Effekt des β-Amyloid-Proteins auf die gliale Cyclooxygenase- und Prostaglandin-Synthese

Projektdetails:

Thematik: Grundlagenforschung
Förderstatus: abgeschlossen
Art der Förderung: Standard Projekt
Institution: Universität Freiburg, Abteilung für Psychiatrie Neurochemisches Forschungslabor
Projektleiter: Prof. Dr. Michael Hüll
Laufzeit: 01. November 2000 - 31. Oktober 2001
Fördersumme: 20.452,00 Euro

Projektbeschreibung

Die Entzündungsreaktion, die bei der Alzheimer-Krankheit auftritt, ist für das Fortschreiten der Neurodegeneration mitverantwortlich. Bestimmte Gewebsbotenstoffe, wie die Prostaglandine, verstärken diese Entzündungsreaktion. Im Gehirn werden diese Botenstoffe von den (Glia-) Nervenzellen synthetisiert. Eine vermehrte Synthese von Prostaglandinen verstärkt das Fortschreiten von Alzheimer. Die Gewebsbotenstoffe werden von spezifischen Enzymen, den Cyclooxygenasen (COX 1 und COX 2), in den (Glia-)Nervenzellen synthetisiert. In verschiedenen Tiermodellen konnte gezeigt werden, dass eine erhöhte Synthese von COX 2 im Gehirn zum vermehrten Absterben von Nervenzellen führt.

In der Arbeitsgruppe von Privatdozent Dr. Michael Hüll von der Universität in Freiburg wird untersucht, in wie weit das ß-Amyloid-Protein die Herstellung von Cyclooxygenasen stimuliert und demzufolge zu einer vermehrten Degeneration von Nervenzellen führt. Die Ergebnisse dieses Forschungsprojektes werden den Effekt des ß-Amyloid-Proteins auf die Entzündungsreaktion bei der Alzheimer-Erkrankung weiter aufklären. Zudem werden mögliche therapeutische Ansätze aufgezeigt, wie mit geeigneten Hemmstoffen die Entzündungsreaktion im Gehirn von Alzheimer-Patienten unterbunden und somit das Fortschreiten der Erkrankung verlangsamt werden kann.

Abschlussbericht

In Alzheimer's disease a small protein fragment called Aβ is overproduced in nerve cells and found in high concentration in the brain. This small protein fragment accumulates outside the nerve cells and forms amyloid plaques. Glial cells, which support the function of nerve cells, react to amyloid and become activated. This activation may be harmful or beneficial to the brain function. On the one hand, activated glial cells can produce substances that harm nerve cells. On the other hand, activated glial cells may also be able to remove amyloid deposits. The removal of amyloid by glial cells has been shown in animals vaccinated with Aβ. While glial cells are much numerous than nerve cells there are not much data conceming the effect of Aβ on glial cell activation.

We investigated whether AB stimulates the synthesis of the enzyme cycloxygenase-2 and the production of prostaglandines in glial cells. Both, the presence of elevated cyclooxygenase-2 protein and prostaglandins have been reported in Alzheimer’s disease. In a series of experiments we found differences between different forms of glial cells: microglia, astroglia from the cortex and astroglia from the mid brain. While differences between neurons from different brain regions are known for a long time, differences between astroglia from different brain regions are just evolving. While neither microglia nor astroglia from the cortex react to Aβ with the production of prostagandins, mid brain astroglia exhibited a complete different reaction. In mid brain astroglia an important "switch" of cell activity, the protein kinase C, was turned on by Aβ. Following the turn of the switch, the gene for cyclooxygenase-2 was activated and the cyclooxygenase-2 protein was synthesized. Furthermore, the enzymatic activity of cyclooxygenase-2 increased and prostaglandins were formed. These experiments demonstrated for the first time an information pathway in astrocytes which translates the presence of Aβ into the production of prostaglandins. Furthermore, this information pathway seems to be present in some but not all astrocytes, depending on their location in the brain. There are more than l0 different protein kinase C "switches" marked with different greek letters (α, β, γ, ...).

While we ruled out protein kinase C α and β biochemical tools which are just evolving may allow further characterization in the near future. The knowledge of the different "switches" which are taggled by Aβ to start harmful or beneficial glial activation may help in the future to modulate the effects of Aβ on glial cells by drugs which act on the specific protein kinase C "switch".

Wissenschaftliche Publikationen auf Basis des geförderten Projekts

Hüll, M., Müksch, B., Shankar Akundi, R., Waschbisch, A., Hoozemans, J.J.M., Veerhuis, R., Fiebich, B.L. (2006). Amyloid β peptide (25–35) activates protein kinase C leading to cyclooxygenase-2 induction and prostaglandin E2 release in primary midbrain astrocytes, 48(8):663-672.

Hüll, M., Hampel, H. (2002). Neuroinflammation in Alzheimer’s disease: potential targets for disease modifying drugs. Ernst Schering Res Found Workshop, 39:159-78.

Hüll, M., Lieb, B., Fiebich, L. (2002). Pathways of inflammatory activation in Alzheimer’s disease: potential targets for disease-modifying drugs. Curr Med Chem, 9:83-88.


Möchten Sie unseren Newsletter abonnieren?

Haben Sie Fragen?

Vertrauen & Transparenz

Logo der Initiative Transparente Zivilgesellschaft
Logo des Deutschen Spendenrates