Toxic Proteins Linked to Alzheimer's Disease Isolated and Defined

Barbara Boughton

August 20, 2009

August 20, 2009 — For the first time, researchers have isolated and defined the structure and relative toxicity of amyloid beta protein oligomers, thought to be instrumental in the neuronal cell death seen in Alzheimer's disease (AD), according to a new study published online August 12 in the Proceedings of the National Academy of Sciences.

In addition to isolating amyloid beta protein oligomers of different sizes, the scientists have determined the relationship between the size of these oligomers and their toxicity — long a question in neurology research.

The new research, as well as helping scientists understand the structural properties of amyloid beta protein oligomers, may be a first step toward developing drugs that target these proteins.

"The research will help guide people in preparing pure amyloid beta protein oligomers to study, and also shows which ones are most toxic and should be a target for new drugs," David Teplow, PhD, senior author and professor of neurology in the David Geffen School of Medicine at the University of California–Los Angeles (UCLA), told Medscape Psychiatry.

Major Contribution

"One of the big puzzles that remain in AD is which forms of amyloid beta protein are particularly toxic and relevant to the disorder. By elucidating which forms are most toxic, this paper really contributes to our understanding," said Frank Longo, MD, PhD, chairman of the Department of Neurology and Neurological Sciences at Stanford University, Palo Alto, California, who was not involved with the study.

In the study, scientists chemically synthesized amyloid beta protein in their laboratory, using a technique known as photo-induced cross-linking of unmodified proteins to create bonds between oligomers.

The researchers were then able to extract and separate oligomers of different sizes — including monomers, dimers, trimers, and tetramers. As well as studying the structural properties of the oligomers with techniques such as circular dichroism spectroscopy and atomic force microscopy, the researchers investigated their effects on differentiated PC12 cells, or mouse adrenal tumor cells that have characteristics similar to neurons.

Largest Oligomers the Most Toxic

The researchers found that the largest amyloid beta protein oligomers were the most toxic but that the relationship between size and toxicity was not linear. Oligomers composed of dimers were 3-fold more toxic than simple monomers, but trimers and tetramers were more than 10-fold more toxic than monomers, Dr. Teplow said.

Yet in the typical Alzheimer's brain, the larger amyloid beta protein oligomers are relatively rare, and the amounts of smaller oligomers are far greater — leading to more toxicity, Dr. Teplow noted.

"The ability to make pure amyloid beta protein oligomers should enable us to do very detailed structural analysis of these compounds and [to] custom design compounds that can prevent the association of oligomers or block sites on these proteins that interact with and injure neurons," he said.

Dr. Longo agreed that the research work done by the UCLA scientists may make it easier for scientists to find a relevant target for new compounds that might address the underlying disease process in AD.

"By knowing in a more defined way which aggregates of amyloid are the most toxic, one can be more efficient in targeting these particular forms," he said.

The next step in the UCLA researchers' work is to develop ways for making large amounts of pure amyloid beta protein preparations, Dr. Teplow said. They will also begin work on creating pure forms of amyloid beta protein 42, which is thought to be strongly linked to AD. In their recent study, the scientists used amyloid beta protein 40 oligomers, which are similar in many ways to the longer structures, Dr. Teplow added.

Dr. Longo suggested that other research that still needs to be done includes studying naturally occurring amyloid beta proteins and their effects on actual neurons from both animals and humans. "Technically, it's much more difficult to work with naturally occurring amyloid beta proteins, so using a synthetic form is a good starting point," he said.

Dr. Teplow and Dr. Longo have disclosed no relevant financial relationships.

Proc Natl Acad Sci. Published online August 12, 2009.

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