Application of abnormal proteins outside the brain induces Alzheimer-like brain pathology in mice

Tübingen, 21.Oktober 2010.Pathological protein deposits linked to Alzheimer's disease and cerebral amyloid angiopathy can be triggered not only by the administration of pathogenic misfolded protein fragments directly into the brain but also by peripheral administration outside the brain. This is shown in a new study done by researchers at the Hertie Institute of Clinical Brain Research (HIH, University Hospital Tübingen, University of Tübingen) and the German Center for Neurodegenerative Diseases (DZNE), to be published in Science on October 21, 2010.

Alzheimer’s disease and a brain vascular disorder called cerebral beta-amyloid angiopathy are characterized by the accumulation of a protein fragment known as Abeta. In Alzheimer´s disease, misfolded Abeta is deposited mainly in so-called amyloid plaques, whereas in cerebral beta-amyloid angiopathy, the Abeta protein aggregates in the walls of blood vessels, interfering with their function and, in some cases, causing them to rupture with subsequent intracerebral bleeding.

In 2006, scientists in Tübingen, led by Mathias Jucker, reported that injection of dilute extracts from Alzheimer's disease brain tissue, or from Abeta-laden mouse brain tissue, into the brains of transgenic mice (genetically modified to produce the human form of Abeta) stimulated Abeta aggregation within the mouse brain (Science 313: 1781-4, 2006).

In the current Science study,Stained brain slice of a transgenic mouse after intraperitoneal administration of an extract containing misfolded Abeta (beta-Amyloid). The black and yellow-green stainings show the induced pathological amyloid deposits Professor Jucker and first author Yvonne Eisele, together with their research team (HIH, University of Tübingen,DZNE) and colleagues Matthias Staufenbiel (Novartis), Mathias Heikenwälder (University of Zürich), and Lary Walker (Emory University Atlanta) report that Abeta deposition can be induced in the transgenic mouse brain by the intraperitoneal administration of mouse brain extract containing misfolded Abeta. This induced Abeta deposition was primarily associated with the vasculature, but was also evident as amyloid plaques between nerve cells.  The time needed to induce amyloid deposition in the brain was much longer for peripheral as compared to direct brain administration. In both cases, the induced amyloid deposition also triggered several neurodegenerative and neuroinflammatory changes commonly observed in the brains of patients with Alzheimer´s disease and cerebral beta-amyloid angiopathy. “The finding that mechanisms exist allowing for the transport of Abeta aggregates from the periphery to the brain raises the question of whether protein aggregation and propagation, which may also be involved in other neurodegenerative brain diseases, can be induced by agents originating in the periphery“, points out Professor Jucker. The present findings provide new clues on pathogenetic mechanisms underlying Alzheimer’s disease; further investigation will likely lead to new strategies for prevention and treatment.

Title of the original publication:
Peripherally Applied A
β-Containing Inoculates Induce Cerebral β-Amyloidosis

Authors: Yvonne S. Eisele1,2, Ulrike Obermüller1,2, Götz Heilbronner1,2,3, Frank Baumann1,2, Stephan A. Kaeser1,2, Hartwig Wolburg4, Lary C. Walker5, Matthias Staufenbiel6, Mathias Heikenwalder7, Mathias Jucker1,2,*

1 Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany;
2 DZNE - German Center for Neurodegenerative Diseases, Tübingen, Germany;
3 Graduate School for Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany;
4 Department of Pathology, University of Tübingen, Tübingen, Germany;
5 Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA, USA,
6 Novartis Institutes for Biomedical Research, Neuroscience Discovery, Basel, Switzerland; 7 Department of Pathology, Institute for Neuropathology, University Hospital, Zürich, Switzerland.

Advanced online publication in Science, Science express Website 21 October 2010 (2:00 pm U.S. Eastern Time/ 8 pm Central European Summer Time) www.scienceexpress.org

Figure note: To use the photo please give the copyright: Science (AAAS)/Eisele

Condition of use: This picture may be used only in connection with the contents of this press release.

Figure legend: Stained brain slice of a transgenic mouse after intraperitoneal administration of an extract containing misfolded Abeta (beta-Amyloid). The black and yellow-green stainings show the induced pathological amyloid deposits.

Contact:
Professor Dr. Mathias Jucker
Universität Tübingen
Universitätsklinikum Tübingen, Zentrum für Neurologie
Hertie-Institut für klinische Hirnforschung (HIH)
German Center of Neurodegenerative Diseases (DZNE)
Tel.:        +49 (0) 7071 / 29-86863
E-Mail:    mathias.jucker@uni-tuebingen.de

Sonja Jülich-Abbas
German Center of Neurodegenerative Diseases (DZNE)
Leiterin der Presse- und Öffentlichkeitsarbeit (komm.)
Telefon:  +49-(0) 228 / 43302-260
Mobil:      +49 (0) 172 / 2838930
E-Mail:     sonja.juelich-abbas@dzne.de

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