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The Journal of Neuroscience, June 1, 2001, 21(11):4066-4073

Calcineurin Links Ca²⁺ Dysregulation with Brain Aging

Thomas C. Foster, Keith M. Sharrow, James R. Masse, Christopher M. Norris, and Ashok Kumar

Department of Molecular and Biomedical Pharmacology, University of Kentucky, College of Medicine, Lexington, Kentucky 40536

Brain aging is associated with altered Ca²⁺ regulation. However, many Ca²⁺ signal transduction mechanisms have not been explored in the aged brain. Here, we report that cytosolic expression and activity of the Ca²⁺-dependent protein phosphatase calcineurin (CaN) increases in the hippocampus during aging. CaN changes were paralleled by increased activation, but not expression, of CaN-regulated protein phosphatase 1 and a reduction in the phosphorylation state of CaN substrates involved in cell survival (i.e., Bcl-2-associated death protein and cAMP response element-binding protein). The age-related increase in CaN activity was not attributable to the inability of CaN to translocate to the membrane and was reduced by blocking L-type Ca²⁺ channels. Finally, increased CaN activity correlated with memory function as measured with the Morris water escape task. The results suggest that altered regulation of CaN is one of the processes that could link Ca²⁺ dyshomeostasis to age-related changes in neural function and cognition.

Key words: aging; apoptosis; calcineurin; calcium; hippocampus; memory; phosphatase; PP2B; PP1; synaptic plasticity; CREB

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21114066-08$05.00/0

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