Editor's Note: This is part one of a two-part series on new findings in Alzheimer's research. Part two will run in Friday's issue.

One of Alzheimer's hallmarks is amyloid plaques - clumps of misfolded amyloid-beta protein. Two papers out this week reported on the plaques, one presenting new data on how to destroy them, and one on how they form in the first place.

In the Sept. 21, 2006, issue of Neuron, researchers from the University of California at San Francisco's Gladstone Institute and the University of Tokyo report that the protease cathepsin B possibly could be harnessed to get rid of those plaques.

Because it is found in amyloid plaques, cathepsin has been thought of as a culprit in Alzheimer's disease, the theory being that the protease cuts amyloid precursor protein into toxic A beta fragments, which form amyloid plaques; the size of the plaques is determined by the relative rates of plaque formation and breakdown. But, as senior author Li Gan told BioWorld Today, "for something to be there doesn't mean it has to commit a crime."

The researchers began to suspect that cathepsin actually might be fighting plaques when they knocked out cathepsin B in a mouse model of Alzheimer's that is engineered to express high levels of human amyloid precursor protein.

Gan and her colleagues suspected that cathepsin might help process APP into A-beta, and so they compared the levels of A-beta in hAPP mice with and without cathepsin B - and came up empty: "We actually saw more A-beta," said Gan, who is an assistant professor of neurology at UCSF. A-beta fragments come in several lengths, which in turn have varying toxicity; cathepsin knockouts also had fewer fragments of the most toxic length than hAPP mice with cathepsin B.

Knocking out cathepsin increased plaque load in hAPP animals, which led Gan and her colleagues to conclude that "maybe the substrate of cathepsin is not the precursor, but the peptide itself." In vitro experiments supported that idea, demonstrating that cathepsin B snips the most toxic A-beta fragments into shorter, less nasty fragments; the enzyme also was able to cut A-beta aggregates.

Through staining experiments, Gan and her colleagues also pinned down the exact localization of cathepsin; they found that in hAPP mice, cathepsin B and A-beta aggregates were co-localized both inside and outside of cells.

In a final set of experiments, Lin and her colleagues took the opposite tack to knockouts, overexpressing CatB in the brains of aged hAPP mice, which have significant plaque formation. There, they found that cathepsin B was as effective as the known A-beta degrading enzyme neprilysin in reducing plaques.

Overall, the results suggested that increasing the clearance of A-beta fragments and aggregates might be a useful approach to combating Alzheimer's disease. Of course, many things can happen on the way to the clinic, and Gan noted that at this point it is "premature" to be counting on any medicines that might come out of the findings. She also noted that "chemically, it is much easier to develop inhibitors than activators," which is one reason that current therapeutic strategies lean toward preventing plaque buildup in the first place.

But while Gan's first order of interest is to see whether increasing cathepsin B activity will reverse cognitive deficits in hAPP mice, she does plan to search for "strategies to safely increase cathepsin B activity." She also noted that such strategies might be indirect: "Cathepsin B is normally inhibited itself. So if you could modulate the activity of the inhibitor, maybe you could increase its activity."

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