Christine von Arnim: the Alzheimer's researcher has a good overall view
“Memory is one of the most exciting research topics I know because it is so close to human reality”, says Christine von Arnim. The Alzheimer’s disease researcher from the University of Ulm is not the only researcher who is intrigued by the philosophy behind the research and interested in far more than just atomistic approaches. The young neurologist covers the entire field of Alzheimer’s research, from experimental laboratory research to patient treatment and care.
Christine von Arnim is head of the Memory Clinic and managing director of the interdisciplinary Centre of Geriatrics in Ulm and as such has a relatively holistic view of the issue of Alzheimer’s. She knows that her basic research makes important contributions to improving our understanding of the pathogenesis (transport proteins involved in the APP metabolism) of the disease. At the same time, she also believes that it is necessary to focus on many aspects in order to be able to develop therapies for this complex disease that still has no cure.
Christine von Arnim’s path into medical research was mapped out from the start: she realised from her mother’s experience as a doctor that medicine provided an excellent basic education. As a doctor she would be able to deal with human beings, something that other scientific disciplines would not enable her to do. In addition, Christine von Arnim soon knew that she wanted to become a researcher. As a medical student at the University of Freiburg (1990 – 1997) she very much enjoyed the lectures given by neuroanatomist Michael Frotscher. After her initial studies, she went on to do her doctorate on a psychiatric topic (receptors in people suffering from depression) and developed an interest in fundamental biological issues, i.e. what is happening in cells. At the age of 23, she thought that she was a bit too young for a scientific career and decided to continue her medical training, first in Mannheim and from 1998 onwards in Ulm. The move from Mannheim to Ulm turned out to be an excellent decision. Christine von Arnim joined the laboratory of Matthias Riepe, who is now head of the Department of Gerontopsychiatry. In Riepe’s lab, she was able to focus on clinical education as well as use the laboratory techniques she had learnt during her doctorate; she contributed to the establishment of chronic hypotaxia models (stroke) and did her first experiments with Alzheimer's mice in which she investigated vascular risk factors. The famous Alzheimer’s disease researcher Konrad von Beyreuther from Heidelberg had a decisive influence on the young neurologist who was increasingly focusing on this neurodegenerative disease, which eventually led to her decision to make the disease her special field of research.
Fascinated by the broad research spectrum in Boston
The day after passing her expert examination, Christine von Arnim started work at the Alzheimer’s Disease Research Centre at the Harvard Medical School in Boston. Her husband, a chemist, joined her. She took up a post in the laboratory of Bradley T. Hyman, a leading Alzheimer’s disease researcher (von Arnim’s motto was if you want to really learn what Alzheimer’s disease is all about, you have to work with the best), a fascinating person, who was also a medical specialist and treating doctor. Hyman’s laboratory covered a broad range of research aspects associated with Alzheimer’s. Christine von Arnim still remembers the lab’s motto, which was “to make the difference, to cure Alzheimer’s”.
Her research group focused on apolipoprotein E. She also worked on intracellular transport mechanisms and the proteins that mediated these transport processes. During her stay in Boston, she learned to use many innovative imaging methods, including fluorescence lifetime imaging (FLIM), which she further developed with Angelika Rück from the Ulm-based ILM when she returned to Ulm in 2006. Christine von Arnim habilitated in 2006 on the cellular mechanisms of transport and processing of amyloid precursor protein (APP) and beta secretase in Alzheimer’s disease. She has been senior physician in the Department of Neurology at Ulm University Hospital since 2006 and was appointed adjunct professor at the University of Ulm in 2008.
With a grant from the Alzheimer Research Initiative, Christine von Arnim began setting up her laboratory in 2006. It is difficult to typecast Christine von Arnim, who had in the meantime become the mother of four children: thousands of Alzheimer's researchers are working on one particular protein; Christine von Arnim is the exception as she likes to be involved in many projects. She is particularly enthusiastic about an epidemiological study (ActiFE: Activity and Function in the Elderly) which involved 1,500 men and women from the Ulm area aged between 65 and 90. Objective activity measurements were carried out for the first time ever and combined with comprehensive geriatric information, medical measurements and biomarkers. The first cohort is currently being analysed and Christine von Arnim hopes that the study will provide them with important information about ways to help people remain healthy as they age. This study approaches the problem of ageing from the opposite angle to normal.
As a treating doctor, Christine von Arnim is well aware of the huge importance of making early diagnoses. Over the last few years, she has been establishing a biobank in the Memory Clinic, where cerebrospinal fluid is stored for research purposes. These samples are of enormous value for research into Alzheimer’s disease. Although Alzheimer’s research in Ulm is not part of one of the prestigious centres of excellence in Germany, the department is nevertheless well equipped and has all the infrastructure necessary to compete with international laboratories in the diagnosis of cerebrospinal fluid and clinical neurochemistry.
Focusing on different aspects
As Christine von Arnim is constantly confronted with complex diseases, she is not very familiar with steep research hypotheses. Although she is convinced that at some stage in the future it will be possible to medically treat Alzheimer’s disease, she currently feels that it is more realistic to focus on many different parameters that could contribute to preventing the disease, including lifestyle, physical activity and nutrition. This holistic approach is in line with modern Alzheimer’s research in general, where basic research and physiological and disease-oriented research, which at one time seemed to be clearly separated from each other, are now becoming increasingly interdisciplinary. Christine von Arnim, who is also a WIN (ed. note: WIN stands for "Wissenschaftlicher Nachwuchs" = up-and-coming young researchers; the WIN-Kolleg supports oustanding young scientists in interdisciplinary research projects) fellow of the Heidelberg Academy of Sciences, is focusing on interdisciplinary cooperation in a project on “neuroplasticity and immunology associated with cognitive impairments in the elderly” which she is carrying out in cooperation with two colleagues. The researchers are focused on neuropsychological phenomena in patients suffering from memory disorders and are doing mass spectrometric investigations of patient cerebrospinal fluid. They hope to use the findings for further research involving cell models.
Asked about “her contribution” to basic Alzheimer research, Christine von Arnim is rather modest, telling us that she sees it as an achievement to have specifically focused, together with other research groups, on transport proteins (e.g. GGA3) associated with the APP metabolism (von Arnim, 2006). In a 2010 paper (Beyer, 2010), von Arnim, some of her Ulm colleagues and Bradley T. Hyman described the discovery of a new intracellular interaction partner (GULP1) and its influence on the APP metabolism.
Review articles on amyloid beta 42, a peptide that forms the primary component of amyloid plaques found in the brains of Alzheimer’s disease patients, show that von Arnim is perhaps somewhat modest about her achievements because of the difficulties associated with obtaining detailed knowledge on the pathogenesis of Alzheimer’s, i.e. the fact that a thorough understanding of the native biological role and processing of APP has remained elusive. In addition, von Arnim and other researchers still lack answers to many other questions related to Alzheimer’s. Although it is known that amyloid beta is continually produced in the human body and that isoform 695 is the predominant form of amyloid beta in neuronal tissue, its physiological importance is largely unknown. It is known that larger quantities of amyloid beta are produced in patients suffering from familial Alzheimer’s disease, while larger amounts are per se present in patients suffering from sporadic, i.e. age-associated Alzheimer’s. Christine von Arnim puts forward several reasons to explain the excessive amyloid beta buildup: it is highly likely that it is not due to the fact that new amyloid beta is produced, but rather to the fact that the degradation, i.e. removal or clearance (enzymatic cleavage) of amyloid beta peptides is less effective. The majority of Alzheimer’s researchers are of the same opinion as Christine von Arnim.
It is still not known how the amyloid precursor protein (APP) is degraded in healthy individuals. According to von Arnim, the physiological role of APP and the question of whether a loss of its functions contributes to Alzheimer’s are also still unclear. Many researchers believe that this is due to the fact that the protein is part of a proteolytic complex that generates different polypeptides. They also believe that each of these polypeptides has specific functions and that APP is a member of a gene family with partially overlapping functions (Müller, Zheng 2012).
Disease cause still remains elusive
Christine von Arnim tells us that several competing hypotheses on the cause of the disease exist. The latest hypothesis proposes that amyloid beta does not just cause harm outside cells, but also inside them. This hypothesis is based on the finding that the plaques do not correlate well with the progression of the disease. This shows once again that it is difficult to specify the cause of Alzheimer’s disease. As the familial form of the disease is associated with mutations that affect the APP metabolism, many researchers have focused on research into amyloid beta. However, Christine von Arnim believes that this approach cannot explain everything. Familial Alzheimer’s disease (which usually strikes between 30 and 60 years of age and which is inherited in an autosomal dominant fashion) is caused by mutations in three genes located on chromosome 21, 14 and 1. A mutation of the apolipoprotein E gene on chromosome 19 is so far the only genetic risk factor for late-onset sporadic Alzheimer’s disease.
All these findings on the genetic risk factors of late-onset Alzheimer’s disease can be considered to represent progress towards explaining the pathogenesis of Alzheimer’s; however, they do not provide any breakthrough insights for the development of new diagnostics and therapies. For example, researchers from Ulm and from the Max Planck Institute of Molecular Genetics recently carried out a genome-wide association study and identified three gene variants as potential risk factors for sporadic Alzheimer’s disease (Schjeide, 2011).
A clinical study carried out by von Arnim’s team and researchers from the Institute of Pharmacology of Natural Products and Clinical Pharmacology deduced new pathogenetic mechanisms using cerebrospinal fluid amyloid beta 42 proteins as biomarkers of Alzheimer-type changes in the brain (Lebedeva, 2010). A paper published in February 2012, which involved three research groups from Ulm, describes a new Alzheimer’s biomarker. And for Christine von Arnim, this discovery is another step on the protracted path to developing effective Alzheimer’s disease diagnostics.
Schjeide, B-M. et. al.: The Role of Clusterin, Complement Receptor 1, and Phosphatidylinositol Binding Clathrin Assembly Protein in Alzheimer Disease Risk and Cerebrospinal Fluid Biomarker Levels, In: Archives of General Psychiatry, 2011;68(2):207-213
Lebedeva, E. et al.: Genetic Variants in PSEN2 and Correlation to CSF ß-amyloid42 levels in AD, Neurobiology of Aging 33, January 2012:201.e9-18; Epub. 18. Sept. 2010
Beyer, A-S. et al.: Engulfment Adapter PTB Domain Containing 1 interacts with and Affects Processing of the Amyloid-beta Precursor Protein, Neurobiology of Aging, 33/April 2010, 732-743
von Arnim, Christine A. F., et al.: GGA1 Acts as a Spatial Switch Altering Amyloid Precursor Protein Trafficking and Processing, Journal of Neuroscience, 27. Sept., 2006; 26(39), 9913-9922
Müller, Zheng: Physiological Functions of APP Family Proteins, Cold Spring Harbor Perspectives in Medicine 2012;4:a006288.
Selkoe. D. et al.: Deciphering Alzheimer Disease, Cold Spring Harbor Perspectives in Medicine 2012;2:a011460.