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首页> 外文期刊>The European Journal of Neuroscience >Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease.
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Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease.

机译：HMG-CoA还原酶活性的阻断通过抑制香叶基香叶基焦磷酸的形成而导致微管稳定蛋白tau的改变：对阿尔茨海默氏病的影响。

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摘要

Histopathologically, Alzheimer's disease is characterized by plaques and tangles that develop progressively over time. Experimental data described a statin-induced decrease in beta-amyloid production, a major constituent of the plaques. Others reported data on statin-mediated changes in neuronal survival and cytoskeleton, including the microtubule-associated protein tau, a major constituent of the tangles. However, these latter reports remain contradictory. To clarify and extend our knowledge on the effect of statin on the cytoskeleton, we challenged rat primary neuron cultures by lovastatin and determined the metabolite that is critical for structural integrity and survival of neurons. During the blockade of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the neuritic network was affected and eventually was completely destroyed. This process was not part of the execution phase of apoptosis and was marked by alterations in the microfilament and microtubule system. The distribution and phosphorylation of protein tau changed. Immunoblot analysis and indirect immunofluorescence revealed a transient increase in tau phosphorylation, which ceased during the execution of apoptosis. All of these effects could be linked to the lack of the geranylgeranylpyrophosphate intermediate. Inhibition of the geranylgeranylation of Rho family GTPases (geranylgeranyl-transferase I) evoked similar changes in neurons. These data and our findings that statin treatment reduced the membrane-bound fraction of RhoA-GTPase in neurons suggest that reduced levels of functional small G proteins are responsible for the observed effects. Our data demonstrate that lovastatin concentrations able to suppress not only cholesterol but also geranylgeranylpyrophosphate formation may evoke phosphorylation of tau reminiscent of preclinical early stages of Alzheimer's disease and, when prolonged, apoptosis.
机译：在组织病理学上，阿尔茨海默氏病的特征是斑块和缠结随着时间的推移逐渐发展。实验数据描述了他汀类药物诱导的β-淀粉样蛋白生成（斑块的主要成分）减少。其他人报告了他汀类药物介导的神经元存活和细胞骨架变化的数据，包括微管相关蛋白tau（缠结的主要成分）。但是，这些后面的报告仍然是矛盾的。为了阐明和扩展我们对他汀类药物对细胞骨架作用的认识，我们通过洛伐他汀对大鼠原代神经元培养物进行了挑战，并确定了对神经元的结构完整性和存活至关重要的代谢物。在3-羟基-3-甲基戊二酰辅酶A还原酶的阻断过程中，神经网络受到影响并最终被完全破坏。该过程不是细胞凋亡执行阶段的一部分，其特征在于微丝和微管系统的改变。蛋白质tau的分布和磷酸化发生了变化。免疫印迹分析和间接免疫荧光显示tau磷酸化的短暂增加，在执行凋亡过程中停止了。所有这些影响都可能与缺少香叶基香叶基焦磷酸酯中间体有关。 Rho家族GTPases（geranylgeranyl-transferase I）的Geranylgeranylation抑制引起神经元的类似变化。这些数据和他汀类药物治疗降低了神经元中RhoA-GTPase的膜结合分数的发现表明，功能性小G蛋白水平降低是观察到的效应的原因。我们的数据表明，洛伐他汀的浓度不仅能够抑制胆固醇，而且还可以抑制香叶基香叶基焦磷酸酯的形成，可能引起tau的磷酸化，使人联想到阿尔茨海默氏病的临床前早期阶段，以及长时间的凋亡。

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