Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
Neurobiol Aging. 2013 Feb;34(2):374-86. doi: 10.1016/j.neurobiolaging.2012.05.003. Epub 2012 Jun 6.
Alzheimer's disease (AD) is characterized by neuronal loss and the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. Cerebrospinal fluid (CSF) levels of β-amyloid and tau/phospho-tau 181 (ptau 181) are also associated with AD. We have previously demonstrated that a single nucleotide polymorphism in calcineurin is associated with CSF ptau 181 levels and AD progression. In this study, we demonstrate that calcineurin protein levels are inversely correlated with dementia severity and Braak tangle stage in AD brains, and calcineurin activity is globally reduced in AD brains. We then sought to model the observed changes in CSF tau by measuring extracellular tau in cultured cells. SH-SY5Y cells treated with calcineurin inhibitors produced reduced calcineurin activity and a corresponding increase in extracellular ptau 181. These findings are consistent with our observations in AD patients, who have elevated CSF ptau 181 and reduced calcineurin activity in brain extracts. Thus, we have identified a gene that contributes to AD pathology and has functional consequences on tau metabolism in cultured cells.
阿尔茨海默病（AD）的特征是神经元丧失以及β-淀粉样斑块和神经原纤维缠结在大脑中的积累。脑脊液（CSF）中的β-淀粉样蛋白和 tau/磷酸化 tau181（ptau181）水平也与 AD 相关。我们之前已经证明钙调神经磷酸酶中的一个单核苷酸多态性与 CSF ptau181 水平和 AD 进展有关。在这项研究中，我们证明钙调神经磷酸酶蛋白水平与 AD 大脑中的痴呆严重程度和 Braak 缠结阶段呈负相关，并且 AD 大脑中的钙调神经磷酸酶活性普遍降低。然后，我们试图通过测量培养细胞中的细胞外 tau 来模拟 CSF 中 tau 观察到的变化。用钙调神经磷酸酶抑制剂处理的 SH-SY5Y 细胞产生了降低的钙调神经磷酸酶活性和相应增加的细胞外 ptau181。这些发现与我们在 AD 患者中的观察结果一致，AD 患者的 CSF ptau181 升高，脑提取物中的钙调神经磷酸酶活性降低。因此，我们已经确定了一个导致 AD 病理学的基因，并且对培养细胞中的 tau 代谢具有功能后果。
