Group leader: Molecular Neuropathology
Moorenstraße 5 40225 Düsseldorf
Our laboratory is primarily interested in the molecular neuropathology of Alzheimer’s disease (AD). The initial trigger in the pathogenesis of AD is the accumulation and aggregation of amyloid-β (Aβ) peptides in the aging brain. These Aβ peptides including the highly aggregation-prone and pathogenic Aβ42 peptides are generated through sequential cleavage of the amyloid precursor protein (APP) by the proteases β- and γ-secretase. We have discovered a new class of small molecules called γ-secretase modulators (GSMs) that selectively lower Aβ42 production but do not affect the overall enzyme activity of γ-secretase. While classical inhibitors of β- and γ-secretase have caused severe side-effects in AD clinical trials, GSMs remain in clinical development and a promising and potentially cost-effective option for the prevention of AD. Ongoing efforts in our laboratory concentrate on a full understanding of the molecular mechanism of GSMs, and the chemical development and preclinical testing of improved GSMs.
We are further interested in novel cellular pathways controlling Aβ production and APP processing. Recently, we discovered that APP is cleaved at multiple sites by the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) resulting in the generation of N-terminally truncated Aβ4-x peptides. Aβ4-x peptides are particularly toxic to neurons and highly abundant in brain tissue of AD patients. ADAMTS proteases have been identified as genetic risk factors for sporadic AD, and we are pursuing their role in AD pathogenesis using a variety of murine and human in vitro and in vivo models.
Other interests of our research group include the mechanism of PSEN mutations in familial AD, the role of inflammation and microglia cells in the disease, and the pathophysiological role of the growth factor progranulin in frontotemporal dementia. The group uses techniques of cellular and molecular biology and protein biochemistry, including gene editing, stem cell cultivation and differentiation, and the use of murine animal models. Synthetic chemistry and chemical biology experiments are performed in collaboration with medicinal chemists.
- Walter S, Jumpertz T, Hüttenrauch M, Ogorek I, Gerber H, Storck SE, Zampar S, Dimitrov M, Lehmann S, Lepka K, Berndt C, Wiltfang J, Becker-Pauly C, Beher D, Pietrzik CU, Fraering PC, Wirths O, Weggen S (2019) The metalloprotease ADAMTS4 generates N-truncated Abeta4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease. Acta Neuropathologica; 137:239-257. PubMed
- Goel P, Jumpertz T, Mikles DC, Tichá A, Nguyen MTN, Verhelst S, Hubalek M, Johnson DC, Bachovchin DA, Ogorek I, Pietrzik CU, Strisovsky K, Schmidt B, Weggen S (2017) Discovery and Biological Evaluation of Potent and Selective N-Methylene Saccharin-Derived Inhibitors for Rhomboid Intramembrane Proteases. Biochemistry; 56:6713-6725. PubMed
- Wirths O, Walter S, Kraus I, Klafki HW, Stazi M, Oberstein TJ, Ghiso J, Wiltfang J, Bayer TA, Weggen S (2017) N-truncated Abeta(4-x) peptides in sporadic Alzheimer's disease cases and transgenic Alzheimer mouse models. Alzheimer’s Research & Therapy; 9:80. PubMed
- 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. PubMed
- 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) PubMed
- 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. PubMed
- 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. PubMed
- 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. PubMed
- 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. PubMed
- 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. PubMed