Sontag Estelle, Nunbhakdi-Craig Viyada, Sontag Jean-Marie, Diaz-Arrastia Ramon, Ogris Egon, Dayal Sanjana, Lentz Steven R, Arning Erland, Bottiglieri Teodoro
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
J Neurosci. 2007 Mar 14;27(11):2751-9. doi: 10.1523/JNEUROSCI.3316-06.2007.
Alzheimer's disease (AD) neuropathology is characterized by the accumulation of phosphorylated tau and amyloid-beta peptides derived from the amyloid precursor protein (APP). Elevated blood levels of homocysteine are a significant risk factor for many age-related diseases, including AD. Impaired homocysteine metabolism favors the formation of S-adenosylhomocysteine, leading to inhibition of methyltransferase-dependent reactions. Here, we show that incubation of neuroblastoma cells with S-adenosylhomocysteine results in reduced methylation of protein phosphatase 2A (PP2A), a major brain Ser/Thr phosphatase, most likely by inhibiting PP2A methyltransferase (PPMT). PP2A methylation levels are also decreased after ectopic expression of PP2A methylesterase in Neuro-2a (N2a) cells. Reduced PP2A methylation promotes the downregulation of B alpha-containing holoenzymes, thereby affecting PP2A substrate specificity. It is associated with the accumulation of both phosphorylated tau and APP isoforms and increased secretion of beta-secretase-cleaved APP fragments and amyloid-beta peptides. Conversely, incubation of N2a cells with S-adenosylmethionine and expression of PPMT enhance PP2A methylation. This leads to the accumulation of dephosphorylated tau and APP species and increased secretion of neuroprotective alpha-secretase-cleaved APP fragments. Remarkably, hyperhomocysteinemia induced in wild-type and cystathionine-beta-synthase +/- mice by feeding a high-methionine, low-folate diet is associated with increased brain S-adenosylhomocysteine levels, PPMT downregulation, reduced PP2A methylation levels, and tau and APP phosphorylation. We reported previously that downregulation of neuronal PPMT and PP2A methylation occur in affected brain regions from AD patients. The link between homocysteine, PPMT, PP2A methylation, and key CNS proteins involved in AD pathogenesis provides new mechanistic insights into this disorder.
阿尔茨海默病（AD）的神经病理学特征是源自淀粉样前体蛋白（APP）的磷酸化tau蛋白和淀粉样β肽的积累。同型半胱氨酸血水平升高是包括AD在内的许多与年龄相关疾病的重要危险因素。同型半胱氨酸代谢受损有利于S-腺苷同型半胱氨酸的形成，导致甲基转移酶依赖性反应受到抑制。在此，我们表明，用S-腺苷同型半胱氨酸孵育神经母细胞瘤细胞会导致蛋白磷酸酶2A（PP2A）甲基化减少，PP2A是大脑中主要的丝氨酸/苏氨酸磷酸酶，最有可能是通过抑制PP2A甲基转移酶（PPMT）。在Neuro-2a（N2a）细胞中异位表达PP2A甲酯酶后，PP2A甲基化水平也会降低。PP2A甲基化减少会促进含Bα的全酶下调，从而影响PP2A底物特异性。它与磷酸化tau蛋白和APP异构体的积累以及β-分泌酶切割的APP片段和淀粉样β肽的分泌增加有关。相反，用S-腺苷甲硫氨酸孵育N2a细胞并表达PPMT可增强PP2A甲基化。这会导致去磷酸化的tau蛋白和APP种类积累，并增加神经保护性α-分泌酶切割的APP片段的分泌。值得注意的是，通过喂食高蛋氨酸、低叶酸饮食在野生型和胱硫醚-β-合酶+/-小鼠中诱导的高同型半胱氨酸血症与脑S-腺苷同型半胱氨酸水平升高、PPMT下调、PP2A甲基化水平降低以及tau蛋白和APP磷酸化有关。我们之前报道过，AD患者受影响的脑区中神经元PPMT下调和PP2A甲基化发生。同型半胱氨酸、PPMT、PP2A甲基化与AD发病机制中涉及的关键中枢神经系统蛋白之间的联系为这种疾病提供了新的机制见解。
