Model shows how mutation tips biochemistry to cause Alzheimer's

“It is a really tiny change but it has tremendous consequences,” said Andrij Baumketner, lead author on the study and a faculty member in the department of physics and optical science at the University of North Carolina at Charlotte. The finding, published in the April 7 issue of the Publication of the National Academy of Sciences, was co-authored by Mary Griffin Krone and Joan-Emma Shea, both from the department of chemistry and biochemistry at the University of California at Santa Barbara.

The group studied the effects caused by the Dutch Mutation, a mutation that has been discovered to be associated with a specific, hereditary form of Alzheimer’s disease. The mutation is small, the simple substitution of one DNA base for another, resulting in the change of only one amino acid residue – glutamic acid changing to the very similar glutamine – among hundreds of amino acids that form a protein known as the amyloid precursor protein (APP). The greatest effect of the Dutch-type mutation on APP, whose primary biological function is unknown, seems to be through a fragment known as amyloid-beta peptide that is created when cells break down the protein. Studies have shown that mutated forms of the fragment have greater tendency to stick to bond together and form protein clumps or aggregates. Some forms of the amyloid-beta clumps have been shown to be toxic to brain cells.

Why the change in one amino acid would cause this peptide to form clumps more readily has, until now, been unclear. Amyloid-beta peptide, unlike most other proteins present in the cell, is largely lacking in specific shape (conformation), the characteristic that usually controls how proteins interact with each other. However the fragment does have two places in its sequence of amino acids – a section known as the “bend” and an area known as the “central hydrophobic cluster” where the polypeptide chain does conform to a more-or-less fixed shape. These areas, in fact, seem to be involved when the fragments bond together into clumps.

The researchers created complex computer models of the two structured areas of the fragment and found that the single amino acid change caused by the mutation had a subtle effect on their properties. In order for fragments to bond together, the structured areas must first undergo a “conformational change” (a change in structural shape) from the conformations they normally have as single, water-soluble amyloid-beta peptides into a “transition state” conformation that leads up to forming clumps. The researchers found that mutation increased the likelihood that the structures would be in a form similar to the transition state before the reaction occurred. When the structured areas were already in the required transition state, bonding was encouraged because less energy was required for the bonding reaction to take place.