Alzheimer's Disease Research
Randall Bateman, MD
Washington University School of Medicine
St. Louis, MO
Title: Stable Isotope Labeling Kinetics of Human Tau in Alzheimer’s Disease
Non-Technical Title: A New Method to Measure Tau Kinetics in Humans with Alzheimer’s Disease
Acknowledgements: This grant is made possible by a bequest from the Estate of David and Annabel Ballard (The Ballard/Harvin Alzheimer’s Research Fund).
Duration: October 1, 2014 - September 30, 2017
Award Type: Standard
Award Amount: $250,000
In Alzheimer’s disease, and amyloid protein called tau is increased in the brain and fluid that surrounds the brain. It is unclear why it is increased. Is this due to increased production or impaired clearance? How much is production or clearance altered? Can drugs be developed that can correct abnormal tau production or clearance? These questions can now be answered and the answers will give drugs that target tau a better chance of working against Alzheimer’s disease.
We have developed stable isotope labeling kinetics (SILK) methods to study the kinetics of proteins in the human central nervous system (CNS). With a tau SILK method, we will label participants with stable isotope amino acids and measure the amount of labeled tau that the brain produces over time. By measuring labeled tau, we will calculate how fast the brain produces tau and clears it away. In Aim 1, we will label young normal participants to study tau kinetics in a normal physiological state. In Aim 2, we will label participants with AD and age-matched cognitively normal controls to answer the question, do tau kinetics change in AD?
The past few decades of AD research have focused on amyloid-beta as the cause of AD, but today more evidence indicates that tau protein plays central roles in AD. Tau is mostly an intracellular protein but is also secreted as extracellular protein in normal conditions, and in increased amounts in AD. The SILK method that we pioneered is uniquely able to measure production and clearance of tau in humans. We believe our study elucidating the kinetics of tau in the human CNS will provide the first measures of why tau is increased in AD (i.e., through increased production versus impaired clearance).
Tau is an important biomarker of AD. Our study elucidating human CNS tau kinetics will enable better designs for prevention and treatment of AD in the future. Specifically, understanding why tau increases in AD will allow for better development of tau-targeted treatments. Our study will also greatly advance the understanding of basic tau biology.
Randall J. Bateman, MD is the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine. Dr. Bateman’s laboratory investigates the causes, as well as future diagnosis and treatment of Alzheimer's disease, utilizing a wide variety of assays and techniques, from basic applications such as quantitative measurement of stable-isotope labeled peptides, to clinical translational studies in diagnostic and therapeutic biomarkers for Alzheimer's disease.
Chihiro Sato, PhD is interested in understanding the basic biology of AD that leads to better prevention and treatment of the disease. For her PhD thesis at the University of Tokyo in Japan, she has studied the structural biology of presenilin 1, whose mutations are the most common cause of familial early-onset AD. During her postdoctoral training at Washington University School of Medicine, she studied the role of notch signaling, one of the downstream signalings of presenilin, in memory and cognition. She is currently a staff scientist at Dr. Randall Bateman's laboratory and leading the proposed project.