Searching for an Alzheimer’s pill

In the context of Alzheimer's research, the term Abeta might sound vaguely familiar to many a layperson. This substance plays an important role in the formation of harmful amyloid plaques in the brains of people with the disease. However, the drugs that affect Abeta still do not prevent people from developing dementia. Jos Prickaerts: “Around seven studies in humans have failed, so the pharmaceutical industry is currently reluctant to invest in the treatment of brain disorders. The chances of finding something are very small. But I believe in my research and that keeps me going.”

A ‘bit’ of scientific theory, for the enthusiasts

Prickaerts is looking for it in the realm of the 'PDE inhibitors'. PDE stands for ‘Phosphodiesterase’, which is an enzyme that plays a role in communication between cells. To shorten a complicated scientific theory: if you inhibit these PDEs, you improve communication between cells, which can have a beneficial effect on memory and other cognitive functions. There are 11 PDE families, numbered 1 to 11. Viagra, for example, is a PDE5 inhibitor. “But we now know that the presence of this enzyme is drastically reduced in older people. That's why we saw an effect on memory in rats, but not in older humans. So we need to find out which PDEs in human brains with Alzheimer's are most impaired and treat those.”

But, a rat with a better memory? How can you actually see that?

“I show a rat two of the same objects on day one. The next day, again two, but one is new compared to the day before. If the rat has forgotten the objects, it finds them both equally interesting, because they’re both new. But if it remembers that one, it leaves that known object to the side. With these kinds of tests, we saw that after taking Viagra they even scored 100% better.” Because people have a better memory function and are of course linguistic, similar tests are done with words. The PDE4 inhibitor that Prickaerts is going to test at the end of this year in about a hundred elderly people with mild cognitive impairment (MCI), was shown in an earlier smaller study to lead to 30% more words being remembered. The new study, co-funded by ZonMW, will run for four years in MUMC's memory clinic and should determine whether there is a real improvement in memory, as well as quality of life.

Reusing existing medicines, creating new ones

The pill that will be administered to the study participants is actually a COPD medicine that has been on the market for a long time: Roflumilast. “This is a PDE4 inhibitor. It makes a difference in terms of development time if you can reuse an existing medicine, which has already been found to be safe, for something else.” In addition, he also works on developing and patenting new molecules himself, because that is what the pharmaceutical industry is interested in. "Without a patent, it is difficult to make money from medicines, so no pharmacist will be interested in them. That’s how crude it is, unfortunately.” Because his new molecules also seem to have an effect on the cellular components that play a role in MS, the syndrome is now also on his list.

The love for Alzheimer's research runs deep

“My love is Alzheimer's research. I find that the most challenging—not just because it runs in my family and sometimes I think I'll also get it. There just isn't a medicine that really works yet. I do my research for the patients and, unfortunately, I need animal testing for that.” Without animal testing, we would not have as much knowledge about the effects of PDEs as we have today. “We can also test some things in cell systems in a petri dish, rather than on animals in the laboratory. But in the end, I want to know if memory will improve and I have to go to that animal—until there are alternatives. Then, I'll be the first to use those.”

How the discouragement policy works in the Netherlands

The number of rules for obtaining permission for animal testing in the Netherlands has been increasing rapidly over the last few decades. “The bureaucracy has made it nearly impossible. You have to go through three agencies, back and forth, which means that I have to wait at least a year before I get permission. For research with humans, you only have to go through two committees. In Belgium, the same European law applies, but there is only one committee that does the testing”, he says.

The consequences of stopping without alternatives are immense

He has great difficulty with how the Netherlands propagates its desire to be world leader in alternatives by 2025, and makes it difficult for researchers to work with laboratory animals, but invests too little in the development of these alternatives. “If you stop all animal research, you can close down a substantial part of the Dutch universities. That would cause massive layoffs in our knowledge economy. And the world's leading position that the Netherlands holds in biomedical research would fade away. If that were the democratic choice of the people, then I would immediately accept it. But the people have no idea at the moment that, for example, the pharmacies would be empty without animal testing. Or that it would be better to have the animal testing done in the Netherlands than in China, where everything is possible and permissible. We are dealing with a minority that cleverly manages to influence politics and the public, with immense consequences.”

Communicating more and not being afraid is the motto

“But, well”, he shrugs his shoulders, “we scientists are often too busy with research and education to be political. We’ve let that fall by the wayside and that’s our fault. We need to communicate much more about the importance of this work and be open about what is really going on—to show what a good life the animals have and how painlessly they can come to their end. We shouldn’t be afraid. Personally, I’m not; I come from a farming environment, so I can take it. Still, I more often keep my mouth shut at a party, about my work with animals. Unless I hear that people voted for the Party for the Animals because of the environment. Then I can’t help but point out the consequences for the future of medicine development."

Text: Femke Kools