Calcium-activated neutral proteinases as regulators of cellular function. Implications for Alzheimer's disease pathogenesis.

Evidence is emerging that calcium-activated neutral proteinases (CANPs) not only participate in intracellular protein turnover but help to regulate the functional reorganization of cytoskeletal proteins in response to calcium and second-messenger stimulation. The high concentration of CANPs in certain neurons has suggested prominent roles for this proteolytic system in neuronal and synaptic function. In addition to acting directly on specific constituents of the cytoplasmic and membrane-associated cytoskeletal networks, CANP may amplify its effects by modulating the activities of protein kinase C and possibly other kinases and phosphatases by limited proteolysis. Given its suspected involvement at the cytoskeleton-membrane interface, calcium-mediated proteolysis is an example of a metabolic process which, if impaired, could provide a unifying basis for the slow progressive development of diverse structural and functional abnormalities within neurons. The multiplicity of mechanisms regulating its activity makes the CANP system a vulnerable target for disruption from various sources. A working hypothesis is advanced that down-regulation (inhibition) of neuronal calcium-mediated proteolysis in Alzheimer's disease is one critical and early step in the development of neurofibrillary degeneration and altered membrane cytoskeleton dynamics, which leads to membrane injury, accumulation of abnormal proteins, and synaptic dysfunction.