Scientists at the Gladstone Institute of Neurological Disease (GIND) have identified a new method to destroy amyloid-beta (AB) proteins, which is a characteristic of Alzheimer's disease (AD). This method was identified via a rodent study.
Led by Dr. Li Gan, the researcher team has discovered that it is possible to trigger the activity of a potent AB-degrading enzyme in mouse models of the disease by reducing its natural inhibitor cystatin C (CysC).
Earlier, the researchers had shown that cathepsin B (CatB) is an AB-degrading enzyme present in all humans, and now researchers have put forth a highly effective approach to promote CatB-mediated clearance of AB.
"Many groups have developed drugs to block the production of AB, but the efficacy and safety of this approach remains to be demonstrated in clinical trials. By identifying an effective strategy to enhance the removal of AB, this research provides a very promising alternative or complementary therapeutic avenue," said GIND Director Dr. Lennart Mucke.
"Our strategy to harness the activity of a powerful AB-degrading enzyme takes advantage of the brain's own defense system to remove the toxic AB build-up. In principle, one could boost the activity of CatB by expressing more of it in the brain or by reducing the activity of CysC, its natural inhibitor. We focused on the latter strategy because it has greater long-term therapeutic potential," said Gan.
Most of the enzymes that degrade proteins are kept in check by regulators called protease inhibitors. Similarly, the protease inhibitor CysC regulates the activity of CatB.
By reducing CysC activity, the scientists were able to unleash the AB-degrading power of CatB, effectively preventing the build-up of AB in mouse models of AD.
The researchers measured brain cell activities that relate closely to learning and memory for analysing the impact of the manipulation on brain function.
Increasing CatB activity by lowering CysC levels prevented AB-induced deficits in those cellular activities.
They also tested the modified AD mice for learning and memory in a water maze. Higher levels of CatB activity improved the ability of AD to learn the maze and to retain the new information. Increasing CatB activity also prevented the premature mortality that is typically seen in these Alzheimer models.
"Our results suggest that CysC reduction has major therapeutic potential. The next step will be to develop pharmacological approaches to inhibit CysC in the human brain," said Gan.
The study was published in the latest issue of the journal Neuron.