In the new study, Oklahoma Medical Research Foundation’s Jordan J.N. Tang, Ph.D., and his colleagues discovered that ApoE4 (along with other apolipoproteins) attaches itself to a particular receptor on the surface of brain cells. That receptor, in turn, adheres to a protein known as amyloid precursor protein. The brain cells then transport the entire protein mass inside.
Once inside, cutting enzymes—called proteases—attack the amyloid precursor protein. These cuts create protein fragments that, when present in the brain for long periods of time, are believed to cause the cell death, memory loss and neurological dysfunction characteristic of Alzheimer’s.
Although researchers have known for more than a decade that ApoE4 was somehow involved in development of Alzheimer’s, Tang’s new study is said to be the first to connect the process of protein fragment formation to ApoE4.
“ApoE4 apparently interacts better with the receptor than its cousins,” said Tang. “This may explain why people who carry the E4 gene have a higher risk of developing Alzheimer’s.”
“These findings may allow us to investigate the possibility of therapeutic intervention at different points in the process,” said Tang. For example, he said, such efforts might focus on developing a compound to interfere with the receptor’s ability to adhere to ApoE4.
“There currently is no effective treatment for Alzheimer’s disease, so we must explore every possible option to find a way to stop it,” he said.
“Dr. Tang’s study shows a beautiful biochemical connection between a genetic risk factor and the development of a disease,” said OMRF President Stephen Prescott, M.D. “This work opens the door to the development of alternate methods for treating—and perhaps even preventing—Alzheimer’s.”
ApoE4 also has been linked to coronary artery disease. “Ultimately, this work could pave the way for similar study of the pathogenesis of other diseases,” said Prescott.
The study was funded by the National Institute on Aging and the Alzheimer’s Association and was done in collaboration with the University of Alabama at Birmingham.
At OMRF, Tang heads OMRF’s protein studies research program and holds the J.G. Puterbaugh Chair in Medical Research. His work with proteases has made important contributions to the study of gastric enzymes, HIV and, most recently, Alzheimer’s disease.