Promotion of Amyloid Filament Formation by ApoE and ACT

About the Research Project
Program
Award Type
Standard
Award Amount
$200,000
Active Dates
April 01, 1995 - September 30, 1997
Grant ID
A1995054
Summary
Alzheimer’s disease is the most common form of dementia and the fourth leading cause of death in the United States. It is estimated that as many as 15% of the population over 65 and almost 50% over 85 have some symptoms of Alzheimer’s disease. As a result, between $80-100 billion a year is spent on the United States alone on the treatment of Alzheimer’s disease victims. This number is rising rapidly as the population ages. Thus it is imperative that we discover the basic cause of the disease and develop appropriate therapies.
When examined in the microscope, the brains of patients who have died of Alzheimer’s disease show three characteristic lesions. There is extensive nerve cell death and there is the presence of two abnormal protein deposits. One of these, called the “amyloid deposit,” is unique to Alzheimer’s disease. Amyloid deposits are composed primarily of a small protein, termed the ” ß-protein,” together with several associated proteins. It has been shown that the ß-protein alone can kill nerve cells in laboratory culture. However, it appears to be more toxic if it is allowed to aggregate into amyloid filaments, supporting the conclusion that amyloid deposition causes nerve cell death in the Alzheimer brain.
We have recently made a set of discoveries that provide a compelling explanation for why amyloid forms only in Alzheimer’s disease brain and only in certain regions involved in higher brain functions, such as personality and memory. We have added one or the other of the two amyloid-associated proteins-antichymotrypsin (ACT) or apolipoprotein E (apoE)-to the amyloid ß-protein. Instead of forming amyloid filaments over the course of many days, the ß-protein now makes filaments in a matter of hours. Furthermore, these filaments kill nerve cells in laboratory culture. Thus, the two amyloid-associated proteins ACT and apoE strongly promote the development of toxic amyloid filaments. The fact that a special form of apoE (apoE4) is the strongest promoter of amyloid filament formation is particularly interesting in light of the finding that individuals who inherit apoE4 are at high risk for developing the most common form of Alzheimer’s disease. Thus, our test tube experiments reflect the process that is occurring in the living Alzheimer brain. Furthermore, we know from other experiments in our laboratory that ACT is overproduced only in those areas of Alzheimer’s disease brain where amyloid deposits form. Thus, the fact that ACT is an amyloid promoting factor explains why the amyloid deposits in the Alzheimer brain show the same regional specificity as does the production of ACT.
It is clear that further understanding of the function of ACT and apoE in promoting the formation of amyloid filaments will greatly enhance our understanding of the pathogenesis of Alzheimer’s disease. We propose to extend the study on the promotion of amyloid filament formation by ACT and apoE using our test tube amyloid polymerization reaction and using nerve cells in culture to test for the toxic activity of the amyloid filaments. We will also initiate a study to identify compounds that interfere with the association of ACT and apoE with ß-protein, and which thus may serve as the basis for an effective therapy for Alzheimer’s disease. Several such compounds have already been identified in our preliminary experiments and are extremely active in preventing the ß-protein from forming amyloid.
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