The role of Alzheimer-related mutations in neuronal death

Projektdetails:

Thematik: Grundlagenforschung
Förderstatus: abgeschlossen
Art der Förderung: Standard Projekt
Institution: Universität Frankfurt, Abteilung Pharmazie
Projektleiter: Prof. Dr. Anne Eckert
Laufzeit: 01. November 1997 - 31. Oktober 1998
Fördersumme: 20.452,00 Euro
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Projektbeschreibung

During Alzheimer’s disease, damage and massive loss of brain cells occur. Recent evidence indicates that this cell death follows a carefully regulated program, also called apoptosis. The time course of the appearance of morphological and biochemical alterations occurs in fixed sequence. Importantly, the nucleus of the cell undergoes extreme alterations and is divided into several nuclei of smaller size. In addition, apoptosis appears to be genetically regulated. During life, apoptosis acts as a natural cell death for deletion of abnormal or infected cells without inflammatory reactions.

Recent findings indicate that specific features of apoptosis as the initiation of the nuclear collapse are enhanced in brain cells of Alzheimer patients. These changes within the nucleus of brain cells are similar to those identified in in vitro experiments of neuronal cell culture after treatment with the peptide ß-amyloid.

In rare cases (about 1-3%) of familial Alzheimer’s disease (FAD), mutations have been detected on the chromosome 21 within the gene, which is responsible for the release of the cell-damaging protein ß-amyloid (APP gene). In the majority of autosomal dominant familial Alzheimer cases (40-50%), mutations in a gene on chromosome 14 have been found (called presenilin-1, PS-1). The highly homologous gene presenilin-2 on chromosome 1 is also involved in a small number of FAD cases. Research indicates that mutations of these genes are linked to increased cell death mechanisms.

For this project Dr. Eckert and her team investigated the phenotypic consequence of expressing FAD-related mutant APP proteins in PC12 cells. The results indicate that vulnerability to oxidative stress triggering cell death is enhanced in PC12 cells bearing the Swedish double mutation form of APP compared to cells bearing ‘healthy’ APP. Her findings suggest an important link between oxidative stress, cell death and Alzheimer’s disease.

Abschlussbericht

Alzheimer's disease is the most common neurodegenerative disorder world wide, causing presenile dementia and death of millions of people. During Alzheimer's disease damage and massive loss of brain cells occur. Recent evidence indicate that this cell death follows a carefully regulated program. The programmed cell death is also called apoptosis. The time course of the appearance of morphological and biochemical alterations as membrane blebbing of the cell surface occurs in fixed sequence. Importantly, the nucleus of the cell undergoes extreme alterations and is divided into several nuclei of smaller size. In addition, apoptosis appears to be genetically regulated. During life, apoptosis acts as a natural cell death for deletion of abnormal or infected cells without inflammatory reactions.

Especially interesting, recent findings indicate that specific features of apoptosis as the initiation of the nuclear collaps are enhanced in brain cells of Alzheimer patients compared to aged non-demented controls. These changes within the nucleus of brain cells are similar to those identified in in vitro experiments of neuronal  cell-culture after treatment with the peptide ß-amyloid, the main constituent of the senile plaques in Alzheimer brain.

In many cases Alzheimer's disease (90%) occurs in the absence of a prior history of the disease in other family members and is designated as sporadic. In approximately 10% of patients, changes of the genetic information were detected (gene mutations). In these cases Alzheimer's disease is inherited as an autosomal dominant trait (familial Alzheimer's disease, FAD). In rare cases of familial Alzheimer's disease (about 1-3%), mutations have been detected on the chromosome 21 within the gene, which is responsible for the release of the cell damaging protein ß-amyloid (APP gene). In the majority of autosomal dominant familial Alzheimer cases (40-50%), mutations in a gene on chromosome 14 have been found (called presenilin 1, PS-1). The highly homologous gene presenilin2 on chromosome 1 is also involved in a small number of FAD cases. Recent research indicates that mutations of these genes are linked to increased cell death mechanisms.

ln our research study, we examined, whether the mutation of the APP gene on chromosome 21 make the cells more sensitive to start their cell death programs. Indeed, our first results indicate that cells bearing this FAD- mutation are very vulnerable to the induction of death, especially after exposure to oxidative stress (generation of free radicals). It seems really remarkable that cells with the FAD-related APP mutation can be forced to die so rapidly. These experiments could maybe explain or elucidate why also more cells die in Alzheimer brains than in non-demented control persons.

In the next part of our study, we will investigate the protective efficacy of drugs, which are used for prevention. This approach may determine which particular drugs (e.g. vitamin E, vitamin C, coenzyme Q, selegeline, estrogene) are of therapeutic value for patients and if FAD patients with gene mutations show particular sensitivity to protection or not. Special interest will be given for the protection to oxidative stress, since the cells with the mutated form of APP can only insufficiently handle this type of cell damage. The basic research in neuronal cell lines with and without Alzheimer-related genetic mutations will open new ways for the development of preventive drug and may help patients which suffer from this serious disease to improve the quality of life.

Wissenschaftliche Publikationen auf Basis des geförderten Projekts

Eckert, A., Steiner, B., Marques, C., Leutz, S., Romig, H., Haas, C., Müller, W.E. (2001). Elevated Vulnerability to Oxidative Stress-Induced Cell Death and Activation of Caspase-3 by the Swedish Amyliod Precursor Protein Mutation. Journal of Neuroscience Research, 64:183-92.

Schindowski, K., Leutner, S., Eckert, A. and Müller W.E. (1998). Age-related alterations in apoptotic cell death and oxidative stress of human peripheral cells. Pharmazie, 53(3):32.


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