Alzheimer’s researchers at the MDC pursue various approaches to better diagnose and treat the disease. Professor Willnow is searching for the genetic causes of the disease. The protein scientist Professor Erich Wanker is seeking new ways to diagnose the disease and identify new active substances to prevent its onset. Dipl.-Ing. Marion Bimmler (MDC; biotech company E.R.D.E-AAK-Diagnostik GmbH, Campus Berlin-Buch) is studying specific autoantibodies that damage the blood vessels in the brain and thus contribute to dementia and Alzheimer’s disease.
Professor Willnow’s research is based on genome-wide association studies (GWAS). In these studies, researchers compare the genomes of approximately 50,000 healthy people with those of around 10,000 people suffering from the sporadic, late-onset form of Alzheimer’s. The late-onset form accounts for about 95 percent of Alzheimer’s patients and is a disease of old age. Its causes are mostly unknown, which is why scientists are searching for genetic risk factors and environmental factors for this form of Alzheimer’s.
By comparing the genomes of healthy people and Alzheimer patients, geneticists can identify which genes are altered in people affected by the disease. Generally either too much or too little of the respective gene product (protein) is generated or the protein does not function correctly. “We study the function of such genes in mice. Currently we are investigating four to five different genes,” said Professor Willnow. “Twin studies also indicate that this sporadic form of Alzheimer’s must have a strong genetic component,” the cell biologist added.
In the familial form of Alzheimer’s, which accounts for only about five percent of the incidence of Alzheimer’s disease and is characterized by onset at a young age, researchers have identified different mutations in three genes. A mutation in one of the three genes is sufficient to induce this early form of Alzheimer’s. This familial form of Alzheimer’s is very aggressive as opposed to the late-onset form.
Nerve cells themselves produce protective factor
A few years ago, during a genome-wide association study, Professor Willnow’s research group discovered that healthy nerve cells generate a protective factor, the transport protein SORLA (abbreviation: sorting protein-related receptor), which reduces the production of the main culprit for Alzheimer’s, the A-beta peptide. A-beta is a small protein fragment that arises from a larger precursor protein, APP. Two different molecular scissors (secretases) cut APP into pieces of A-beta. This process takes place in the brain of healthy people and ensures that nerve cells communicate with each other.
However, if too much A-beta is formed which the body cannot dispose of, the nerve cells die off and neuronal communication is disturbed. Cognitive defects are the consequence. Excess A-beta also leads to the dangerous build-up of plaque deposits in the brain, which additionally damage the nerve cells. “Since the amount of A-beta in the brain constantly increases with the age of the individual, the risk of developing Alzheimer’s in old age rises dramatically,” Professor Willnow said. He demonstrated that a loss of the protective factor SORLA in mice leads to increased A-beta formation. He detected the same phenomenon in the brains of people affected by Alzheimer’s. Some patients make less SORLA, so that increasingly the toxic A-beta is formed and deposited in the brain. In studies on mice he showed that increased production of the protective factor SORLA significantly reduces the amount of A-beta in the brain.
Professor Wanker: Development of new tools for diagnosis and treatment
Professor Wanker’s research focuses on the proteins that have been identified to be causally related to Alzheimer’s and other neurodegenerative diseases such as Huntington’s disease and Parkinson’s disease. The biochemist is primarily interested in why the healthy peptide A-beta is transformed into a pathogenic peptide. A few years ago researchers showed that the pathogenic A-beta in the brain self-propagates and spreads in the brain. In this context, researchers speak of “seeds” – soluble toxic structures that A-beta produces in the brain. Professor Wanker studies these structures, some of which are from the dissected brains of deceased Alzheimer’s patients, in cell cultures in his laboratory. “We have developed a new method by which we can quantify the dissemination of these abnormal structures. “Our aim is to discover drugs that will prevent them from spreading in order to inhibit the manifestation of the disease,” Professor Wanker said.
Dipl.-Ing. Bimmler: Autoantibodies in the brain damage blood vessels
Blood vessel damage in the brain is another component of the complex Alzheimer’s disease and other dementias. A few years ago, Dipl.-Ing. Marion Bimmler (MDC), Dr. Peter Karczewski and Petra Hempel (E.R.D.E.-AAK-Diagnostik GmbH) provided evidence in studies on rodents that a group of antibodies of the immune system can damage blood vessels in the brain. If these antibodies are dysregulated, they attack the body, which is why they are called autoantibodies.
The so-called agonistic acting autoantibodies (agAAB) bind to specific surface proteins (receptors; alpha1 adrenergic receptors) of blood vessel cells and there trigger a constant stimulation of the receptor. Thereby, the concentration of calcium ions is increased in the cell. The agAAB activate the growth of smooth vascular muscle cells and induce a thickening of the blood vessel walls, thus causing a disruption of the blood flow in the brain. In studies on rodents, the biotechnologists could show this reduced blood flow by means of magnetic resonance imaging (MRI).
Using immunofluorescence microscopy, they were also able to demonstrate a significant decrease in vascular density in sections of the cerebral cortex. Moreover, the Virchow-Robins spaces of the animals – they surround the blood vessels in the brain – were greatly dilated. Excessive widening (dilation) is considered the sign of the presence of damage to very small blood vessels (microangiopathies). The researchers thus provided proof that antibodies to the alpha -1- adrenergic receptor cause damage to the larger and smaller blood vessels in the brain of rodents.
In previous studies, Marion Bimmler and her research team examined the blood of patients with Alzheimer‘s / vascular dementia and found that half of them had such autoantibodies. In cooperation with the Charité – Universitätsmedizin Berlin and the University Hospital of Jena, these autoantibodies were removed from the blood of a small number of patients with Alzheimer’s / vascular dementia. “The patients who underwent hemodialysis benefited from the treatment. Both their memory skills and their ability to cope with everyday life improved or remained constant and did not deteriorate during the observation period of 12 – 24 months. We have thus demonstrated a therapeutic option (proof of concept)” said Bimmler. “In contrast to the patients who received the treatment, the condition of the untreated patients who continued to have autoantibodies in their blood deteriorated during the same period.” A further study is currently being planned.
Main risk factors for Alzheimer’s
Metabolic diseases such as type 2 diabetes, elevated cholesterol levels and obesity are among the main risk factors for Alzheimer’s. The greatest genetic risk factor, according to Professor Willnow, is apolipoprotein E, a regulator of cholesterol. People with a specific variant of this gene have a four times higher risk of developing Alzheimer’s than carriers of other genes. Just how a dysregulation in the glucose and lipid metabolism can cause damage in the brain, however, is still unclear. For some time Professor Willnow has been exploring the molecular mechanisms underlying this interaction. The main focus of research is on a new class of signal receptors.
Marion Bimmler and her team were also able to detect agonistic autoantibodies in people with type 2 diabetes. “Perhaps,” the researcher said, “these are one of the reasons why diabetics develop dementia and Alzheimer’s more frequently than non-diabetics.”
Possibility of delaying the onset of the disease
Against this background, the researchers are convinced that it is possible to delay the onset of Alzheimer’s. This includes paying attention to one’s health, exercising, and eating a good diet.
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
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