MECHANISMS OF CELL-DEATH IN ALZHEIMERS-DISEASE

The etiology of Alzheimer's disease (AD) as well as its exact pathogen esis are unknown. Eventhough the deposition of beta A4 and the formati on of neurofibrillary tangles represent impressive morphological hallm arks of the disease, several lines of evidence suggest that both lesio ns are not sufficient as causes of the neurodegenerative process. On t he other hand, in vitro studies have shown that beta A4 is neurotoxic and is able to induce apoptotic cell death in neuronal cell cultures. Cells dying by apoptosis (programmed cell death) can be visualized in the tissue with a molecular biologic technique detecting fragmented nu clear DNA. Using this method, we have detected 50 xmore neurons and 25 xmore glial cells with nuclear DNA fragmentation in the brains of pati ents with AD than in non-demented controls. In contrast to previous st udies, most of these cells did not reveal the characteristic morpholog ical hallmarks of apoptosis. Most dying cells were not located within amyloid deposits and most dying cells did not bear a tangle. On the ot her hand, being in physical contact with an amyloid deposit increased the risk of a cell to dye by factor 5.7 and carrying a neurofibrillary tangle imposed a 3 times higher risk compared to unaffected nerve cel ls. Taken together, these data indicate that nerve cell death in AD oc curs via a mechanism of programmed cell death different from classical apoptosis. Eventhough plaques and tangles increase the risk of cells to degenerate, both lesions are not the sole responsibles of the degen erative process, suggesting the existence of other factors that trigge r the initiation of the cell death program in AD.