weggen, S., Eriksen, J., Sagi, S., Pietrzik, C. U., Golde, T. E., Koo, E. H. (2003) Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage in the amyloid precursor protein and ErbB-4 and signaling through the APP intracellular domain. J. Biol. Chem. 278: 30748-30754. undefinedPubMed

10. Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., Kang, D. E., Marquez-Sterling, N., Golde, T. E., Koo, E. H. (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414:212-216. undefinedPubMed

Prof. Dr.
Sascha Weggen

Molecular Neuropathology

Prof. Dr. Sascha Weggen

Department of Neuropathology
Molecular Neuropathology Group
Heinrich Heine University
Tel.: +49 211 81-04506
Fax: +49 211 81-04577
Verantwortlich für den Inhalt: E-Mail sendenNeuroscience Network Düsseldorf