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16.04.2012

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.

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.

Getting old and staying healthy – physical exercise is highly important. (© Dieter Schütz/pixelio.de)

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

Disease cause still remains elusive

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 Phosphorylation-dependent interaction of the transport protein GGA1 with the BACE enzyme that cleaves APP. The four photos on the left (showing GGA1; A, C, E, G) and FLIM images in pseudocolours, co-transfected with wildtype BACE (D) or the mutants BACE-S498D (F) and BACE-S498A (H) in N2a cells. Non-phosphorylated BACE mutants (S498A) do not show an altered fluorescence lifetime. (© von Arnim)
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.
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Literature:

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.

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