A single amino acid can determine where an enzyme cuts a precursor to the amyloid beta protein — and the difference can translate into either a healthy brain or Alzheimer’s, according to a Canadian study.
The research showed that a shorter version of amyloid beta does not turn into the plaque whose buildup causes the disease, while a longer, stickier version does.
Scientists are developing drugs such as BACE1 inhibitors to block the enzyme that does the cutting. Since BACE1 is needed for other brain processes, including the production of nerve insulation known as myelin, blocking it generates toxic side effects, however.
A University of British Columbia team argues that guiding the BACE1 enzyme’s “scissors” to cut in a specific direction, instead of blocking the enzyme altogether, could lead to treatments without side effects.
Their study, “BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer’s Pathogenesis,” was published in the Journal of Neuroscience.
The team based its work on two earlier discoveries. In one, Italian researchers reported that a gene mutation caused early onset of Alzheimer’s. The second study reported that a mutation actually protected people from Iceland against the disease.
Genes contain coding for proteins. Both of the mutations were in the same spot in the coding used to produce the precursor of amyloid beta. But the mutations generated different versions of the amino acid used to create the protein.
The Canadians discovered that the amino acids affected how the BACE1 enzyme cut the protein. With the Icelandic mutation, BACE1 produced a shorter amyloid fragment — one that did not clump into the plaque littering the brains of Alzheimer’s patients.
In contrast, the Italian mutation prompted the enzyme to cut the precursor protein in a way that led to the clumping.
Over time, the shorter fragments protected the Icelanders from developing Alzheimer’s.
If scientists can figure out a way to control how BACE1 cuts the precursor protein, they may be able to prevent amyloid clumping.
“If we can adjust where BACE1 cuts the precursor protein, we will have a very precise way of slowing the buildup of plaque in the brain, without affecting other processes,” Dr. Weihong Song, a psychiatry professor and Alzheimer’s specialist at the university, said in a press release.
“This provides a new target in our search for a drug — instead of sledgehammer, it’s more like a scalpel,” added Song, the senior author of the study.
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