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Biosensor reveals new information about suspected cause of Alzheimer's disease

September 01, 2005

Chemists and biologists at Northwestern University have found a way to detect and estimate the size and structure of a miniscule toxic protein suspected of triggering Alzheimer's disease. The findings, researchers say, could help scientists better understand the underlying mechanisms of the disease and lead to the development of new treatments that could slow or possibly arrest its progression.

The findings also could potentially be used to diagnose Alzheimer's disease in living people instead of during an autopsy, says Amanda J. Haes, Ph.D., a co-author of the study. At present, Alzheimer's can only be accurately diagnosed after death.

Haes, a National Research Council postdoctoral researcher at the Naval Research Laboratory in Washington, conducted this work while she was a graduate student at Northwestern under the direction of Richard Van Duyne. The findings were presented today at the 230th national meeting of the American Chemical Society, the world's largest scientific society.

Haes, in cooperation with Van Duyne, Northwestern professor William Klein and research associate Lei Chang developed a method to detect small harmful proteins in cerebrospinal fluid using nanoscale optical biosensors. The proteins, known as ADDLs (amyloid ?-derived diffusible ligands) are so small that they can't be detected by conventional diagnostic tests. They are usually less than 5 nanometers wide and are found in extremely low concentrations.

Discovered by Klein in 1998, ADDLs accumulate in the brain tissue of individuals with Alzheimer's disease at levels up to 70 times higher than found in people who don't have the disease. Many researchers now suspect that ADDLs cause some of the earliest symptoms of Alzheimer's disease. ADDLs, they theorize, attack and disrupt synapses, the sites on nerve cells that are critical for memory formation and information processing. ADDLs tend to stick together, and some researchers suspect that as they aggregate, they're more apt to damage neurons.

"It's becoming more evident that the size of â-amyloid (ADDL) molecules matters - that only ADDLs of a certain size cause problems for neurons in the early stages of Alzheimer's disease," Haes says. "These nanoscale biosensors may one day allow us to determine, based on size, if an individual has ADDLs that will affect his or her cognitive function. However, there are still many hurdles that must be overcome before we can use it as a diagnostic tool."

The biosensors developed by the Northwestern team are based on tiny, triangular silver particles that absorb and scatter light. On the outside surfaces of nanoparticles is a layer of ADDL-specific antibodies. These antibodies bind specifically to any ADDL molecules found in cerebrospinal fluid. When this happens, the color of the silver nanoparticles shifts slightly. The researchers detected these color shifts using a specialized light detector called ultraviolet-visible spectrometer. In a small sample pool, comparing cerebrospinal fluid extracted from two people diagnosed with Alzheimer's disease and two people who weren't, Haes found that ADDL levels were elevated in the diseased patient samples in comparison to control patient samples.

Alzheimer's disease is an irreversible disorder of the brain, robbing those who have it of memory, overall mental and physical function, and eventually leading to death. It is the most common cause of dementia among people over age 65, affecting an estimated 4.5 million Americans, according to the National Institute on Aging.

The American Chemical Society is a nonprofit organization, chartered by the U.S. Congress, with a multidisciplinary membership of more than 158,000 chemists and chemical engineers. It publishes numerous scientific journals and databases, convenes major research conferences and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.

American Chemical Society