Of mice and memory
Albuquerque Journal (NM)
Feb. 10--Inside a research laboratory on the north campus of the University of New Mexico, genetically modified mice with Alzheimer's disease, who have been treated with drugs and imaged with nanoparticles, are finding their way home again.
Although it's a long journey from mice to humans, the breakthrough discovery could one day help people who suffer the disease's memory losses and cognitive decline, robbing them of the pleasures of daily living and eventually stealing their lives.
Alzheimer's affects more than 5.3 million Americans and is expected to triple by 2050, unless treatment is discovered to slow, stop or prevent the disease, says researcher Laurel O. Sillerud, a biophysicist at UNM.
"Mice love to swim," Sillerud says of testing the mice, who have cheated Alzheimer's.
In the tests, mice are put in a milky bath on a platform. The water is opaque so the mice, who have been trained for the task, must rely on memory to find the platform and get out of the water, he says.
Without Alzheimer's, mice can find the platform again in five seconds.
With Alzheimer's and without recall, mice cannot find the platform and get out of the water, swimming aimlessly around and around, much like people with Alzheimer's disease wander.
Mice treated with drugs and imaged with nanoparticles or SPIONS, superparamagnetic iron oxide nanoparticles that can detect their disease progression and remission through magnetic resonance, can find the platform in 10 to 15 seconds, he says.
Lisa Kuuttila, CEO and chief economic development officer at STC.UNM, UNM's technology transfer and economic development organization, says the research is brilliant:
"This innovation overcomes a major hurdle in Alzheimer's disease treatment as there is currently no comparable method for clinical imaging of Alzheimer's disease progression and regression. It's possible that this innovation can be moved from the lab to the clinic relatively quickly as it is non-toxic, non-radioactive and noninvasive."
But without more funding and additional researchers, Sillerud doesn't know if or when people could be treated with the nanoparticles: "We have a tiger by the tail. With support for this, we could revolutionize Alzheimer's diagnosis and treatment."
Sillerud says he didn't start out to research Alzheimer's, until his wife, Anna Champlin, chief of interventional radiology at University Hospital, was diagnosed with the disease when she was 50 years old. Nine years later in 2009, she passed away.
A pioneer in nanotechnology, Sillerud has developed similar research for cancer and was instrumental in founding nanoMR in Albuquerque. The company uses immunomagnetic technology to identify and target blood pathogens, including bacteria and cancer cells, with biologic identifiers and magnetic resonance.
Although the exact origin and nature of Alzheimer's disease is unknown, a neuroinflammatory response against an abnormal formation of plaques and tangles containing the fibrous protein amyloid-B is associated with the disease, he says.
In the past 12 years of his research, Sillerud and his team used the nanoparticles and magnetic resonance imaging to detect that disease process.
The nanoparticle is an iron oxide molecule coated in antibodies that recognize the plaques and tangles and inflammation that surrounds them in the brain: After the plaques and inflammation are identified, the iron oxide molecules amplify the signal from the plaques so they are more effectively detected by MRI, he says.
"The first step was measuring the intensity of the disease," he says. "Using SPIONS enhances the appearance of the plaques. The nanoparticles enhance our ability to monitor both processes. We are the first to demonstrate the targeting of inflammation with nanoparticles."
Few other imaging techniques can measure the Alzheimer's disease process in the brains of living creatures, he says. Although injectable agents can allow positron emission tomography (PET) to identify them, it is about 10 times more expensive than using MRI, he says.
"Since clinical MRI systems ... are widely available now, this opens the possibility that quantitative AD (Alzheimer's disease) research that is noninvasive and non-toxic could finally be realized in humans," Sillerud writes in a research paper published last year in the Journal of Alzheimer's Disease.
The nanoparticles are digested within days of their injection. Sillerud adds they are non-toxic because they are less concentrated than the amounts of naturally occurring iron oxide in the brain.
Because SPIONS are coated with antibodies that specifically target the plaques and tangles and inflammation, fewer are found in other organs of the research mice, he says. He adds that before the nanoparticles are passed out of the body, they are broken down. The nanoparticles have not appeared intact in feces or urine.
A soon-to-be published paper in the same journal describes how those nanoparticles imaged the reduction of the disease process after the mice were fed resveratrol, a compound found in foods that inhibits inflammation, and a similar synthetic compound, LD-55, named for its research creator Lorraine Deck. The synthetic compound worked better than the natural one, he says.
He stresses that more research is required to support the work by duplicating the results. A new round of research will test five more compounds developed from starting points of known substances, such as one based on curcumin, the active ingredient in curry that is thought to inhibit inflammation.
"People in India, where they eat lots of curry, don't have much Alzheimer's," he says. "Many others have studied resveratrol and curcumin, but we have made unique derivatives, which are the subject of UNM patents."
Neil Buckholtz, director of the Division of Neuroscience at the National Institute on Aging, National Institutes of Health, says Sillerud's work is "very interesting. But it's in the very early stages."
The ability to distinguish individual plaques, tangles and inflammation is remarkable, he says, agreeing that imaging with MRI is more affordable than with PET scans, which cost thousands of dollars each.
Recent funding increases at the NIA could allow funding of more research like Sillerud's work and others, he says: "We got a significant allocation last week. It's a good sign. Alzheimer's is a huge public health issue."
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