The objective of the work package is to improve S&T experience and knowledge of researchers in molecular neuropathology by long term trainings at the Institute of Neuropathology, Zürich, Switzerland and exchange of know-how and experience with the scientific experts.

The department of Neuropathology of the University of Greifswald has focussed on the research of the pathogenesis of neurodegenerative diseases with special emphasis on the role of transport processes at the blood-brain-barrier. Alzheimer’s disease (AD) is the most common cause of dementia. This neurodegenerative disorder is characterized morphologically by the accumulation of the beta-amyloid peptide (Abeta) as intraparenchymal Abeta plaques and cerebrovascular beta-amyloid angiopathy (CAA), as well as the formation of neurofibrillary tangles. Most therapeutic approaches to AD currently focus on reducing Abeta burden in the brain. P-glycoprotein (P-gp) that belongs to the ATP binding cassette (ABC) superfamily of transporters acts as an active transport protein of Abeta. Our previous studies showed a significant, age-related reduction of P-gp expression by the endothelial cells of the blood-brain-barrier that correlates with an increased accumulation of Abeta in the brain.

The broad aim of our studies is to establish the role of P-gp in the pathogenesis of AD, and thereby to develop a novel approach to risk management and effective therapeutic strategies for AD. Since the activity of P-gp can be modulated pharmacologically it could display a target for new prevention or disease-modifying treatment of AD. Our future research focuses on experiments with different transgenic mouse models of AD.

Therefore, one researcher will be sent to Institute of Neuropathology (INP), Zurich, Switzerland for long term training courses on novel technologies. The Institute of Neuropathology with its director Prof. Adriano Aguzzi has an outstanding reputation in the field of research of neurodegenerative disorders. In addition, the institute hosts the National Reference Center for Human Prion Diseases (NRPE) which coordinates the diagnostic activities in the field of transmissible spongiform encephalopathies (TSEs) in Switzerland. Among many awards Prof. Aguzzi is carrier of the highest German medical award - the Robert-Koch-Prize.

Methods to be learned focussed on the molecular pathology of the Alzheimer’s Disease include: (1) Preparation of Abeta using brain extracts from humans with Alzheimer Disease (AD) or APP/PS1 transgenic mice; (2) injection of Abeta preparations intracerebrally into transgenic mice, FVBAPP/PS1-MDR1a/b-/-- mice and FVBAPP/PS1-MDR1a/b+/+ , respectively.

Furthermore, an expert scientist will stay at the Institute of Neuropathology for 1 week in 2009 to exchange know-how and experience on specific topics related to molecular neuropathology. The scientist will be invited from Institute of Neuropathology. And, an expert scientist from the Institute of Neuropathology will stay at EMAU Greifswald for 1 week in 2010 to exchange know-how and experience on specific topics related to neurodegenerative diseases. The scientist will be invited by the University of Greifswald.

PD Dr. Silke Vogelgesang [WP leader]

Dr. Anja Brenn [Coworker]

Prof. Adriano Aguzzi

Institute of Neuropathology (INP), Zürich, Switzerland

• Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, Kunert-Keil C, Walker LC, Warzok RW. Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics. 2002 Oct;12(7):535-541
• Kuhnke D, Jedlitschky G, Grube M, Krohn M, Jucker M, Mosyagin I, Cascorbi I, Walker LC, Kroemer HK, Warzok RW, Vogelgesang S. MDR1-P-Glycoprotein (ABCB1) Mediates Transport of Alzheimer's Amyloid-β Peptides – Implications for the Mechanisms of Aβ Clearance at the Blood-Brain Barrier. Brain Pathol 2007; 17 (4): 347-353.