Programme de bourses "Echanges Universitaires"

Identification of an intracellular adaptor protein as a novel antigen in Alzheimer’s disease (AD): functional implication in AD pathophysiology and in AD therapy

A protein expression array screen was used to identify novel antibodies produced in patients affected with Alzheimer’s disease (AD) from the blood serum. From several interesting hits obtained in this screen, an intracellular cytoskeleton associated adaptor protein was chosen for further analysis. Interaction studies involving immunoprecipitation from human brain tissue and ELISA revealed that amyloid precursor protein (APP) and candidate protein interact directly with one another. APP is aberrantly processed leading to the formation of Aß plaques in the brain, which is one of the hallmarks and believed causes of AD. Moreover, we also observed a dysregulation in the protein expression levels and the cellular distribution of the candidate protein in AD affected human brains as compared to normal unaffected human brains.
Several other additional experiments done with human brain tissue and transgenic mouse models of AD further favor a strong link between the two proteins. This data led us to investigate the functional role and the possible pathophysiology of this interaction. The interaction of APP to cytoskeleton associated adaptor protein could occur during trafficking of APP. Supporting this, we observed decreased trafficking of APP to the cell surface on silencing the cytoskeletal adaptor protein. Silencing of the protein was performed by transfecting human cell lines with siRNA constructs. This is a particularly striking observation, as APP trafficking is directly linked to APP processing, in other words to Aβ production  (Thinakaran and Koo 2008).

Considering that neuroimmunity is a common feature of the majority of neurodegenerative diseases, this project will contribute more to an advancement in the field of neurodegeneration. Considering that AD affects a growing number of elderly people, adequate options for treatment and prevention are urgent medical needs. Therefore, we hope that our results will be of great interest to the scientific community, health care professionals, policy makers, patients and families alike.

Figure 1. Representative model hypothesizing the role of the cytoskeletal adaptor protein in the pathogenesis of Alzheimer’s disease.

Project Participants

Dr. Antonella Santuccione, MD Division of Psychiatry Research University of Zurich August Forel-Str. 1 CH - 8008 Zurich Switzerland +41(0)764960867 +41(0)443842555 antonella.santuccione@bli.unizh.ch

Dr. Aparna Shetty Room 1.5, Bahnhofsplatz 2, 28757 Bremen Germany +49(0)17623497126 +49(0)4034839478 dolphinaps@googlemail.com