Christian Haass, speaker of the DZNE's Munich site, and a professor at LMU Munich, is a pioneering researcher in the area of Alzheimer's disease. His work has contributed decisively to our understanding of the basic molecular and cellular mechanisms of the disease, and thereby paved the way for the development of therapy approaches.
On May 9th, he was honored as a winner of the Lundbeck Foundation'sBrain Prize for 2018. Haass will share the prize with three other neuroscientists, Bart De Strooper (London and Leuven), Michael Goedert (Cambridge, UK) and John Hardy (London). The Brain Prize, which is considered to be the world's most important prize for brain research, includes a cash prize of one million euros. In the Interview, Haass looks back on his career in Alzheimer's research and discusses the challenges involved in developing medications and the successes achieved in such development to date.
Prof. Haass, you began your Alzheimer's research work in 1990. How much was known about the disease back then?
Amazingly little. It was known that certain types of characteristic deposits form in the brains of Alzheimer's patients – namely, plaques consisting of amyloid beta-protein aggregates and tau protein fibrils. In addition, it was understood that a certain gene – the APP gene – provides instructions for making amyloid precursor protein, and that amyloid beta is a fragment that is cut from amyloid precursor protein.
So it was clear that the ways in which amyloid beta forms needed to be studied, but no one had any idea of how to proceed, since no model systems that included amyloid formation were available for study. Furthermore, it was assumed that amyloid beta occurred only in patients, since it is a protein typically associated with disease. We had no nerve cells of Alzheimer's patients, however, nor were there any mouse models in which the relevant process could be studied.
Since the risk of contracting Alzheimer's increases with age, we thought it would be logical to ask whether amyloid beta could also form in healthy people, in small amounts. We tested this idea in a very simple system of cultured human cells and, sure enough, discovered that amyloid beta was being formed. That first experiment, which took no longer than a week to carry out, turned the field of Alzheimer's research upside down. We found that practically all cells, including skin and kidney cells, produced amyloid beta when cultured! So we finally had a model system in which we could study amyloid formation at the molecular level – and identify and test relevant medications.
You then studied "secretases," which cut amyloid beta from the amyloid precursor protein. What did you learn, in the process, about amyloid beta's role in the course of the disease?
As we were pursuing our work on secretases, the first genetic changes leading to a hereditary form of Alzheimer's disease were described. The pertinent mutations in the amyloid precursor protein were occurring precisely at the sites where it was being cut by the secretases. We, along with colleagues in the U.S., then discovered that all mutations that lead to genetically related Alzheimer's either increase amyloid production in general or increase production of a toxic form of amyloid that more readily clumps and forms plaques in the brain. This clearly shows that amyloid beta triggers the disease.
Could secretases be suitable target molecules for therapies?
In principle, they are very suitable, but secretases also have important biological functions, and thus we have to proceed very carefully. We found, for example, that beta-secretase – one of the two secretases that lead to amyloid production – plays a vital role in the electrical insulation of nerve fibers. Complete inhibition of beta-secretase would thus entail significant side effects. On the other hand, one could attempt to reduce secretase activity. Gamma-secretase, which is also involved in amyloid production, can be modulated in such a way that it produces less of the toxic form of amyloid, while otherwise still retaining its basic function. I think this is a very promising approach.
All therapies aimed at reducing toxic-amyloid formation currently face another obstacle. Amyloid formation stands at the beginning of a long cascade of events that ultimately lead to the dying-off of nerve cells in the brain. When the first symptoms of Alzheimer's appear, it is already too late for such therapies, because amyloid plaques form many years earlier, and the disease, once triggered by amyloid, then continues to progress – possibly, even independently of amyloid. Ideally, we would be able to look at people when they are 40 or 50 and determine if they have an increased risk of contracting Alzheimer's later on. But that is still a tall order at present. What's more, it's crucial that any long-term therapies for still-healthy people have no side effects whatsoever.
Are there any ideas about how to influence the later course of the disease?
Indeed there are. In this regard, we have looked at microglia, which are the brain's primary immune cells. They remove waste organic material such as plaques and dead cells. A protein known as TREM2 that is found on microglia seems to be a key factor in activating and controlling the complete functionality range of microglial cells. People with mutations in the TREM2 gene have an increased risk of contracting Alzheimer's in old age. This is interesting in that it implies that there continue to be modulators for the disease even at such a late stage.
We came up with a strategy for a way to selectively stabilize TREM2 and thereby activate microglial cells, with the aim of strengthening the cells' mechanisms for defense against amyloid plaques. My dream is that such therapies would be effective even at later stages of the disease, so that we would be able to treat even patients who already have slight dementia when they first seek treatment.
One of the DZNE's strengths is that its clinical research and basic research areas collaborate closely. How is this strength reflected in your research?
Four years ago, we moved into a new facility in Munich that is devoted solely to dementia research, throughout a spectrum from biophysics to patients. There, clinical practitioners and basic researchers cooperate very closely on Alzheimer's research – in fact, the closeness of the two sides' cooperation is unprecedented, in my experience. This has greatly changed my life as a researcher, because it has fulfilled my long-held dream of working in an institute that does away with all boundaries between clinical research and basic research, and where all staff work toward the same main goal: to understand Alzheimer's and related diseases – and develop cures for them.
For example, we are looking for molecular indicators that would enable us to understand the inflammatory reactions that take place in the brains of Alzheimer's patients. We are searching for possible candidates for such indicators in mouse models, and, at the same time, are establishing a clinical cohort study that will enable us to test such markers in patients with mild cases of Alzheimer's. In parallel we are planning to participate in a worldwide clinical trial using a secretase inhibitor in a special and very unique cohort of patients suffering from genetically inherited Alzheimer's disease. This cohort allows us to start treatment in patients, who will develop Alzheimer's disease, 5 to 7 years before onset. The DZNE is thus greatly accelerating transfer of basic research findings to the treatment sector, where they can benefit people.
Text: Dr. Katrin Weigmann