Mechanisms of cell death in Alzheimer's disease: Role of presenilins

Presenilins are often mutated in familial forms of Alzheimer's disease (AD). Such mutations sensitize cells in culture to different apoptotic stimuli eg. staurosporine, calcium ionophore, growth factor withdrawal. The altered responses to apoptotic stimuli in cells carrying presenilin mutations include increased intracellular calcium concentrations and enhanced production of reactive oxygen species. Presenilin mutations also result in increased production of amyloid beta (Abeta) indicating that presenilins participate in the cleavage of amyloid beta-protein precursor (AbetaPP). In fact, presenilin is part of the gamma-secretase complex which together with beta-secretase cleaves AbetaPP and produce Abeta, later forming the senile plaques typical for AD pathology. Here we review the current knowledge about the mechanisms of cell death in AD with focus on the role of presenilin and presenilin mutations in apoptosis. It appears that presenilin and its different fragments, generated after proteolytic cleavage, have a regulatory role in apoptosis. In addition, different studies show that the cellular levels of presenilin are controlled by proteasomal degradation both under normal and stress conditions.