Alzheimer's investigators open a new front in BACE1 war

The cleaving action of the BACE1 enzyme is considered one of the essential steps in creating concentrations of amyloid beta, the toxic proteins found in the brains of Alzheimer's patients. And as a result, as the leading amyloid beta programs foundered in late-stage studies, BACE1 became a prime target in the research community, with Merck leading the way in the clinic with a late-stage therapy.

The problem with BACE1, though, is that it plays a number of roles, some needed for the healthy working of the human body, and a range of early-stage programs has triggered some nasty side effects. But now scientists at the RIKEN-Max Planck Joint Research Center in Japan say that they may have found a new way to tackle BACE1 while avoiding the side effects.

Researchers led by Yasuhiko Kizuka, Shinobu Kitazume, and Naoyuki Taniguchi at RIKEN, in collaboration with Tamao Endo and Shigeo Murayama at the Tokyo Metropolitan Institute of Gerontology, say that the enzyme GnT-III plays a key role in attaching a sugar to BACE1 in the brain. Eliminating the sugar prevented the cleaving by repositioning BACE1, and in hybrid mouse models the investigators say they got the desired reduction in amyloid beta along with improvements in cognition.

Because the process is "highly selective," they add, they were able to do that without knocking out BACE1's role in unrelated functions, preventing the quick death that afflicts rodents when you simply knock out BACE1. That makes GnT-III a good target for Alzheimer's, which they've begun screening for. And it raises the role of glycosylation, the modification of proteins by sugars, to a new level of importance in drug research.

"Although a sugar change is often considered just a marker for disease or a specific cell type, our team has clearly demonstrated the functional role of a glycan during AD development," says Yasuhiko Kizuka. He added that "this work offers a good opportunity for many AD researchers to reconsider the importance of glycosylation."

- here's the release

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