Mice and memory
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Mouse models may someday lead to potential Alzheimer’s drug candidates for humans, says Buck Institute researcher Veronica Galvan, above, with one of the animals in her study.
It's been almost six years since Veronica Galvan, Ph.D. first became intrigued by the way in which cells kill themselves.One thing led to another and the Argentinean-born scientist is now the lead researcher in a study that has revealed one of the pathways by which Alzheimer's disease affects brain neurons.The Buck Institute scientist and Novato resident has led a team of investigators working with 200 genetically engineered mice. They have discovered that the sticky deposits - “plaque” - long associated with the neurodegenerative disease are not its cause.How do mice, which do not develop Alzheimer's in nature, get the disease?“We put a protein in them when they are one-cell embryos,” Galvan said. The protein is from a human, hereditary form of the disease. The mice then develop plaque and lose the connections between their brain nerve cells. “They lose their memory, the ability to learn. It's progressive,” she said.
“The whole community believed this variant protein - the amyloid peptide - was the only cause of the disease. But there were hints this wasn't true,” Galvan said.One very telling indication of this is that “a lot of people die with a lot of amyloid plaque, but don't have any memory problems.”“The alteration we produced allowed normal neuron connections to occur, even in the presence of the senile plaques,” said Dale Bredesen, M.D., CEO of the Buck Institute. The recent research findings came out of the Bredesen Laboratory; one of a number of the institute's distinctive labs, it investigates programmed cell death mechanisms and implications.Galvan and her fellow researchers found that, despite plaque, some of the mice functioned quite well, their memories intact.How do you measure mouse memory?
“Mice love to swim - they can float like little corks,” Galvan said. The researchers devised a pool for them - a 3-foot-long sink with only enough water so that they couldn't touch the bottom.They colored the water white so the mice couldn't see the bottom, then added a small platform “island” that was barely underwater.The little swimmers would find the island; Galvan would gently guide those who didn't.The mice would “make a spatial map” of their pool and the island.The researchers chose this test of spatial awareness in part because the loss of spatial cognition is one of the first indications of Alzheimer's in humans.Amyloid-beta binds to the protein that is associated with Alzheimer's disease, which is its precursor - where the amyloid is generated from - Galvan said.“Our collaborators in San Diego - the lab of Eddie Koo at UC San Diego - have very exciting data that suggests that this binding of amyloid to the precursor is how the amyloid exerts toxicity; thus it may very well be that we have blocked this process with our mutation on the precursor protein. This is another explanation for the mechanism underlying the effect we see in the mice.” This molecular pathway has been likened to a biochemical switch. Moving forward, it enables the formation of memory; reversing it leads to the rearranging of memory. Alzheimer's develops when this molecular switch becomes stuck in reverse.The Buck Institute's finding, a significant advancement in Alzheimer's research, was published in the April 24-28 online edition of the Proceedings of the National Academy of Sciences.The prevailing thinking about Alzheimer's has been that it is a “toxic” disease, Bredesen said.
Galvan - whose husband, Alexei Kurakin, Ph.D. is also a researcher in the Bredesen Lab - said this latest research underscores the complexity of Alzheimer's, a neurodegenerative disease that afflicts 4.5 million Americans.The disease looms large on the government's health care burden horizon as baby boomers approach the age in which it manifests itself.“In cancer, there are so many processes that have to take place or not take place,” Galvan said. “I think it will be exactly the same with Alzheimer's disease. What is it that makes some people resistant to it. What is the role of mental stimulation? There are just so many contributing factors.”This latest research provides new drug targets that could provide interventions at earlier stages of Alzheimer's, Galvan said.Key, she said, is 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.”