Helena Karlström Group
Genetic and pharmacological modulation of the Alzheimer-related gamma-secretase complex
Alzheimer disease (AD) is the most common form of dementia, affecting millions of people worldwide. In the current situation there is no cure for the neurodegenerative disease with a fatal outcome 7-10 years after the patient received her diagnosis. AD is not only a major medical problem but also an economic problem for our society because there is no effective treatment, while life expectancy increases.
Amyloid beta-peptide (Abeta) is the principal component of the senile plaques that characterize AD. The peptide aggregates and is stored in the brain early in the disease process. The Abeta peptide is generated from the larger protein APP, which is cleaved by two enzymes (the beta-secretase and the gamma-secretase complex).
Gamma-Secretase is an enzyme complex consisting of presenilin (PS), nicastrin, Aph-1 and Pen-2. Currently, approximately 90 proteins have been identified and characterized as substrates for the gamma-secretase complex. One of these is the Notch receptor, which is an important molecule in many tissues and organs during development. It is therefore very important to keep this signaling pathway intact, while blocking Abeta formation.
In the current situation all known gamma-secretase blockers inhibit both APP and Notch cleavages, and there is a great need to find compounds that distinguishes between these two processes.
To address this, we need to understand the underlying mechanism of the gamma-secretase activity towards various substrates.
Therefore, our projects aim to i) find domains and regions in the different components of the gamma-secretase complex on a molecular level (i.e DNA and protein level) that differ between substrate cleavage activities. Moreover, we will ii) analyze established and new inhibitors and modulators in our cell based systems in order to find molecules that can prevent Abeta production specifically and also to understand their mechanisms. Finally, we iii) aim to understand the impact of familial Alzheimer disease (FAD) mutations for altered Abeta production.
|Helena Karlström||PhD, Associate Professor|
|Tobias Weber||PhD, Postdoc|