Safe, effective drugs for Alzheimer's in the offing

In a first, scientists including those from India have found a way to specifically inhibit an enzyme partly responsible for Alzheimer's, paving the way for new drugs for the disease without any severe side effects.
The method involves blocking only harmful processes, while other important functions remain intact.
The team headed by Professor Lawrence Rajendran from the University of Zurich in Switzerland developed a targeted substance that blocks the pathogenic function of an enzyme in the cells without affecting its other vital functions.
Protein deposits in the brain are hallmarks of Alzheimer's disease and partly responsible for the chronically progressive necrosis of the brain cells.

The protein clumps mainly consist of the beta amyloid peptide (A beta), a protein fragment that forms when two enzymes, beta and gamma secretase, cleave the amyloid precursor protein (APP) into three parts, including A beta, which is toxic.
If beta or gamma secretase is blocked, this also inhibits the production of any more harmful beta amyloid peptide. For many years biomedical research has concentrated on these two enzymes as therapeutic points of attack.

However, the results of clinical studies using substances that block gamma secretase have been sobering. The problem is that the enzyme is also involved in other key cell processes.

Inhibiting the enzymes in patients triggered severe side effects, such as gastrointestinal hemorrhaging or skin cancer.
For a number of years researchers have also been focusing their efforts on beta secretase. A large number of substances have been developed, including some highly promising ones that reduced the amount of A beta in mouse models effectively.
"The current beta 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," said Rajendran.
To address this, Saoussen Ben Halima, who works in the lab of Rajendran, and her fellow researchers studied how beta 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 beta 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, including those from Indian Institute of Technology, Kharagpur, exploited this spatial separation of the protein processing within the cell.
"We managed to develop a substance that only inhibits beta secretase in the endosomes where the beta 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," said Rajendran.