Health + Behavior

UCLA researchers determine toxicity levels of Alzheimer's clusters in brain

Findings provide target for new classes of therapeutic drugs

Scientists have long suspected that Alzheimer's disease is caused by plaques formed when the small protein amyloid-beta (Aβ) binds to itselfin clusters andundergoes a chemical change, creating protein depositsin the brain.
However, recent studies have suggested it is not the plaques that causeAlzheimer's but the small, grape-like clusters of Aβ. 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 creatingvarious sizes of Aβ clusters in the laboratory that exactly match what forms in the brains of Alzheimer's patients,UCLA neurologistshave determined that toxicity increases dramatically as the clusters increase in size from two to three to four Aβ proteins. The researchers also report that although larger clusters are more toxic than smaller ones, large formations are relatively rare;smaller formationsare 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 Aβ clusters in a very pure and precise way that duplicates what forms inthe Alzheimer's brain will enable scientists to make detailed studies of their structures, aiding future drug development.
The researchis currently availablein the early online edition of Proceedings of the National Academy of Sciences.
Alzheimer's is the most common form of late-life dementia. More then5 million Americans have been diagnosed with the disease and 24 million people worldwide— a number that isexpected to reach 81 million by the year 2040.
"We now have the best understanding yet of what types of toxic Aβstructures we should target with new classes of therapeutic drugs," Teplow said.
Whileresearchers found that the larger the Aβ cluster, the greater the toxicity, they also discoveredthat the increase in toxicity with these clusters is not linear.
"Clusters that contain two Aβ molecules are more toxic than a single Aβ molecule, and those with three molecules are more toxic that those with two," Teplow said. But clusters of the Aβ molecule known asdimers (two Aβmolecules forming a cluster) are three timesmore toxic than simple monomer compounds; trimers (three Aβ 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 inthe brains of Alzheimer's patients, the larger clusters are relatively rare, Teplow said, and becausesmaller clusters are found infar 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 Aβ 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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