Elevated plasma cholestrol does not affect brain Aβ in mice lacking the low-density lipoprotein receptor
Elevated plasma cholestrol does not affect brain Aβ in mice lacking the low-density lipoprotein receptor
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DOI：
10.1111/j.1471-4159.2007.04614.x
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发表时间：
2007-08-01
影响因子：
4.7
通讯作者：
Buxbaum, Joseph D.
中科院分区：
文献类型：
--
作者：
Elder, Gregory A.;Cho, Julie Y.;Buxbaum, Joseph D.
流行病学研究支持血管危险因素（包括高胆固醇血症）与阿尔茨海默病（AD）之间的关联。最近，人们对高胆固醇血症可能直接促进β-淀粉样蛋白（A β）产生的可能性非常感兴趣。事实上，体外研究表明，增加细胞胆固醇水平会增强AP的产生。然而，在AD转基因小鼠模型中的研究并没有一致地发现血浆胆固醇升高导致体内AP产生或沉积增加。在这项研究中，我们确定了外周血胆固醇升高是否会影响低密度脂蛋白受体（LDLR）无效突变小鼠的AP产生。我们发现，无论是由高胆固醇、高脂肪还是高脂肪/高胆固醇饮食诱导的血浆胆固醇水平显著升高，都不会影响大脑AP 40、A β 42或APP的水平，也不会影响A β 42/40或APP-CTF/APP的比值，也不会显著改变大脑胆固醇水平。然而，通过转录后机制，LDLR-/小鼠脑中的ApoE蛋白水平升高。总的来说，这些研究认为，血浆胆固醇水平通常不会调节大脑A β的产生。
Epidemiological studies support an association between vascular risk factors, including hypercholesterolernia, and Alzheimer's disease (AD). Recently, there has been much interest in the possibility that hypercholesterolernia might directly promote P-amyloid (A beta) production. Indeed, in vitro studies have shown that increasing cellular cholesterol levels enhances AP production. However, studies in AD transgenic mouse models have not consistently found that elevated plasma cholesterol leads to increased AP production or deposition in vivo. In this study, we determined whether elevated peripheral cholesterol influences AP production in mice with a null mutation of the low-density lipoprotein receptor (LDLR). We show that dramatically elevated plasma cholesterol levels, whether induced by high cholesterol, high fat, or high fat/high cholesterol diets, did not affect either levels of brain AP40, A beta 42, or APP, or the A beta 42/40 or APP-CTF/APP ratios, nor substantially alter brain cholesterol levels. ApoE protein levels in brain were, however, elevated, in LDLR-/mice by post-transcriptional mechanisms. Collectively, these studies argue that plasma cholesterol levels do not normally regulate production of brain A beta.