Purifying the Most Toxic Forms of Beta Amyloid from the Brains of Patients with Alzheimer’s Disease

David Brody, MD, PhD
Washington University School of Medicine (St. Louis, MO)
Year Awarded:
2014
Grant Duration:
July 1, 2014 to June 30, 2017
Disease:
Alzheimer's
Award Amount:
$250,000
Grant Reference ID:
A2014270S
Award Type:
Standard
Award Region:
US Midwestern

Co-principal Investigators

Michael Gross, PhD
Washington University

Purification and Characterization of Amyloid-beta Oligomers from Human Brain

Summary

Alzheimer’s disease is the most common cause of problems with memory, thinking, and behavior in older people; it is most likely caused by accumulation of a small protein called beta amyloid. Despite decades of work, there is no cure or effective treatment for Alzheimer’s disease, in part because our attempts so far have not focused on the most toxic forms of beta amyloid. We have developed methods to accurately measure these toxic forms of beta amyloid in the brains of Alzheimer’s patients, and we now propose to purify these beta amyloid samples so that we can study them in detail. This project is vital because understanding the toxic forms of beta amyloid will help us efficiently design effective treatments to prevent them from forming, block their toxicity, or eliminate them from the brain.

Details

The goal of this project is to purify and characterize small, toxic proteins that may be the root cause of dementia in Alzheimer's disease. Alzheimer’s disease is the most common cause of problems with memory, thinking, and behavior in older people; it is most likely caused by accumulation of a small protein called amyloid-beta in the brain. There is no cure or effective treatment for Alzheimer’s disease despite decades of work, possibly because our attempts so far have not focused on the most toxic forms of amyloid-beta. We have developed methods to accurately measure these toxic forms of amyloid-beta in the brains of Alzheimer’s disease patients, and we now propose to purify these samples in order to study them in detail. This project is vital because understanding the toxic forms of amyloid-beta will help us efficiently design effective treatments to prevent them from forming, block their toxicity, or destroy them in the brain.

In the first part of the project, we will purify these toxic forms of amyloid-beta from the brains of human patients with Alzheimer's disease who donated their brains for research. For the second part of the project, we will examine the structure of these toxic forms of amyloid-beta, and determine which properties are responsible for their toxicity. 

There are three major innovations built into our project design:

  1. We have developed the first quantitative, sensitive, and specific test for the toxic forms of amyloid-beta, and we will use this test to guide the purification process. Without such a test, purification would be impossible.
  2. We will use two cutting-edge mass spectrometry techniques to characterize the structure of toxic forms of amyloid-beta. 
  3. We will focus on amyloid-beta samples gathered from human brains, thus leveraging a unique resource at Washington University St. Louis, where we have access to a bank of more than 1,000 well-characterized brains given by donors.  
Once this study is complete, the foreseeable benefits include the discovery of new targets for therapies, development of more accurate animal models, and opportunities to provide a new perspective on the causes of Alzheimer's disease.

About the Researcher

David Brody is a, board-certified neurologist at Washington University in St Louis (WUSTL), specializing in neurodegenerative diseases and traumatic brain injury. He spends approximately 80 percent of his time performing research and 20 percent involved in clinical, teaching and administrative roles. Areas of active research include investigations of amyloid-beta oligomers, assessments of mechanisms underlying amyloid-beta and tau pathology in the setting of traumatic brain injury, and advanced neuroimaging methods in traumatic brain injury. Dr. Brody did his undergraduate work in biology at Stanford University; completed the Medical Scientist Training Program at Johns Hopkins University, with a PhD in biomedical engineering; and received residency training in neurology at Barnes-Jewish Hospital affiliated with WUSTL.