Molecular Neurodegeneration
Prof. Dr. Dr. h.c. Christian Haass
Group Leader and Site Speaker
Feodor-Lynen-Str. 17
81377 München

christian.haass@dzne.de
 +49 89 4400-46549

Areas of investigation/research focus

Prof. Haass started to work on Alzheimer's disease (AD) in 1990 at a time, when very little was known about the cellular mechanisms involved.  Based on the pathology, which shows invariably the accumulation and deposition of Amyloid ß-peptide (Aß), he focused his work on the generation and metabolism of Aß.  Christian Haass hypothesized against the widely accepted general opinion in this field that Aß may be produced from its precursor in a physiologically normal pathway and not necessarily in a pathological process.  Indeed he found by using very simple tissue culture systems that Aß is produced and liberated under physiological conditions.  This pivotal finding was a major breakthrough for the entire field, since it allowed elucidating the molecular principles behind Aß generation as well as the identification of the enzymes (the so-called secretases) involved in generation and liberation of the peptide and finally the development of selective inhibitors to therapeutically lower Aß production in patients. Christian first concentrated on the cellular mechanisms behind Aß production. Doing so he made a number of major observations:  Two enzymes, which he called beta- and gamma-secretase produce Aß, while a third enzyme, alpha-secretase, prevents Aß generation.  Moreover, beta-secretase was found to be the rate limiting enzyme and gamma-secretase to be a rather unusual protease cleaving within the hydrophobic environment of a membrane. Using his tissue culture assay he was able to demonstrate how mutations, which cause very aggressive familial variants of AD, affect production of Aß, a finding which provided strong support for a major pathological role of Aß and which was the basis for the amyloid cascade hypothesis.

 more Infos

Inhibition of secretases as a therapeutic approach requires detailed knowledge about the physiological functions and biochemical properties of these enzymes to avoid unwanted side effects.  Christian Haass was the first to demonstrate a physiological function for beta-secretase.  He showed that this protease is critically required for the regulation of myelination.  Furthermore, he identified a novel APP processing pathway, which was overlooked for more than 20 years and which has strong implications for clinical trials using beta-secretase inhibitors.  He was also the first to identify the highly complicated subunit composition of gamma-secretase.  All these findings not only helped to understand several signaling pathways critically involved in brain development (such as myelination and cell differentiation) but also provided the basis for several current therapeutic approaches.  Very recently he also investigated the role of microglia and inflammation in neurodegenerative disorders.  This work led to the spectacular finding that microglial phagocytosis may be impaired late during neurodegeneration and opened up a completely unexpected road towards new therapeutic developments for patients already developing disease symptoms.  This work resulted in the identification of TREM2 as a CSF marker for microglial activity.  In a unique cohort of subjects with autosomal dominant AD, CSF sTREM2 was abnormally increased 5 years before the expected onset of symptoms. This will not only greatly facilitate research on inflammatory disease overarching mechanisms, but may also provide a very valuable therapeutic marker.

Key Publications

Suárez-Calvet M, Caballero MA, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, Levin J, Danek A, Ewers M, Haass C for the Dominantly Inherited Alzheimer Network. Early changes of CSF sTREM2 in Dominantly Inherited Alzheimer’s Disease follow markers of Amyloid Deposition and Neuronal Injury. Sci Transl Med. 2016 Dec 14; 8:369ra178. doi: 10.1126/scitranslmed.aag1767
Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, Hornburg D, Evans LDB, Moore S, Daria A, Hampel H, Müller V, Giudici C, Nuscher B, Wenninger-Weinzierl A, Kremmer E, Heneka MT, Thal DR, Giedraitis V, Lannfelt L, Müller U, Livesey FJ, Meissner F, Herms J, Konnerth A, Marie H, Haass C. eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015 Oct 15; 526:443-7. doi: 10.1038/nature14864
Gernot Kleinberger, Yoshinori Yamanishi, Marc Suárez-Calvet, Eva Czirr, Ebba Lohmann, Elise Cuyvers, Hanne Struyfs, Nadine Pettkus, Andrea Wenninger-Weinzierl, Fargol Mazaheri, Sabina Tahirovic, Alberto Lleó, Daniel Alcolea, Juan Fortea, Michael Willem, Sven Lammich, José L. Molinuevo, Raquel Sánchez-Valle, Anna Antonell, Alfredo Ramirez, Michael T. Heneka, Kristel Sleegers, Julie Van Der Zee, Jean-Jacques Martin, Sebastiaan Engelborghs, Asli Demirtas-Tatlidede, Henrik Zetterberg, Christine Van Broeckhoven, Hakan Gurvit, Tony Wyss-Coray, John Hardy, Marco Colonna, Christian Haass. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Science Translational Medicine. 2014 Jul 01; 6 doi: 10.1126/scitranslmed.3009093
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, De Strooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27; 314:664-6. doi: 10.1126/science.1132341
Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003 May 01; 5:486-8. doi: 10.1038/ncb960

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