Mechanism of cell death in Alzheimer’s disease
|Art der Förderung:
||Universität Münster, Interdisziplinäres Klinisches Forschungszentrum (IKF)
||Prof. Dr. Jochen Prehn
||01. November 1996 - 31. Oktober 1998
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Neurons in the brain can die for many different reasons. It has long been assumed that most of the cell death observed in many brain disorders is passive in nature. Research of the past years, however, has provided substantial evidence that neuronal death in chronic disorders such as Alzheimer’s disease resembles a ‘suicide’ process known as programmed cell death.
Programmed cell death is an active process and is regulated by the activity of a set of genes. For this project Dr. Prehn has investigated the effects and the mode of action of these important cell death-regulating genes using molecular biology and cell biology approaches.
These studies have been performed in neuronal cultures using three different models:
(i) Neuronal injury induced by exposure to 13-amyloid peptides, the major components of the plaques of Alzheimer’s disease that are critically involved in the disease process.
(ii) Neuronal injury induced by exposure to pro-oxidants, highly reactive and toxic metabolites that are generated by ß-amyloid peptides and other sources in Alzheimer’s disease.
(iii) Neuronal injury induced by agents that directly activate programmed cell death.
The results indicate that Bcl-xl inhibited the death of nerve cells induced by exposure to toxic agents relevant for Alzheimer’s disease and demonstrate a role for mitochondria and free radicals in this process. Research on the role of an active cell death program in the pathophysiology of Alzheimer’s disease may lead to the development of new concepts for the treatment or prevention of Alzheimer’s disease in the future.
Research of the past years has provided substantial evidence that the death of neurons in Alzheimer's disease and related neurodegenerative disorders involves the activation of a “suicide” process known as programmed cell death. Programmed cell death is an active process that is regulated by the activity of a set of genes such as bcl-x, and is executed by a family of protein-digesting enzymes called caspases. However, it is not yet fully understood how pathophysiological conditions such as increased ß-amyloid production and increased oxidant stress are able to cause the activation of this suicide program.
We focussed our research on the role of mitochondria in this process. We exposed cultured neurons to ß-amyloid peptides, the major component of the cerebral plaques found in Alzheimer's disease, to pro-oxidants and to agents that directly activate programmed cell death. We found significant alterations in mitochondria functions such as an increased production of free radicals, changes in mitochondrial membrane potential and changes in mitochondrial morphology.
Interestingly, these mitochondrial changes were followed by the activation of the apoptosis-executing proteases. Mitochondria may thus play a key role in programmed cell death. The protein product of the apoptosis-regulating bcl-x gene is mainly localized to mitochondria and is believed to regulate mitochondrial function. We are thus currently investigating the effects of bcl-x overexpression on changes of mitochondrial function caused by ß-amyloid peptides, pro-oxidants and apoptosis-inducing agents.
We are continuing our research on the role of mitochondria and an active cell death program in the pathophysiology of Alzheimer's disease and hope this research may lead to the development of new concepts for the treatment of Alzheimer's disease.
Wissenschaftliche Publikationen auf Basis des geförderten Projekts
Krohn A.J., Wahlbrink T., Prehn, J.H.M. (1999) Mitochondrial depolarization is not required for neuronal apoptosis. J Neurosci., 19(17):7394-404.
Krohn, A.J., Preis, E., Prehn, J.H.M. (1998). Staurosporine-induced apoptosis of cultured rat hippocampal neurons involves caspase-1-like proteases as upstream initiators and increased production of superoxide as a main downstream effector. J. Neurosci., 18:8186-8197.
Luetjens, C.M., Lankiewicz, S., Bui, N.T., Krohn, A.J., Poppe, M., Prehn, J.H.M. (2001). Up-regulation of BCL-XL in responde to subtoxic ß-amyloid: role in neuronal resistance against apoptotic and oxidative injury. Neuroscience, 102:139-150.