Building on research that identified a rare genetic mutation in Italian people that leads to the early onset of Alzheimer's and one in Icelandic people that delays the onset of the condition, a researcher at the University of British Columbia has discovered that using an enzymatic scissor the right way could stave off the cognitive decline associated with the disease.

To conduct their investigation into the ways in which the mutations might inform Alzheimer's treatments, Dr. Weihong Song and his team injected a group of mice with a virus that elicited the mutation associated with the Italian populace and gave another group of mice a virus to create the Icelandic mutation. The mutations take place on a protein that serves as the precursor for amyloid beta, a different protein that forms plaques in the brains of individuals afflicted by Alzheimer's disease.

If the precursor proteins can be cut in such a way as to make the resultant amyloids shorter and less sticky, then they resist clumping and won't form plaques.

Both the Italian and Icelandic mutations take place on the same location of the precursor protein's chain of 770 amino acids. Song and his team found that in the case of the Italian mutation, the amino acid alanine is replaced with valine. This directs the enzyme BACE1 to cut the protein into longer strands that are stickier and lead to early onset Alzheimer's. In the case of the Icelandic mutation though, the alanine is replaced by threonine, which directs BACE1 to cut the protein into shorter strands that are less sticky.

An illustration of how swapping an amino acid in beta amyloid precursor proteins results in longer and shorter strands (Credit: Brian Kladko and Weihong Song/University of British Columbia)

So, Song has concluded that if BACE1 can be directed to chop up the precursor proteins into smaller strands, we can gain greater control over eliminating or delaying the disease. This is different from previous research that has looked at developing drugs that silence BACE1, which halt the enzyme's more beneficial effects, such as producing myelin, an electrically insulating sheath found around the axon of some nerve cells.

"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," said Song, a Psychiatry Professor and Alzheimer's researcher. "This provides a new target in our search for a drug – instead of sledgehammer, it's more like a scalpel."

Song's work joins that of researchers at the Salk Institute who, last year, discovered that boosting the level of a protein known as Neuregulin-1 can help fight Alzheimer's by upping the levels an enzyme called neprilysin, which in turn breaks up plaques. It also aligns with a study done earlier this year at Rockefeller University that examined a different set of proteins and enzymes related to Alzheimer's. In that study, it was determined that suppressing a plasma-based protein called Factor XII, which is released as part of a flood on enzymes that occur when beta amyloids are present, could improve cognitive function in mice with the disease.

Song's work appears in The Journal of Neuroscience.

Source: The University of British Columbia

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