APP processing and Abeta localization at super-resolution and glycan biomarkers for Alzheimer disease - Sophia Schedin Weiss research

Research focus

Project 1: Interactions between gamma-secretase and gamma-secretase associated proteins visualized by fluorescence techniques.

Alzheimer Disease (AD) is characterized by the accumulation of amyloid-beta peptide, which forms toxic oligomers and insoluble plaques in the brains of AD patients. This peptide is formed after proteolytical processing of the amyloid precursor protein (APP) by the sequential action of the two enzymes beta-secretase and gamma-secretase. Several mutations in the gene for presenelin, the active component of gamma-secretase, are associated with AD, supporting the role of gamma-secretase in AD pathology. Inhibition of this enzyme has been a widely investigated approach in the search for AD treatments. However, clinical trials indicate that inhibition of gamma-secretase leads to toxic side effects due to the processing of physiologically important substrates, for instance Notch. It has been proposed that gamma-secretase associated proteins (GSAPs) can regulate the enzymatic activity of gamma-secretase by affecting its substrate selectivity. I use fluorescence techniques for studying the interactions between gamma-secretase and GSAPs, for instance proximity ligation assay (PLA), FRET and FLIM.

Project 2: Roles of protein glycosylation in Alzheimer disease

I intend to investigate whether protein glycosylation is affected in Alzheimer disease (AD) and how it contributes to the development of this disease. The number of reports on this subject is so far limited, despite the fact that some interesting findings have been made. I will study whether glycosylation of proteins is affected in cerebrospinal fluid and in brains of AD patients. For the latter studies, emphasis will be put on the glycoproteins that are known to be involved in the pathophysiology of AD. If I find differences in glycosylation of such proteins, I will proceed by determining the effects of the glycans on the functions of these glycoproteins. The techniques used in this project include mass spectrometry, binding assays, western blotting and other types of cell biological and biochemical work.

Group members