MetLife Foundation honors Munich scientist
It has long been established that the plaques in the brain described by Alois Alzheimer in 1906 are the main cause of the disease. They are neurotoxic, meaning that nerve cells close to those insoluble aggregates will die. A building block of the plaques is the so-called amyloid β-peptide or Aβ. This is only part of a protein, a peptide, which can accumulate and subsequently build plaques in aging brains. Haass had been focusing on the life cycle of Aβ for two years when he achieved a major breakthrough in 1992. “We were able to show that the body produces Aβ throughout one’s life and at all times,” he explains. “The highest concentrations were found in human neurons where the peptide builds up as a byproduct of a normal metabolic process in the brain.” These findings helped to establish a new concept of Aβ as a normal sign of aging in the human body.
The generation of Aβ in neurons has been one of the most fascinating aspects of this peptide. Haass and his team could show that Aβ initially is part of a protein which they call APP, short for “Aβ precursor protein”. The function of this membrane-bound protein is still unknown, although Haass has found out that it is cut by two enzymes. One of them, the γ-secretase, cleaves APP while it is bound in the membrane. “It was considered a biochemically impossible event,” Haass remembers. “But since then other substrates of the enzyme have been found which are also cut in the membrane. We could even demonstrate that γ-secretase belongs to a whole new class of enzymes.” Y-secretase is comprised of several proteins. Among these, presenelins 1 and 2 are especially important because they compose the enzyme’s active center – and act as the “scissors” that cut APP. “More than 100 mutations in both presenilins are known, and they are all associated with early the onset Alzheimer’s which develops only in young patients and is hereditary,” explains Haass. “We’re currently working on the interactions between the different components that make up γ-secretase.”
His team is also looking for mechanisms that influence the precision of the enzymatic cuts by γ-secretase. They may lead to an increasing accumulation of Aβ and the subsequent build-up of plaques – the critical event in the development of Alzheimer’s. But another player enters the picture here: An enzyme called β-secretase has to cut APP as well to generate Aβ. In fact, both enzymes have to work together to produce the dangerous peptide. Haass and his coworkers are particularly interested in mechanisms that regulate the activity of β-secretase. “Both enzymes are considered prime targets for therapies”, he explains. “If they could be blocked, age-dependent neuropathology which causes Aβ-aggregation could be slowed down.”
Many questions remain open, but Alzheimer’s research has brought the fight against the disease to a new and very promising level. “We know the enzymes that play a role in the development of Alzheimer’s and the function of all the important genes,” says Haass. “I’m an enthusiastic proponent of a vaccination for Alzheimer’s and drugs to block the molecular scissors that cut Aβ. Ten years ago I was convinced that the disease could never be successfully fought because we didn’t understand the crucial molecular mechanisms. Now, however, even the details are known and I’m expecting major breakthroughs in prevention and therapy.”
Christian Haass was born in Mannheim in 1960. He studied biology and earned his Ph.D. in Heidelberg. After a few years of postdoctoral work and as Assistant Professor of Neurology at Harvard Medical School in Boston, he returned to Heidelberg in 1995. Four years later he became chair of biochemistry at LMU Munich where he also founded the “Alzheimer’s and Parkinson’s Laboratory”. Haass is recipient of the Gottfried Wilhelm Leibniz Prize, the most prestigious award for scientists in Germany, the “International Alois Alzheimer Award” and other awards.