The protein amyloid beta, which accumulates in clumps or plaques in the brains of people with Alzheimer’s disease, is the subject of new research that aims to disrupt the biochemical carving of its precursor protein before it reaches its final, toxic shape.
The latest drugs being tested attempt to silence the enzyme BACE1 which cuts the precursor protein. However, BACE1 has other functions, such the production of myelin that are beneficial. Stopping it altogether could bring unwanted side effects.
The researchers have found that changing where the cut is made by essentially guiding the enzyme’s scissors to a different point could achieve the same goal, with less collateral damage.
The research is on two discoveries in the past decade of two rare mutations: one found in Italian people that leads to early onset Alzheimer’s disease, and another found in Icelandic people that staves off Alzheimer’s disease. Both mutations appear to affect the same point on the precursor protein’s chain of 770 amino acids, swapping one acid for another.
The research team injected one set of mice with a virus carrying the Italian gene mutation, and another set with the Icelandic mutation.
They found that the amino acid substitution affected where the precursor protein was cleaved. The Icelandic mutation resulted in a shortened form of amyloid beta, which does not become “sticky” and turn into plaque. The Italian mutation produced a longer, “stickier” version of amyloid beta, which ultimately becomes the plaque that kills neurons.
The effects were a matter of degree: each mutation led to more cuts in one location or more cuts in the other location. But simply reducing the levels of mutated precursor protein could translate into more years of life before cognitive decline sets in.
Reprinted from materials provided by the University of British Columbia.