The calcium rationale in aging and Alzheimer's disease. Evidence from an animal model of normal aging.

Calcium is required for the function of all cells in the body, including neurons. Considerable research has described the function of calcium in the regulation of numerous processes including neurotransmitter release, cytoarchitecture and growth, and activation of enzyme systems including kinases and phosphatases. Calcium is intimately involved in a variety of “plastic” changes in the brain. For example, during adaptive processes such as learning and development, changes in transmembrane calcium fluxes correlate with changes in neuronal excitability and structural connectivity. Calcium thus is likely to have key roles in the cellular processes underlying aging-related changes in the brain, including normal age-associated memory impairments as well as more severe dementias, including Alzheimer’s disease. The pivotal role of calcium in so many neuronal processes dictates the need for precise regulation of its intracellular levels. Any dysregulation, however subtle, could lead to dramatic changes in normal neuronal function. Recent studies from our laboratory and those of others have implicated altered calcium influx with agingrelated changes at both the behavioral and the neurophysiological levels. These findings led to and continue to support the calcium hypothesis’s* which posits that in the aging brain, transient or sustained increases in the average concentration of intracellular free calcium contribute to impaired function, eventually leading to cell death. The hypothesis suggests that the final common pathway that may contribute to cognitive deterioration of aging vertebrates, including persons with Alzheimer’s disease or other aging-related dementias, is increased free calcium within neurons. The functional impairment that characterizes a patient at a particular time in the aging-related disease process may be relieved by reducing excessive calcium influx. Additionally, because calcium dysregulation terminating in cell death is likely to be