In an ongoing quest to find how exactly amyloid b protein is made from the amyloid precursor protein, researchers led by David Kang at the University of California, San Diego, have made a big step in the right direction. In a study published recently in the Journal of Biological Chemistry, Kang's team found that Ran-binding protein 9, RanBP9, plays a role by conjugating with another protein to form a scaffold that initiates the enzymatic cleavage of APP to Ab. The role of RanBP9, says Kang, could make it a possible new therapeutic target for Alzheimer's disease. Current therapeutic targets are major enzymes; because tweaking their production could wreak unexpected havoc in the body, scientists are searching for less dramatic alternatives.
Ab, which collects as senile plaques in the brains of people with Alzheimer's disease, is generated from APP by two enzymatic cleavages: first by b-secretase (BACE1) and then by g-secretase (Presenilin). How BACE1 finds APP, though, remained unclear.
"What we found was a protein called RANBP9 that seems to bring these two guys together in scaffolding kind of way," Kang says. "RanBP9 appears to interact with both BACE1 and APP and also another molecule called LRP, and bring these guys together so that the first cleavage can occur."
In previous work, Kang, who is an assistant professor of neurosciences, studied how LRP, or low-density lipoprotein receptor-related protein, can not only remove Ab by carrying it out of the brain but also stimulate its production. While LRP is a huge protein with a large extracellular domain, Kang narrowed the segment that is needed to generate Ab to a 37-amino acid stretch within the intracellular domain. "This region had never been studied before," Kang says.
In a study last year, Kang used a yeast two-hybrid screen of a mouse cDNA library using the 37-amino acid region as bait, and found four proteins that bound especially well. One of these was RanBP9. In their most recent work, Kang's idea was that perhaps LRP works by recruiting RanBP9. Sure enough, when he expressed it in mammalian cells, he found a "huge increase" in Aband when he used RNAi to knock it down in cells, he saw a significant drop in Ab. "It told us that, in fact, it's normally involved in APP processing and Ab generation," he says.
Next steps include making knockout animals for RanBP9 and testing in animal models to see if they can confirm their findings in vivo. Kang is also convinced of the possibility of RanBP9 as a therapeutic target. "What we would like to do is assess whether or not there are some small molecules or compounds that can inhibit this protein and thereby reduce Ab production," he says.