Selective changes of calcineurin (protein phosphatase 2B) activity in Alzheimer's disease cerebral cortex.

Abstract

Neurofibrillary tangles, which contain abnormally hyperphosphorylated forms of tau protein, are one of the neuropathological hallmarks of Alzheimer's disease (AD). This altered phosphorylation state of tau protein may be due to increased kinase activity or/and decreased phosphatase activity. In the present study, we characterized human calcineurin phosphatase activity in postmortem superior frontal cortex and sensorimotor cortex and measured calcineurin phosphatase activity in samples from individuals with moderate to severe AD (n = 7) and age-matched controls (n = 5). Basal phosphatase activity was reduced by 25% (P < 0.05) in AD frontal cortex. Nickel-stimulated calcineurin activity was decreased by 52% (P < 0.05) and 30% (P < 0.05) in P2 and total cell homogenate, respectively, compared to age-matched controls. No differences in phosphatase activities were detected in the sensorimotor cortex. The decrease in nickel-stimulated calcineurin phosphatase activity in frontal lobe correlated with the neurofibrillary tangle pathology (total cell homogenate, r = -0.77, P < 0.05; P2 fraction, r = -0.76, P < 0.02), but not with diffuse or neuritic plaques. Despite the changes in calcineurin phosphatase activity in the superior frontal cortex, calcineurin protein levels determined by immunoblot were similar in control and AD cases. In addition, no changes in calcineurin regulatory proteins (cyclophilin A and FKBP12) levels were observed. These studies suggest that decrease of calcineurin activity may play a role in paired-helical filament formation and/or stabilization, and the decrease of activity was not accompanied by a decrease of calcineurin protein expression.

• Authors: Q Lian, C J Ladner, D Magnuson, J M Lee
• Journal: Experimental neurology (Exp Neurol) Vol. 167 Issue 1 Pg. 158-65 (Jan 2001) ISSN: 0014-4886 [Print] United States
• PMID: 11161603 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Cobalt
• Manganese
• Nickel
• Calcineurin
• Cyclophilin A
• Tacrolimus Binding Protein 1A

Topics

• Aged
• Alzheimer Disease (metabolism, pathology)
• Brain Chemistry (drug effects)
• Calcineurin (analysis, metabolism)
• Cell Membrane (chemistry, metabolism)
• Cerebral Cortex (metabolism, pathology)
• Cobalt (pharmacology)
• Cyclophilin A (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Frontal Lobe (metabolism, pathology)
• Humans
• Immunoblotting
• Manganese (pharmacology)
• Neurofibrillary Tangles (pathology)
• Nickel (pharmacology)
• Plaque, Amyloid (pathology)
• Postmortem Changes
• Somatosensory Cortex (metabolism, pathology)
• Tacrolimus Binding Protein 1A (metabolism)