For more than a decade, Chennai-born researcher Lawrence Rajendran, now a professor at the University of Zurich in Switzerland, has been after one of the holy grails of medical science - finding a cure for the debilitating Alzheimer's disease. It's a neurodegenerative disorder that affects some 40 million people worldwide and an estimated 605 billion US dollars - nearly one per cent of the world's gross domestic product - is spent on taking care of these patients.

Despite steadfast progress in detecting it early and accurately, a cure has eluded medical science so far. Pharmaceutical giants have invested multi-billion dollars on research and there are many drugs in various stages of clinical trials, but none has been able to provide a breakthrough.

Now, an international team of researchers (including some from India) led by Rajendran may have breached the deadlock. It has developed a substance that blocks the disease-causing function of an enzyme in cells exclusively while leaving its other vital functions unaffected. The work was reported in the journal Cell Reports in the last week of February.

The enzyme in question is beta-secretase - which, along with another one called gamma-secretase - is responsible for production of protein fragments called beta-amyloid. Plaques formed by clumping together of beta-amyloid are believed to be responsible for the death of brain cells, which results among other things in memory loss and cognitive dysfunction. Researchers knew for a while that blocking any of these enzymes could inhibit the production of the harmful beta-amyloid, but complete blocking of them was found to affect many other vital physiological functions.

Beta-secretase has been the most promising target in recent years as many substances used to inhibit gamma-secretase failed.

Studies have shown that the enzyme plays a role in as many as 20 proteins. For instance, one or more gamma-secretase inhibitors were found to interfere with the workings of a signalling pathway called Notch signalling, which is vital for critical cellular functions. Interfering with the signalling pathway could trigger severe side effects such as gastrointestinal haemorrhaging or even skin cancer.

There are similar concerns with beta-secretase too. Many substances that block the beta-secretase enzyme have been under investigation by various research groups, including some associated with big pharmaceutical companies. "They are bound to fail as they too can trigger nasty side effects," says Rajendran, who specialises in systems and cell biology of neurodegeneration.

There are many challenges associated with a drug for Alzheimer's disease. The drug should be able to cross the blood brain barrier, should be active there and have minimum side effects. "More importantly, a scientist should also know at what stage of the disease, the drugs should be administered," says Rajendran.

For, the production of beta-amyloid from its precursor amyloid precursor protein (APP) is not the only thing that beta-secretase does. "For instance, it aids the production of myelin, a sheath around nerve fibres that is important for quick and efficient transmission of electrical impulses along the nerve cells," Rajendran told KnowHow.

"It is important to reduce the production of beta-amyloid, but it is equally - if not more - important that we preserve its other crucial physiological functions," says Saoussen Ben Halima, Rajendran's doctoral student who hails from Tunisia.

What paid off for Rajendran's team, which includes two researchers from the Indian Institute of Technology, Kharagpur, and Madurai Kamaraj University in Tamil Nadu, is an interesting line of enquiry opened by Saoussen - whether the APP function of beta-secretase can be selectively blocked.

Studies by Rajendran in the past had clearly shown that the production of beta amyloid by beta-secretase happens inside sub-cellular compartments called endosomes whereas other vital proteins are produced by beta-secretase outside of these compartments.

With this insight, Rajendran's team approached Sabyasachi Mishra, now an assistant professor of chemistry at IIT Kharagpur. Mishra, then a post-doctoral student with another professor at Zurich University, carried out computer simulations to study how the enzyme interacts with different proteins and helped understand how different inhibitors can effectively block its selective functions.

"Apart from saving time and resources, such simulations could provide an understanding at atomic level which helped perform more focussed experiments," says Mishra.

Those inhibitors were synthesised by another Indian chemist, Muruga Poopathy Raja, who is now with Madurai Kamaraj University. One of these inhibitors was found to be very effective as it bound with the beta-secretase enzyme, leaving APP untouched, in endosomes. "This turned out to be a smart strategy as it could avoid side effects," says Raja.

"This looks like an interesting piece of work," says Satyajit Mayor, director of the Bangalore-based National Centre for Biological Sciences. This suggests that careful tailoring of inhibitors against the enzyme and substrates (proteins with which a particular enzyme interacts) can be differentiated according to the characteristics of the enzyme and substrate reactions, says Mayor, a well-known authority on the workings of cells and their complex signalling processes.

"Since our results look promising in stem cell-derived neurons, we are quite hopeful that this could work. In the next steps, we are looking for funding to develop a better version of this inhibitor, which has better pharmacological properties and then test in mice models before we go on to humans. Since our inhibitor is the first one to show no side effects, we are pretty hopeful that this could be useful for patients," says a confident Rajendran.

Are we on the cusp of discovering a drug for Alzheimer? If yes, a few Indian scientists may have to doff their hats to that.