p35/Cdk5 pathway mediates soluble amyloid‐β peptide‐induced tau phosphorylation in vitro
p35/Cdk5 pathway mediates soluble amyloid‐β peptide‐induced tau phosphorylation in vitro
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DOI：
10.1002/jnr.10299
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发表时间：
2002-08
影响因子：
4.2
通讯作者：
T. Town;Joseph Zolton;Reed Shaffner;Billy Schnell;Robert M. Crescentini;Yajuan Wu;J. Zeng;A. Delledonne;Demian F. Obregon;Jun Tan;M. Mullan
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文献类型：
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作者：
T. Town;Joseph Zolton;Reed Shaffner;Billy Schnell;Robert M. Crescentini;Yajuan Wu;J. Zeng;A. Delledonne;Demian F. Obregon;Jun Tan;M. Mullan
阿尔茨海默病(AD)的病理特征是淀粉样多肽(Aβ-β)沉积为老年斑，并出现主要由过度磷酸化的tau蛋白组成的神经原纤维缠结(NFT)。最近的研究表明，细胞周期蛋白依赖性激酶5(CDK5)通过其强大的激活剂p25激活可以促进tau在AD特异的磷酸表位上的磷酸化，并且在AD患者中p35到p25的裂解增加，提示CDk5可能是一种致病的tau蛋白激酶。我们感兴趣的是可溶形式的Aβ对CDK5介导的AD样tau磷酸化的潜在影响，因为先前对人的活组织以及老化的犬和灵长类动物的脑的研究表明，营养不良的轴突在神经炎斑块形成之前就出现了。我们用p35载体(N2a/p35细胞)转染N2a细胞，分化后用Aβ1-42可溶性多肽(Saβ1-42)攻击这些细胞。结果表明，与对照组相比，相对较低水平的Saβ1-42(1-5μM)剂量依赖性地增加分化的N2a/p35细胞AD特异性磷酸表位的tau磷酸化，这种作用可被针对p35的反义寡核苷酸阻断。SAβ1-42诱导的tau磷酸化伴随着p25/p35比值和CDK5活性的增加(但不是蛋白质水平)。此外，阻断L型钙通道或抑制钙蛋白酶可完全消除这一作用。综上所述，这些数据表明，Saβ是p25/CDK5通路的有效激活剂，在体外可以促进AD样tau的磷酸化。©2002 Wiley-Liss公司
Alzheimer's disease (AD) is pathologically characterized by deposition of amyloid‐β peptides (Aβ) as senile plaques and by the occurrence of neurofibrillary tangles (NFTs) composed primarily of hyperphosphorylated tau protein. Activation of cyclin‐dependent kinase 5 (Cdk5) via its potent activator p25 has recently been shown to promote phosphorylation of tau at AD‐specific phosphoepitopes, and increased cleavage of p35 to p25 has been demonstrated in AD patients, suggesting that Cdk5 may represent a pathogenic tau protein kinase. We were interested in the potential effect of soluble forms of Aβ on Cdk5‐mediated AD‐like tau phosphorylation, insofar as previous studies of human biopsies and aged canine and primate brains have shown that dystrophic neurites appear before the formation of neuritic plaques. We transfected N2a cells with a p35 vector (N2a/p35 cells) and, after differentiation, challenged these cells with Aβ1–42 peptide in soluble form (sAβ1–42). Results show that sAβ1–42 at relatively low levels (1–5 μM) dose‐dependently increases tau phosphorylation at AD‐specific phosphoepitopes in differentiated N2a/p35 cells compared with controls, an effect that is blocked by antisense oligonucleotides against p35. sAβ1–42‐induced tau phosphorylation is concomitant with an increase in both p25 to p35 ratio and Cdk5 activity (but not protein levels). Additionally, blockade of L‐type calcium channels or inhibition of calpain completely abolishes this effect. Taken together, these data indicate that sAβ is a potent activator of the p25/Cdk5 pathway, resulting in promotion of AD‐like tau phosphorylation in vitro. © 2002 Wiley‐Liss, Inc.