| Alzheimer's disease (AD) is the most common cause of dementia in the United States. AD is characterized by two neuropathological hallmarks, plaques and neurofibrillary tangles. Plaques are extracellular aggregations of β-amyloid peptide. Neurofibrillary tangles are intracellular accumulation of paired helical filaments (PHF), which are abnormally phosphorylated tau protein.; Tau exists as a mixture of highly heterogeneous phosphoproteins; however, tau isolated from PHFs is both abnormally phosphorylated and hyperphosphorylated. The hyperphosphorylation of tau may be caused by an imbalance of kinase/phosphatase systems in AD. Previous studies suggest that decreased protein phosphatase activity, particularly protein phosphatase 2B (calcineurin), a key neuronal protein phosphatase, may be responsible for an increased phosphorylation of tau in AD. In the current studies, we attempt to address following questions: (1) Is there any alteration of calcineurin activity in AD brain? (2) What are the causes of this alteration? (3) What role does the alteration of calcineurin activity play in the abnormal phosphorylation of tau in AD?; We measured calcineurin phosphatase activity in samples from individuals with moderate to severe AD and age-matched controls. Our results indicate calcineurin phosphatase activity is decreased in selective areas of AD brain, the decrease in activity correlates with the NFT pathology in AD. In PC12 cell line, inhibition of calcineurin phosphatase activity by FK506 caused increased phosphorylation of tau protein, similar to those found in AD. Further studies indicate that decrease of calcineurin phosphatase activity is not due to alterations in protein levels of calcineurin and its regulatory factors, or the interaction between calcineurin and the scaffolding protein AKAP79 in AD. The observed decrease of activity may be the result of increased oxidative stress in AD. Results from these studies suggest that decrease of calcineurin phosphatase activity may contribute to the hyperphosphorylation state of tau and/or the stabilization of NFTs in AD, and the decrease of calcineurin activity might be the link between two major pathological processes in AD, increased oxidative stress and abnormal phosphorylation of tau. |
