German Center for Neurodegenerative Diseases (DZNE)
and Technische Universitaet Muenchen (TUM)
Alzheimer’s disease (AD) is the most common form of dementia. It is mostly seen in older people over 65, and the disease worsens over time. Currently, there is no treatment available for the disease. The characteristic trait of AD is the amyloid plaque formation in the brain. The amyloid plaque forms by accumulation of Aß peptides. Aß peptides are generated upon amyloidogenic processing of the amyloid precursor protein (APP). APP is first cleaved by the protease BACE1, and subsequently by gamma-secretase (Figure 1).
Fig 1: Amyloidogenic processing of APP (modified from Saftig & Lichtenthaler 2015)
Gamma-secretase is an intramembrane protease that can act on numerous substrates, including APP as described above. Gamma-secretase cleaves its substrates within the membrane, releasing their intracellular domains (ICD) to the cytosol, and the remaining peptide to the extracellular space (e.g. Aß peptide). Although many substrates have been identified, little is known about the features that makes a protein a substrate of gamma-secretase. Answering this important issue is essential for developing safe drugs with little side effects that selectively target the gamma-secretase cleavage of APP, but not the cleavage of other substrates.
Our research aims to find out the features that differentiate between a substrate and a nonsubstrate. In this direction, we are testing numerous factors that might be important in gamma secretase cleavage (e.g. sequence motifs, post-translational modifications etc.). We screen for gamma secretase activity, we examine the generation of both ICD and Aß-like fragments. Evaluating the levels of these fragments with different parameters will provide us valuable information about substrate features that are important in gamma secretase activity. Resolving these features will shed light on how gamma-secretase selects and cleaves its substrates, and thus is likely to lead to major improvements in development of substrate-specific drugs that selectively target AD.