Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
J Alzheimers Dis. 2010;19(3):1007-19. doi: 10.3233/JAD-2010-1298.
Accumulation of amyloid-beta (Abeta) 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 Abeta and phosphorylated tau levels. However, the mechanisms by which cholesterol and 27-OHC regulate Abeta production and tau phosphorylation remain unclear. Leptin, an adipocytokine involved in cell survival and in learning, has been demonstrated to regulate Abeta production and tau hyperphosphorylation in transgenic mice for AD. However, the involvement of leptin signaling in cholesterol and cholesterol metabolites-induced Abeta 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 approximately 80% and incubating organotypic slices from adult rabbit hippocampus with 27-OHC reduced leptin levels by approximately 30%. 27-OHC induces a 1.5-fold increase in Abeta (40) and a 3-fold increase in Abeta (42) and in phosphorylated tau. Treatment with leptin reversed the 27-OHC-induced increase in Abeta and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3beta 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.
淀粉样蛋白-β (Abeta) 肽的积累和过度磷酸化的 tau 蛋白沉积是阿尔茨海默病 (AD) 的两个主要病理标志。我们已经表明，富含胆固醇的饮食及其代谢产物 27-羟胆固醇 (27-OHC) 会增加 Abeta 和磷酸化 tau 的水平。然而，胆固醇和 27-OHC 调节 Abeta 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 转基因小鼠的 Abeta 产生和 tau 过度磷酸化。然而，瘦素信号在胆固醇和胆固醇代谢物诱导的 Abeta 积累和 tau 过度磷酸化中的作用尚未得到检验。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，以及瘦素处理对 27-OHC 诱导的 AD 样病理学的影响程度。我们的研究结果表明，用富含 2%胆固醇的饮食喂养兔子 12 周会使瘦素水平降低约 80%，而用 27-OHC 孵育成年兔海马器官型切片会使瘦素水平降低约 30%。27-OHC 诱导 Abeta (40) 增加 1.5 倍，Abeta (42) 和磷酸化 tau 增加 3 倍。瘦素处理通过降低 BACE-1 和 GSK-3β 的水平，逆转了 27-OHC 诱导的 Abeta 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物通过改变瘦素信号诱导 AD 样病理学。我们提出，瘦素给药可能预防与胆固醇和氧化胆固醇代谢物水平升高相关的散发性 AD 形式的进展。
