Role of ApoE in Neurodegeneration

Project Summary

It is well-known that if Alzheimer's disease runs in the family, your chance of getting Alzheimer's disease as you age is high. At least part of the reason for this has been discovered through genetic research in Alzheimer's disease, highlighting the role of inheritance of different forms of the gene apolipoprotein E. Just like eye color, one can inherit different types of the apolipoprotein E gene. The different types are named E2. E3, and E4, The most common apolipoprotein E type is apoE3. Roughly one in four Americans has apoE4 and, one in twenty has apoE2. Astonishingly, inheritance of apoE4 dramatically increases the risk of Alzheimer's disease, shifts the age of onset at least live years younger and is associated with a worse neuropathological picture compared to the common apoE3 individuals. Even more surprisingly, individual who inherit apoE2 are substantially protected from getting Alzheimer's disease. The exact structures of apoE2, E3, and E4 are known. What has remained a mystery is how subtle changes in the protein structure that distinguish E1, E3, and E4 lead to such profound changes in the biology of Alzheimer's disease. This is a critically important clue; not only do approximately one in four Americans have increased risk for Alzheimer's disease due to inheritance of apoE4, but the protection afforded by apoE2 provides the kind of biological clue that one might be able to take advantage of to develop protective strategies for the general population. Multiple ideas about how apoE influences Alzheimer's disease have been suggested over the last decade—but in great part they have not been able to be tested and refined, or used as a starting point for therapy. We believe that this is because the proposed mechanism of apoE's action is that the different types of apoE change the rates of deposition or kinetics - the rate of synthesis and clearance of the amyloid molecule that ultimately becomes the senile plaques that form in the brains of Alzheimer patients. Until this past year, there was no method to measure these rates, and so the ideas could not be tested. Moreover, the normal role of apoE in brain function has remained elusive, so it has not been clear how this might relate to brain dysfunction The current proposal outlines a program of attack on the question of how apoE influences Alzheimer's disease with three laboratories, at Harvard. Washington University and Stanford, bringing to bear new techniques and reagents. We propose that these laboratories join together sharing resources, reagents. and expertise to learn how apoE2. apoE3 and apoE4 differ from one another in terms of brain function and Alzheimer processes. The laboratories are expert in advanced microscopy methods, advanced biochemical techniques, and novel cell culture and molecular approaches. Together these approaches will now allow us to directly test the ideas about apoE's impact on brain function. The principal investigators bring years of experience in their fields, unique technical capabilities, and a commitment to work together to make a difference. The BrightFocus Centennial award would provide the opportunity to do so.