Reopening Development of β-secretase Inhibitors as a Therapy for Alzheimer's Disease

One approach to the treatment of Alzheimer's disease is to interfere in the production of β-amyloid rather than trying to clear it after it has been produced. Insofar as Alzheimer's is a disease of amyloid accumulation, the evidence suggests it results from a gradual failure of clearance and filtration mechanisms operating on cerebrospinal fluid, and amyloid levels are fairly dynamic on a short time frame. This makes blocking production more viable here than in age-related conditions where the causative metabolic waste accumulates and clears only slowly. One possible way to block production is to interfere with the proteins that produce β-amyloid from amyloid precursor protein, but as this article points out, that has proven to be challenging:

Protein deposits in the brain are hallmarks of Alzheimer's disease and partly responsible for the chronically progressive necrosis of the brain cells. Nowadays, these plaques can be detected at very early stages, long before the first symptoms of dementia appear. The protein clumps mainly consist of the β amyloid peptide (Aβ), a protein fragment that forms when two enzymes, β and γ secretase, cleave the amyloid precursor protein (APP) into three parts, including Aβ, which is toxic. If β or γ secretase is blocked, this also inhibits the production of any more harmful β amyloid peptide. Consequently, for many years biomedical research has concentrated on these two enzymes as therapeutic points of attack. To date, however, the results of clinical studies using substances that block γ secretase have been sobering. The problem is that the enzyme is also involved in other key cell processes. Inhibiting the enzymes in patients therefore triggered severe side effects, such as gastrointestinal hemorrhaging or skin cancer.

For a number of years researchers have also been focusing their efforts on β secretase. A large number of substances have been developed, including some highly promising ones that reduced the amount of Aβ in mouse models effectively. Nevertheless this presents the same challenge: "The current β secretase inhibitors don't just block the enzyme function that drives the course of Alzheimer's, but also physiologically important cell processes. Therefore, the substances currently being tested in clinical studies may also trigger nasty side effects - and thus fail." To address this, researchers studied how β secretase might be inhibited selectively - in other words, the harmful property blocked without affecting any useful functions. In a series of experiments, the scientists were able to demonstrate that the Alzheimer's protein APP is cleft by β secretase in endosomes, special areas of the cells that are separated by membrane envelopes, while the other vital proteins are processed in other areas of the cell. The researchers exploited this spatial separation of the protein processing within the cell.

"We managed to develop a substance that only inhibits β secretase in the endosomes where the β amyloid peptide forms. The specific efficacy of our inhibitor opens up a promising way to treat Alzheimer's effectively in future, without causing the patients any serious side effects." The researchers' next goal is to hone their drug candidate so that it can initially be tested in mice and ultimately in clinical studies on Alzheimer's patients.



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