Sophia Schedin Weiss
APP processing and Abeta localization at super-resolution and glycan biomarkers for Alzheimer disease
APP processing and Abeta localization at super-resolution
Alzheimer Disease (AD) is characterized by the accumulation of amyloid-beta peptide (Abeta), which forms toxic oligomers and insoluble plaques in the brains of AD patients. Several studies suggest that intracellular Abeta is neurotoxic and correlates with AD pathology. The peptide is formed after proteolytic processing of the amyloid precursor protein (APP) by the enzymes BACE1 and gamma-secretase. However, despite intensive research there are still knowledge gaps regarding the exact location of APP processing and Abeta in neurons. To collect more pieces to this puzzle, we use super-resolution microscopy such as Stimulated Emission Depletion (STED) microscopy and Stochastic Optical Reconstruction Microscopy (STORM), which provide ˃10-fold improved resolution as compared to traditional light microscopy techniques. This improved resolution is necessary to resolve small structures in neurons, such as the synaptic cleft, which is only around 20 nm wide. These techniques recently enabled us to pinpoint the synaptic location of gamma-secretase and Abeta . To take even more advantage of super-resolution microscopy, we are developing advanced labeling techniques for incorporating fluorophores site-specifically on different parts of APP, which will allow live-cell imaging and improve the resolution even further.
Glycan biomarkers for Alzheimer disease
AD starts to develop many years before symptoms appear. It is therefore necessary to develop pre-symptomatic biomarkers for AD that could enable earlier diagnosis of the disease. Pre-symtomatic biomarkers would also be useful to start clinical trials earlier, reduce the heterogeneity of patient groups and follow treatment efficacy in clinical trials. Although glycans are considerably less studied than proteins and genes, several studies indicate that protein glycosylation is altered in AD. With this background, we have used a glycomics approach to identify a new type of selective glycan biomarkers for early detection of AD. We use a liquid chromatograpy-mass spectrometry approach to identify asparagine-linked (N-linked) glycans whose expression is altered in cerebrospinal fluid from AD patients compared to healthy individuals. Based on the N-glycan profile we then develop simple and robust multi-well plate assays. We also analyze the N-glycan profile in AD brain to investigate how changes in glycosylation relate to AD pathogenesis.
Lenka Hromadkova Visiting PhD student
Michael Axenhus Medical student
Neuronal Aβ42 is enriched in small vesicles at the presynaptic side of synapses
Yu Y, Jans DC, Winblad B, Tjernberg LO, Schedin-Weiss S
Life Science Alliance, Published online June 2018.