Amyloid-β toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease.
Amyloid-β toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease.
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DOI：
10.3233/jad-2011-110890
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Viña J
中科院分区：
文献类型：
--
作者：
Lloret A;Badia MC;Giraldo E;Ermak G;Alonso MD;Pallardó FV;Davies KJ;Viña J
淀粉样蛋白β肽(Aβ)毒性和tau蛋白过度磷酸化是阿尔茨海默病(AD)的特征。然而，它们的分子关系如何影响疾病的病因、进展和严重程度还没有被阐明。我们现在报道，胎鼠皮质神经元与Aβ孵育上调钙调神经磷酸酶基因RCAN1的表达，这是由Aβ诱导的氧化应激所介导的。钙调神经磷酸酶(PPP3CA)是一种丝氨酸-苏氨酸磷酸酶，可使tau去磷酸化。RCAN1蛋白抑制钙调神经磷酸酶的这种活性。RCAN1的表达增加也会导致一种tau激酶--糖原合成酶激酶-3β(Gsk3β)的上调。因此，增加RCAN1的表达可能会减少磷酸化的tau去磷酸化(通过抑制钙调神经磷酸酶)而增加tau的磷酸化(通过增加Gsk3的β活性)。我们发现，事实上，原代皮质神经元与Aβ孵育会导致tau磷酸化增加，除非RCAN1基因的表达被沉默，或者添加抗氧化剂。因此，我们提出了一种将Aβ毒性与tau过度磷酸化在AD中联系起来的机制：在我们的假设中，Aβ导致线粒体氧化应激并增加活性氧的产生，从而导致RCAN1基因表达的上调。然后，RCAN1蛋白抑制钙调神经磷酸酶并诱导GSK3β的表达。这两种机制都将tau转变为过度磷酸化状态。我们还发现，ApoE基因为ε4/ε4(AD高危人群)的淋巴细胞比携带ApoEε3/ε3或ε3/ε4基因的人具有更高的RCAN1和磷酸化tau水平。因此，RCAN1的上调可能是阿尔茨海默病风险的一个有价值的生物标记物。
Amyloid-β peptide (Aβ) toxicity and tau hyperphosphorylation are hallmarks of Alzheimer’s disease (AD). How their molecular relationships may affect the etiology, progression, and severity of the disease, however, has not been elucidated. We now report that incubation of foetal rat cortical neurons with Aβ up-regulates expression of the Regulator of Calcineurin gene RCAN1, and this is mediated by Aβ-induced oxidative stress. Calcineurin (PPP3CA) is a serine-threonine phosphatase that dephosphorylates tau. RCAN1 proteins inhibit this phosphatase activity of calcineurin. Increased expression of RCAN1 also causes up-regulation of glycogen synthase kinase-3beta (GSK3β), a tau kinase. Thus, increased RCAN1 expression might be expected to decrease phospho-tau dephosphorylation (via calcineurin inhibition) and increase tau phosphorylation (via increased GSK3β activity). We find that, indeed, incubation of primary cortical neurons with Aβ results in increased phosphorylation of tau, unless RCAN1 gene expression is silenced, or antioxidants are added. Thus we propose a mechanism to link Aβ toxicity and tau hyperphosphorylation in AD: In our hypothesis, Aβ causes mitochondrial oxidative stress and increases production of reactive oxygen species, which result in an up-regulation of RCAN1 gene expression. RCAN1 proteins then both inhibit calcineurin and induce expression of GSK3β. Both mechanisms shift tau to a hyperphosphorylated state. We also find that lymphocytes from persons whose ApoE genotype is ε4/ε4 (with high risk of developing AD) show higher levels of RCAN1 and phospho-tau than those carrying the ApoE ε3/ε3 or ε3/ε4 genotypes. Thus up-regulation of RCAN1 may be a valuable bio-marker for Alzheimer’s disease risk.