Modulation of β-amyloid and phosphorylated tau production by statin

阿尔茨海默病的疾病改善疗法尚未建立，阿尔茨海默病的主要病理特征包括β-淀粉样蛋白（Aβ）和磷酸化tau蛋白的积累，分别形成老年斑和神经原纤维缠结。先前的流行病学研究表明，胆固醇代谢受损与阿尔茨海默病的发展之间存在密切联系。此外，淀粉样蛋白发生在富含胆固醇的膜结构域。他汀类药物抑制胆固醇的生物合成，并具有潜在的其他多重作用，称为多效性，是最广泛使用的降胆固醇药物。在本研究中，我利用培养细胞研究了染色对β-淀粉样蛋白和磷酸化tau蛋白产生的调节作用。最初建立了稳定表达淀粉样蛋白前体蛋白（APP）或tau的SHSY-5Y和Neuro2a细胞，以供进一步测定。当细胞与他汀类药物孵育时，全长APP和APP c端片段水平升高。高浓度他汀可显著提高Aβ42/40比值。总tau蛋白和磷酸化tau蛋白水平明显不受他汀类药物治疗影响。这些结果表明，细胞渗透性他汀类药物对APP代谢有影响。

Disease-modifying therapy has not been established in Alzheimer disease, in which ardinal pathological features include the accumulation of β-amyloid(Aβ) and phosphorylated tau forming senile plaque and neurofibrillary tangles, respectively. Previous epidemiological studies have suggested there is close link between impaired cholesterol metabolism and development of Alzheimer disease. Furthermore, amyloidogenesis occurs in cholesterol-rich membrane domains. Statins that inhibit cholesterol biosynthesis and have potential other multiple actions called pleiotropic effects, are the most widely used cholesterol-lowering agents. TheyIn this study, I investigated the effects of stain on modulation of β-amyloid and phosphorylated tau production using culture cells. SHSY-5Y and Neuro2a cells that stably express either amyloid precursor protein (APP) or tau were initially established for further assay. When cells were incubated with statin, the levels of full-length APP and APP C-terminal fragments were elevated. At high concentration of statin, Aβ42/40 ratio was markedly increased. Total and phosphorylated tau levels were apparently unaffected by statin treatment. These results suggest that cell-permeable statin have an effect on APP metabolism.