Visualization of Aβ Production

Aβ is a key player in Alzheimer’s disease. However, it is totally unclear which cells produce Aβ and where within cells this production occurs.

Presenilin (PS)/γ-secretase is involved in many essential biological events such as neurogenesis and skeletal formation but also plays a pivotal role in the pathogenesis of numerous diseases (e.g., Alzheimer’s disease, Cancers, Hematopoietic defects, etc.). The goal of this project is to develop an assay that allows the “visualization” of PS/γ-secretase activity in live mice. To achieve this goal, we will improve the sensitivity of biosensor that we have recently developed to monitor PS/γ-secretase activity in cells (aim 1). Moreover, the optimized biosensor will be expressed and validated in the brain of live mice (aim 2). The innovation in this project comes from the design of a novel PS/γ-secretase biosensor and utilization of the fluorescence imaging approach that allow to maintain normal physiological environment of the cells while monitoring PS/γ-secretase activity. Our novel biosensor(s) would allow for the first time to study the dynamic behavior of endogenous PS/γ-secretase longitudinally in different anatomical and subcellular regions in living mice. Upon completion of this work, the proposed studies will provide a necessary tool for better understanding of the dynamics of PS/γ-secretase and its association with the diseases. Furthermore, it could also enable a breakthrough needed for more efficient preclinical drug testing and for a successful clinical trial design.