Last week I wrote about beta-amyloid protein, one of the two proteins (the other is tau)that is misfolded in Alzheimer’s disease. “Misfolded” refers to the fact that in Alzheimer’s disease, these two proteins are found in abnormal 3-D forms that are related to the dysfunction and death of brain cells.
Alpha, beta, and gamma secretase process APP
This week’s post is about the specific enzymes that act like scissors, cutting beta amyloid out of the larger APP protein molecule from which it is released. Those enzymes are named alpha, beta, and gamma secretase. The diagram shows where each of those enzymes cuts the APP molecule.
As you can see, beta and gamma secretase produce the protein fragment we call beta-amyloid and alpha secretase cuts right through the middle of the beta-amyloid segment, thus stopping beta-amyloid formation.
Developing drugs to target beta secretase
The first step in producing beta-amyloid—both the harmless Aβ40 and the Aβ42 that clumps up in insoluble deposits around brain neurons—is the cut made by beta secretase just outside of the membrane. (The aqua rectangle in the diagram represents a portion of cell membrane.)
Much effort has been expended to produce drugs that will stop beta secretase from making that initial cut. This is not a simple matter because APP is not the only protein that beta secretase cuts. In fact, beta secretase is involved in the processing of many proteins, some of which are important to neuronal function. Stopping the cutting, or cleavage, of APP without interfering with the cleavage of other proteins is difficult. Making the problem harder is the fact that most good of beta secretase will not travel through the blood brain barrier, a glial cell construction that determines which molecules from blood are allowed to enter the brain.
Some drugs for type 2 diabetes inhibit beta secretase
The good news is that some oral drugs used to control type 2 diabetes are inhibitors of beta secretase. Those are Rosiglitazone and Pioglitazone. Both of these enter the bloodstream, but Rosiglitazone might not be able to get into brain—it may not cross the human blood brain barrier. Pioglitazone can enter brain.
Although approved for use in type 2 diabetes, these drugs have not been approved for use in Alzheimer’s. Both were being tested on persons with Alzheimer’s disease, but no positive results have been reported. Recently, the FDA warned that cardiac risks were associated with Rosiglitazone use, and since it wasn’t helping brain function, studies on Rosiglitazone were discontinued.
Pioglitazone is still being tested on Alzheimer’s patients in phase two clinical trials. A new drug, CTS-21166, is being tested in healthy non-demented volunteers (phase 1 clinical trials). In these volunteers CTS-21166 reduces the amount of beta amyloid found blood plasma, without significant negative side-effects.
Developing drugs to target gamma secretase
Gamma secretase makes the final cut that releases beta amyloid from the APP molecule. Inhibiting the function of gamma secretase is problematic because most inhibitors won’t cross the blood brain barrier to enter brain, and because some very important proteins (in addition to APP) rely on processing by gamma secretase to make them fully functional. One of those proteins, called Notch, is so important that removing it from mice is lethal. For this reason, many laboratories are working to find drugs that will modulate or control the activity of gamma secretase, without shutting it down completely. The best of these drugs inhibit gamma secretase cleavage of APP with little or no reduction in cleavage of Notch.
Drugs that target gamma secretase, without stopping Notch processing
Several such drugs are in clinical trials now. Phase one testing (on healthy non-demented volunteers) is being performed on Begacestat and PF-3084014. Both these drugs reduced concentrations of beta-amyloid in blood plasma, but not in cerebrospinal fluid (indicating they may not be crossing the blood brain barrier). Another drug, CHF-5074, has no effect on Notch processing at all and reduces brain Aβ while improving behavioral performance in animals. This drug is also being tested in phase 1 trials. No results are available yet.
In testing on Alzheimer’s individuals (phase 2 and phase 3 trials). A drug called BMS-708163 decreased beta-amyloid in cerebrospinal fluid. Another drug, tarenflurbil, was tested but had no positive effects. Tarenflurbil’s failure to perform may have been due to confounding factors in the study, and it will probably be re-tested.
Finally, a simple sugar (monosaccharide), NIC5-15, is being tested. This sugar is safe, but whether it is effective in reducing beta-amyloid production remains to be seen.
A large number of drugs are known that stimulate alpha secretase activity. Since alpha secretase chops APP in the middle of the region that would become beta-amyloid, stimulating alpha secretase activity should decrease Aβ formation. These drugs are entering phase 1 clinical trials; no results are available yet.
It should be possible to decrease beta amyloid production by using the kinds of drugs discussed today. But equally important is preventing beta amyloid from clumping and forming deposits in brain. Next time, we’ll look at drugs that prevent aggregation and/or promote the breakdown and removal of beta amyloid deposits.
Information about specific drugs is from the review Alzheimer’s disease: clinical trials and drug development, by Francesca Mangialasche, Alina Solomon, Bengt Winblad, Patrizia Mecocci, and Miia Kivipelto (Lancet Neurol 2010; 9: 702–16).