Antioxidantien gegen die Alzheimer-Krankheit

Projektdetails:

Projektbeschreibung

Die Bildung von Sauerstoffradikalen, auch oxidativer Stress genannt, trägt zum Fortschreiten der Alzheimer-Erkrankung bei. Oxidativer Stress im Gehirn von Alzheimer-Patienten, führt zu Schädigungen der Erbinformation DNA und verstärkt somit das Absterben von Nervenzellen.

Dr. Christoph Schmitz von der Universität Aachen und Professor Dr. Harry Steinbusch von der Universität Maastricht werden in Ihrem Kooperationsprojekt den Einfluss von Antioxidantien auf die Reparaturrate von DNA-Schäden im Tiermodell untersuchen. Diese Substanzen können Sauerstoffradikale unschädlich machen. In ersten Untersuchungen haben beide Wissenschaftler Hinweise erbracht, dass Nervenzellen mit Amyloid-Ablagerungen eine verminderte Fähigkeit besitzen, Schädigungen der DNA zu korrigieren. Die Reparaturrate von DNA-Schäden kann durch den Einsatz von Antioxidantien, wie der Superoxid-Dismutase, erhöht werden. Dieses Enzym besitzt die Fähigkeit, Sauerstoffradikale unschädlich zu machen und schützt somit die Nervenzellen vor oxidativem Stress.

Die Ergebnisse dieses Forschungsprojektes werden das Grundlagenwissen über die Wirkung von Antioxidantien auf die Degeneration von Nervenzellen erweitern, wie sie bei der Alzheimer-Krankheit auftreten.

Abschlussbericht

Alzheimer's disease (AD) is a disease in which the patients are mostly elderly people showing progressive memory disturbances called dementia. Other problems of patients with AD are personality and orientation disturbances. In addition to these problems of the individual patient, AD has an enormous impact on the lives of people surrounding the patient as well as on society.

During the last years here has been a substantial increase in the understanding of the biological processes involved in AD. Despite this increased understanding, however, there is currently no effective treatment available for people with Alzheimer's disease. When you look at the brains of AD patients closely, specific alterations in and around brain cells are visible. These characteristic alterations are called plaques and tangles. Interestingly, specific regions in the brains of people with AD are more vulnerable to the disease process than other regions.

As we all know, AD is typically manifested in the elderly people. Since aging is the most important risk factor for AD, we have focussed our research on several processes which play important roles both in aging and in AD. During aging and in AD, for example, the genetic material (DNA) within brain cells is increasingly damaged. Fortuitously cells in our body have the capacity to repair DNA damage by so called DNA repair mechanisms.  During aging and in AD, it seems that these repair mechanism cannot keep up with the amount of damaged DNA.

To investigate the DNA repair mechanisms during aging, we are using the aging mouse brain as a model for the aging human brain. Interestingly we have found that brain cells in regions of the aging mouse brain which correspond to the vulnerable regions of the AD brain show a lack in DNA repair. Brain cells in the other regions in the aging mouse brain that correspond to the brain regions in AD patients which are less vulnerable to the disease process; do not show this lack of DNA repair. Most importantly these latter regions show a loss of cells during aging.

When we interpreted these findings we formulated the hypothesis that some regions in the aging brain are protected against the Alzheimer's disease process by losing those cells which otherwise would have made problems. Similarly the other regions which do not lose these cells do develop Alzheimer's disease pathology. Therefore our findings in the aging mouse brain could provide a new explanation for the vulnerability of specific brain regions in Alzheimer's disease.

Our current research is focussing on the question whether the amount of DNA damage in the aging brain could be decreased by a certain diet, which is called 'dietary restriction without undernutrition'. This diet combines high loads of antioxidants with a diminished caloric intake. If this being the case, an effective possibility for the prevention of AD could be designed based on this diet.

Wissenschaftliche Publikationen auf Basis des geförderten Projekts

Brasnjevic, I., Rutten, B.P.F., Steinbusch, H.W.M., Schmitz, C. (2006). Synapse and neuron loss in transgenic mouse models of Alzheimer's disease. In: Frontiers in Alzheimer's disease research (Eileen M. Welsh, ed). Nova Science Publishers, Hauppauge, pp. 97-126.

Schmitz, C., Rutten, B.P.F., Wirths, O., Pielen, A., Steinbusch, H.W.M., Korr, H., Czech, C., Blanchard, V., Tremp,G., Beyreuther, K., Pradier, L., Multhaup, G., Bayer, T.A. (2004). Plaque in Hippocampal Neuron Loss Exceeds Amyloid Plaque Load in a Transgenic Mouse Model of Alzheimer’s Disease. American Journal of Pathology, 164(4):1495-502.

Rutten, B.P.F., Korr, H., Steinbusch, H.W.M., and Schmitz, C. (2003). The aging brain: less neurons could be better. Mechanisms of Ageing and Development, 124(3):349-355.

Rutten, B.P.F., Wirths, O., Van de Berg, W.D.J., Lichtenthaler, S.F., Vehoff, J., Steinbusch, H.W.M., Korr, H., Beyreuther, K., Multhaup, G., Bayer, T.A., and Schmitz, C. (2003). No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the β-cleaved c-terminal app fragment. Neurobiology of Disease, 12(2):110-120.

Rutten, B.P.F., Steinbusch, H.W.M., Korr, H., Schmitz, C. (2002). Antioxidants and Alzheimer's disease: from bench to bedside (and back again). Current Opinion in Clinical Nutrition and Metabolic Care, 5(6):645-651.