Apr. 25, 2006 There are approximately 200 mice at the Buck Institute that should have the symptoms of Alzheimer’s disease (AD). But these mice, despite the fact that their brains are loaded with the sticky deposits commonly associated with the neurodegenerative disease, have normal memories, and show no signs of the brain shrinkage and neuron damage commonly associated with AD.
The study involving the mice, due to be published the week of April 24-28 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS), provides both new drug targets for AD, as well as a completely new understanding of the disease itself.
What allows the mice, genetically engineered to develop the senile plaques associated with AD, to be so mentally nimble? Buck scientists saved the mice from their prescribed fate by a blocking a newly discovered molecular pathway that they believe is a critical determinate in the development of the disease that affects approximately 4.5 million Americans and is the most common form of dementia in older people.
That pathway involves a biochemical “switch” associated with the everyday process of memory making and memory re-arranging. Similar to a car going both forward (memory-making) and in reverse (memory re-arranging), Buck scientists believe the symptoms of Alzheimer’s develop when the molecular switch gets stuck in the reverse position.
A team of Buck scientists, led by Veronica Galvan, PhD, took a new approach to studying a protein called APP (amyloid precursor protein), which is located at the points of connection between neurons and consists of chain of 695 building blocks called amino acids. In the mid 1980’s, scientists determined that molecular “cuts” (caused by the action of enzymes) at APP’s 595th and 635th amino acids release the so-called beta-amyloid peptides, which congregate into the toxic amyloid plaques commonly associated with AD. Many scientists believe these plaques cause excessive pulling back of the connections between neurons, leading to the memory loss which affects those with the disease.
But Buck scientists have now discovered that beta-amyloid accumulation is only part of the story. A fundamental step in the process that leads to AD may stem from activity at a different location on APP. They have been focusing on the final portion of APP, the last 31 amino acids in its sequence, called C31. They believe C31 acts as a signaling switch, regulating the normal process of memory-making and memory-rearranging and that a molecular cut at this location significantly contributes to nerve damage and memory loss. When Galvan and her team blocked the molecular cut of C31 in mice genetically-engineered to have AD-like symptoms, the mice showed none of the symptoms of AD even though their brains contained an excess of the beta-amyloid plaques.
“This research casts a totally new light on Alzheimer’s disease,” said Dale Bredesen, MD, CEO of the Buck Institute and head of the laboratory where the study was conducted. “The current thought is that Alzheimer’s is a toxic disease, with the amyloid plaques acting as a ‘bomb’ that destroys neurons. In actuality, AD may be a more subtle disease, which develops when the normal process of nerve signaling goes out of balance.” Bredesen added, “The alteration we produced allowed normal neuron connections to occur, even in the presence of the senile plaques.”
“This research provides new drug targets that could address Alzheimer’s at an earlier stage of the disease,” said Galvan. “We may have to abandon the idea of a ‘linear, unique cause’ for AD if we want to address its true nature. The good news is that, as we unravel the various complex processes that contribute to AD, we will find multiple opportunities for intervention.” Galvan adds, “That is why we are trying to develop a compound that will mimic the genetic alteration we have created in the mouse; this may lead to therapies that are additional or complementary to treatments targeted at the amyloid plaques.”
Joining Bredesen and Galvan as co-authors of the paper are Olivia Gorostiza, AS, and Junli Zhang, MD, who provided instrumental technical assistance; Surita Banwait, MD, Anna V. Lognvinova, MD, Marina Ataie, KunLin Jin, MD, and David Greenberg, MD, of the Buck Institute; Sarah A. Sagi, PhD, and Nathalie Chevallier, PhD, of the University of California, San Diego; Elaine Carlson, MT, of the University of California, San Francisco; and Sandhya Sitaraman, BS, of the Massachusetts Institute of Technology.
The work was supported by the National Institutes of Health, the Joseph Drown Foundation, and grants to the Buck Institute from American Bioscience, Inc., the John Douglas French Alzheimer’s Association and the Alzheimer’s Association.
The Buck Institute is the only freestanding institute in the United States that is devoted solely to basic research on aging and age-associated disease. The Institute is an independent nonprofit organization dedicated to extending the healthspan, the healthy years of each individual’s life. Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating conditions such as Alzheimer’s and Parkinson’s disease, cancer and stroke. Collaborative research at the Institute is supported by new developments in genomics, proteomics and bioinformatics technology.
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