Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de LLobregat, Spain.
Curr Alzheimer Res. 2012 Feb;9(2):248-56. doi: 10.2174/156720512799361682.
Phosphorylation and, therefore, binding capacity of microtubule-associated protein tau is regulated by specific kinases and phosphatases. Activation of tau kinases plays a crucial role in tau- hyper-phosphorylation in Alzheimer disease (AD) and related tauopathies. Among phosphatases, protein phosphatase 2A, PP2A, is a principal tau dephosphorylating enzyme in the brain. PP2A acts as trimer composed of a catalytic (PP2A C), a scaffolding (PP2A A) and a regulatory (PP2 AB; B55α) subunit. Several abnormalities of PP2A have been reported in AD, including decreased mRNA and protein levels of the PP2A C (not replicated by other studies); decreased protein levels of the PP2A A and B55α; reduced PP2A C methylation at Leu309 due to impaired function methyltransferase type IV; increased PP2A C phosphorylation at Tyr307; up-regulation of the PP2A inhibitors I1 and I2; and loss of enzymatic activity. These observations indicate that PP2A is a putative target of therapeutic intervention considering that enhancing PP2A activity would decrease tau hyper-phosphorylation in AD. In spite of these achievements further studies are needed to replicate the reported individual different alterations converging in PP2A in AD.
磷酸化，因此，微管相关蛋白 tau 的结合能力受特定激酶和磷酸酶调节。tau 激酶的激活在阿尔茨海默病 (AD) 和相关 tau 病中的 tau 过度磷酸化中起着关键作用。在磷酸酶中，蛋白磷酸酶 2A (PP2A) 是大脑中 tau 的主要去磷酸化酶。PP2A 作为三聚体发挥作用，由一个催化亚基 (PP2A C)、一个支架亚基 (PP2A A) 和一个调节亚基 (PP2A AB；B55α) 组成。AD 中已经报道了几种 PP2A 的异常，包括 PP2A C 的 mRNA 和蛋白水平降低（其他研究未复制）；PP2A A 和 B55α 蛋白水平降低；由于功能甲基转移酶 IV 受损，导致 Leu309 处的 PP2A C 甲基化减少；PP2A C 在 Tyr307 处的磷酸化增加；PP2A 抑制剂 I1 和 I2 的上调；以及酶活性丧失。这些观察结果表明，PP2A 是治疗干预的一个潜在靶点，因为增强 PP2A 活性可以降低 AD 中的 tau 过度磷酸化。尽管取得了这些成就，但仍需要进一步研究来复制 AD 中报告的不同个体变化在 PP2A 中的汇聚。
