Scientists have long suspected that Alzheimer's disease is caused by plaques formed when the small protein amyloid-beta (A?) binds to itself in clusters and undergoes a chemical change, creating protein deposits in the brain.
However, recent studies have suggested it is not the plaques that cause Alzheimer's but the small, grape-like clusters of A?. The clusters vary in size, and the relationship between cluster size and toxicity — the ability to kill nerve cells — has never been determined accurately.
Now, by creating various sizes of A? clusters in the laboratory that exactly match what forms in the brains of Alzheimer's patients, UCLA neurologists have determined that toxicity increases dramatically as the clusters increase in size from two to three to four A? proteins. The researchers also report that although larger clusters are more toxic than smaller ones, large formations are relatively rare; smaller formations are more numerous and are thus an inviting target for the development of new therapeutic drugs.
In addition, said senior author and UCLA neurology professor David Teplow, developing the ability to make A? clusters in a very pure and precise way that duplicates what forms in the Alzheimer's brain will enable scientists to make detailed studies of their structures, aiding future drug development.
The research is currently available in the early online edition of Proceedings of the National Academy of Sciences.
Alzheimer's is the most common form of late-life dementia. More then 5 million Americans have been diagnosed with the disease and 24 million people worldwide — a number that is expected to reach 81 million by the year 2040.
"We now have the best understanding yet of what types of toxic A? structures we should target with new classes of therapeutic drugs," Teplow said.
While researchers found that the larger the A? cluster, the greater the toxicity, they also discovered that the increase in toxicity with these clusters is not linear.
"Clusters that contain two A? molecules are more toxic than a single A? molecule, and those with three molecules are more toxic that those with two," Teplow said. But clusters of the A? molecule known as dimers (two A? molecules forming a cluster) are three times more toxic than simple monomer compounds; trimers (three A? molecules) and tetramers (four) are more than 10 times more toxic than monomers, he said.
This suggests that larger, more toxic clusters should be the target for scientists trying to stop the disease. But in the brains of Alzheimer's patients, the larger clusters are relatively rare, Teplow said, and because smaller clusters are found in far greater amounts, they are, taken in total, more toxic to the brain than larger ones.
"Think of the molecules being wrapped in very weak Velcro," Teplow said. "A number of molecules can bind together to form large clusters, but they break apart very easily."
Having developed a process in the lab to make pure forms of these A? clusters of specific sizes will enable detailed study of their structures to show where every atom is.
"This will make development of drugs much easier and, likely, more successful," Teplow said.
Other authors included Kenjiro Ono, of UCLA and Japan's Kanazawa University School of Medicine, and Margaret M. Condrona, of UCLA.
Funding was provided by the Japan Human Science Foundation, a Pergolide Fellowship from Eli Lilly Japan, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the National Institutes of Health, the Alzheimer's Association and the Jim Easton Consortium for Alzheimer's Drug Discovery and Biomarkers at UCLA.
The UCLA Department of Neurology encompasses more than a dozen research, clinical and teaching programs that cover brain mapping and neuroimaging, movement disorders, Alzheimer's disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks first among its peers nationwide in National Institutes of Health funding.
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