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.
About the Researcher
Dr. Maesako is a post-doctoral research fellow in the lab of Dr. Oksana Berezovska at Massachusetts General Hospital (MGH). During his graduate school career at Kyoto University/Japan, Dr. Maesako worked with Prof. Ayae Kinoshita, investigating the effect of environmental factors that include diet and exercise on the pathological and behavioral progression of Alzheimer’s disease (AD) using mouse models. His work resulted in a series of publications that support the beneficial roles of exercise in AD, and one of his first author papers was selected as The Journal of Biological Chemistry Paper of the Year 2012. During his post-doc training at Dr. Berezovska lab at MGH (2014-present), Dr. Maesako has mainly focused on the presenilin (PS)/γ-secretase biology. PS/γ-secretase is involved in many essential biological events and also plays a significant role in the broad range of diseases that are related to brain, skin, immune system, etc. Dr. Maesako has been awarded several Foundation awards and fellowships, and has been working hard for the proposed research by developing and optimizing several novel Förster resonance energy transfer (FRET)-based imaging assays to address unsolved questions in AD.
In 2006 at Kyoto University, Prof. Yamanaka successfully developed the induced pluripotent stem cells (iPSC). This development is widely recognized as the work for his Nobel Prize in Physiology or Medicine 2012. In the same year at the same place, I was an undergraduate student and thus was lucky enough to watch the process of iPS technology growing, and how impressively this technology could impact the scientific community all over the world. My experience during the undergraduate study at Kyoto University naturally inspired me to be a scientist. I have a broad experience in molecular biology and have been involved in the Alzheimer’s disease research for about 10 years. Currently, I’m learning the cutting-edge microscopy techniques at Massachusetts General Hospital. By utilizing my extensive experience in molecular biology and microscopy, I would like to develop assays that are useful in translational studies (e.g., drug discovery and testing its efficacy in vivo) since I believe this would be crucial for the transition of findings from basic science research to clinic. I am deeply grateful to the donors of BrightFocus Foundation who made this research possible.
First published on: June 20, 2019
Last modified on: September 19, 2019