Mechanisms of cell death in Alzheimer's disease

The etiology of Alzheimer's disease (AD) as well as its exact pathogenesis are unknown. Eventhough the deposition of beta A4 and the formation of neurofibrillary tangles represent impressive morphological hallmarks of the disease, several lines of evidence suggest that both lesions are not sufficient as causes of the neurodegenerative process. On the 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 nuclear DNA. Using this method, we have detected 50 x more neurons and 25 x more glial cells with nuclear DNA fragmentation in the brains of patients with AD than in non-demented controls. In contrast to previous studies, most of these cells did not reveal the characteristic morphological hallmarks of apoptosis. Most dying cells were not located within amyloid deposits and most dying cells did not bear a tangle. On the other 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 cells. Taken together, these data indicate that nerve cell death in AD occurs 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 degenerative process, suggesting the existence of other factors that trigger the initiation of the cell death program in AD.