Alzheimer's- Finding The Right Target
Alzheimer's disease is the most common form of old age dementia - the only one of the top 10 causes of death that cannot be prevented, cured or slowed down once it begins. Most therapies have failed or only provide modest improvement.
Alzheimer's disease is believed to be caused by a protein known as amyloid beta protein, or Abeta - which clumps together, forming plaques that kill brain cells.
Researchers have been trying unsuccessfully to develop drugs that prevent this clumping for many years. Such drugs require a ‘target’ they can bind to, so that they can prevent Abeta’s toxic actions.
Now a new study from UCLA suggests that a particular segment of the toxic version of Abeta contains a unique hairpin structure that facilitates clumping.
One form of the Abeta protein, Abeta40, has 40 amino acids - while a second form, Abeta42, has two extra amino acids at one end. Abeta42 has long been believed to be the toxic version, but no one knew exactly why it was so much more toxic than Abeta40.
In this study, the research team used computer simulations in which they looked at the structure of the two versions of Abeta proteins. They determined which structures formed more frequently than others and then they physically created mutant Abeta peptides using chemical synthesis.
In this way, they found that the structure that made Abeta42 toxic was a hairpin-like turn at the very end.
This is the first study to show that this particular hairpin structure accounts for the special ability of Abeta42 to aggregate into clumps that kill brain cells. On the other hand, Abeta40, the protein with two less amino acids at the end, does not do the same thing.
With their results, the UCLA researchers hope they have found the most relevant target yet for the development of drugs that can successfully fight Alzheimer's disease.