The appearance of neurofibrillary tangles (NFT), one of the major hallmarks of Alzheimer's disease (AD), is most likely caused by inappropriate phosphorylation and/or dephosphorylation of tau, eventually leading to the accumulation of NFTs. Enhanced phosphorylation of tau on Ser(262) is detected early in the course of the disease and may have a role in the formation of tangles. Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). Furthermore, we observed elevated interactions between MARK2 and tau in post-mortem human AD brains, compared to samples from non-demented elderly controls. Our results from transfected cells demonstrate a specific interaction between MARK2 and tau, as well as MARK2-dependent phosphorylation of tau at Ser(262). Furthermore, the elevated interactions between MARK2 and tau in AD brain sections suggests that MARK2 may play an important role in early phosphorylation of tau in AD, possibly qualifying as a therapeutic target for intervention to prevent disease progression.

译文

神经原纤维缠结 (NFT) 的出现是阿尔茨海默氏病 (AD) 的主要标志之一,很可能是由tau的不适当磷酸化和/或去磷酸化引起的,最终导致NFT的积累。在疾病过程的早期检测到Ser(262) 上tau的增强磷酸化,并且可能在缠结的形成中起作用。已知几种激酶如微管亲和调节激酶 (MARK) 、蛋白激酶A、钙钙调蛋白激酶II和检查点激酶2在体外使Ser(262) 上的tau磷酸化。在这项研究中,我们利用原位邻近连接测定法来研究MARK2 (四种标记同工型之一) 在AD中的作用。我们证明,在稳定转染的表达人重组tau的NIH/3T3细胞中,MARK2与tau相互作用并在Ser(262) 磷酸化tau。星形孢菌素,一种蛋白激酶抑制剂,显著降低了MARK2和tau之间的相互作用,也降低了Ser(262) 处tau的磷酸化。此外,与来自非痴呆的老年对照的样本相比,我们观察到死后人类AD大脑中MARK2和tau之间的相互作用升高。我们来自转染细胞的结果证明了MARK2和tau之间的特异性相互作用,以及在Ser(262) 处tau的MARK2-dependent磷酸化。此外,在AD脑切片中MARK2和tau之间的相互作用升高表明,MARK2可能在AD中tau的早期磷酸化中起重要作用,可能有资格作为干预预防疾病进展的治疗靶标。

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