Purification and Characterization of Amyloid-Beta Oligomers from Human Brain

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.

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.