Los Angeles: Scientists have discovered that a unique hairpin-like structure of a protein is responsible for killing brain cells in Alzheimer`s, making it a new target for treatment of the neurodegenerative disease.
Alzheimer`s disease is the most common cause of late-life dementia. The disorder is thought to be caused by a protein known as amyloid-beta, or Abeta, which clumps together in the brain, forming plaques that are thought to destroy neurons.
For decades, researchers have been trying, with limited success, to develop drugs that prevent this clumping. Such drugs require a "target" - a structure they can bind to, thereby preventing the toxic actions of Abeta.
Now, a new study from the University of California, Los Angeles found that while researchers may have the right target in Abeta, they may be missing the bull`s-eye.
"The Abeta protein is composed of a sequence of amino acids, much like a pearl necklace composed of 20 different combinations of different colours of pearl," lead researcher David Teplow said.
Teplow and colleagues focused on a particular segment of a toxic form of Abeta and discovered a unique hairpin-like structure that facilitates clumping.
One form of Abeta, Abeta40, has 40 amino acids, while a second form, Abeta42, has two extra amino acids at one end.
Abeta42 has long been thought to be the toxic form of Abeta, but until now, no one has understood how the simple addition of two amino acids made it so much more toxic then Abeta40.
In his lab, Teplow and colleagues used computer simulations in which they looked at the structure of the Abeta proteins in a virtual world.
The researchers first created a virtual Abeta peptide that only contained the last 12 amino acids of the entire 42-amino-acid-long Abeta42 protein.
By taking thousands of snapshots of the various molecular structures the peptides created, the researchers determined which structures formed more frequently than others. From those, they then physically created mutant Abeta peptides using chemical synthesis.
"We studied these mutant peptides and found that the structure that made Abeta42 Abeta42 was a hairpin-like turn at the very end of the peptide of the whole Abeta protein," Teplow said in a statement.
"Our lab is the first to show that it is this specific turn that accounts for the special ability of Abeta42 to aggregate into clumps that we think kills neurons. Abeta40, the Abeta protein with two less amino acids at the end of the protein, did not do the same thing," Teplow said.
The study was published in the Journal of Molecular Biology.