POMONA, Calif. - 07/09/2012 --
Scientists at Western University of Health Sciences in Pomona, Calif. report that studies with zebrafish have provided an important clue to understanding how Alzheimer’s disease begins.
In this week’s online edition of PLoS ONE, Graduate College of Biomedical Sciences Associate Professor Doug Ethell, PhD, and College of Optometry Assistant Professor Joshua Cameron, PhD, FAAO, report that an Alzheimer’s-linked peptide, amyloid-beta, causes aberrant blood vessel branching in the brains of young zebrafish. This mechanism may explain confusing results from recent clinical trials for Alzheimer’s and provide important insights for prevention of this disease. Click here to view the article: http://dx.plos.org/10.1371/journal.pone.0039598
“Alzheimer’s is kind of a plumbing problem,” Ethell said. “The brain makes amyloid-beta throughout life, and it is usually removed by the bloodstream and degraded in the liver. If a problem develops with amyloid-beta clearance, then it accumulates in the brain and becomes a big problem. High concentrations of amyloid-beta cause the peptides to wrap around each other, like carpet fibers, forming toxic oligomers. Later on, these oligomers aggregate into plaques that cause another set of problems. One of the biggest mysteries in Alzheimer’s research is, what is the normal physiological function of amyloid-beta? If we know that, then we might be able to figure out what causes the problem with amyloid-beta clearance, and stop it from happening.”
In this study the investigators showed that a normal function of amyloid-beta is to regulate blood vessel branching. They found that higher levels of amyloid-beta resulted in more blood vessel branches in the brains of zebrafish.
“At first it might seem paradoxical that increasing the number of blood vessels would reduce the clearance of amyloid-beta, so think of it like the sprinklers on your lawn,” Ethell said. “Ten sprinkler heads might provide the perfect pattern, but if another 10 or 50 sprinklers were added to the same line, you might get only a trickle from each one. Eventually there would be patches of green grass around the sprinkler heads and dead grass in between -- not very efficient.”
This mechanism has been around for hundreds of millions of years, and studies have found that it works the same in the zebrafish brain as it does with blood vessel cells from the human umbilical cord.
“The zebrafish we used are like those you might find at your local pet store, except they’ve been modified to express a green fluorescent protein in their blood vessels,” Ethell said. “In this study, we captured images of blood vessels in their brains and then generated 3-D maps to track the branching points.”
Alzheimer’s disease is the sixth-leading cause of death in the U.S., with more than 5.4 million cases. Early in the disease, patients lose their ability to make new memories and become easily disoriented. As it progresses, Alzheimer’s robs them of their ability to reason, speak, interact with others or even care for themselves.
As 76 million baby boomers age, the number of Alzheimer’s cases in the U.S. is expected to balloon from 5 million to 13 million by 2050, representing a pending health care catastrophe.
“Insights we’re getting about amyloid-beta from these zebrafish will help us find early pressure points in the Alzheimer’s disease process that can be targeted for therapeutic intervention, and maybe prevent the disease from starting in the first place,” Ethell said. “There is a major shift in the field toward Alzheimer’s disease prevention, with a push for early biomarkers to identify Alzheimer’s pathology years before people have memory problems.”
Ethell’s lab has also developed an early diagnostic test for Alzheimer’s that requires only a small amount of blood. He will present those findings at the Alzheimer’s International Conference in Vancouver in July.