Leptin reduces the accumulation of Abeta and phosphorylated tau induced by 27-hydroxycholesterol in rabbit organotypic slices.
Leptin reduces the accumulation of Abeta and phosphorylated tau induced by 27-hydroxycholesterol in rabbit organotypic slices.
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DOI：
10.3233/jad-2010-1298
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Ghribi O
中科院分区：
文献类型：
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作者：
Marwarha G;Dasari B;Prasanthi JR;Schommer J;Ghribi O
β淀粉样蛋白（Aβ）的聚集和过度磷酸化的tau蛋白沉积是阿尔茨海默病（AD）的两个主要病理标志。我们已经证明富含胆固醇的饮食及其代谢产物27-羟基胆固醇（27-OHC）会增加Aβ和磷酸化tau水平。然而，胆固醇和27-OHC调节Aβ产生和tau磷酸化的机制仍不清楚。瘦素是一种参与细胞存活和学习的脂肪细胞因子，已被证明可调节AD转基因小鼠中Aβ的产生和tau蛋白的过度磷酸化。然而，瘦素信号转导在胆固醇和胆固醇代谢物诱导的Aβ积累和tau蛋白过度磷酸化中的参与还有待研究。在这项研究中，我们确定了高胆固醇饮食和27-OHC对瘦素表达水平的影响，以及瘦素治疗对27-OHC诱导的AD样病理的影响程度。我们的研究结果表明，喂养兔子2%的胆固醇丰富的饮食12周，瘦素水平降低约80%，孵育器官型切片成年兔海马与27-OHC瘦素水平降低约30%。27-OHC诱导Aβ40增加1.5倍，Aβ42和磷酸化tau增加3倍。瘦素治疗通过分别降低BACE-1和GSK-3β的水平来逆转27-OHC诱导的Aβ和磷酸化tau的增加。我们的研究结果表明，富含胆固醇的饮食和胆固醇代谢产物通过改变瘦素信号传导诱导AD样病变。我们认为，瘦素管理可能会阻止与胆固醇和氧化胆固醇代谢产物水平升高相关的散发性AD的进展。
Accumulation of amyloid-β (Aβ) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer’s disease (AD). We have shown that cholesterol-enriched diets and its metabolite 27-hydroxycholesterol (27-OHC) increase Aβ and phosphorylated tau levels. However, the mechanisms by which cholesterol and 27-OHC regulate Aβ production and tau phosphorylation remain unclear. Leptin, an adipocytokine involved in cell survival and in learning, has been demonstrated to regulate Aβ production and tau hyperphosphorylation in transgenic mice for AD. However, the involvement of leptin signaling in cholesterol and cholesterol metabolites-induced Aβ accumulation and tau hyperphosphorylation are yet to be examined. In this study, we determined the effect of high cholesterol diet and 27-OHC on leptin expression levels and the extent to which leptin treatment affects 27-OHC-induced AD-like pathology. Our results show that feeding rabbits a 2% cholesterol-enriched diet for 12 weeks reduces the levels of leptin by ~ 80% and incubating organotypic slices from adult rabbit hippocampus with 27-OHC reduced leptin levels by ~ 30%. 27-OHC induces a 1.5-fold increase in Aβ40 and a 3-fold increase in Aβ42 and in phosphorylated tau. Treatment with leptin reversed the 27-OHC-induced increase in Aβ and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3β respectively. Our results suggest that cholesterol-enriched diets and cholesterol metabolites induce AD-like pathology by altering leptin signaling. We propose that leptin administration may prevent the progression of sporadic forms of AD that are related to increased cholesterol and oxidized cholesterol metabolite levels.