The possible prediction for the onset of Alzheimer's disease : lipoprotein-free Aβ

为了评估脂蛋白是否在生理上能够平衡和调节体内的sAβ稳态，我们测量了正常对照组、阿尔茨海默病（AD）患者和唐氏综合征（DS）患者血浆中可溶性a β水平与年龄的关系。sAβ稳态的重塑，特别是sAβ42-脂蛋白相互作用，发生在正常60岁以上，而轻度AD患者似乎破坏了这种抗淀粉样蛋白生成机制，导致无脂蛋白sAβ42显著增加。类似的功能丧失也发生在唐氏综合症患者身上。无脂蛋白sAβ从症状前到症状期均显著升高，并随着ad样病理的进展而下降。sAβ与脂蛋白颗粒的分离也发生在脑实质中，在AD脑实质沉积之前，可溶性无脂蛋白二聚体Aβ的存在支持了这一假设。更多的证据表明，功能下降的脂蛋白可能是代谢条件产生的主要决定因素，导致sAβ水平升高和脑淀粉样变性。这些数据与正常对照和AD患者的CSF可溶性Aβ分析结果一致。阿尔茨海默病患者脑脊液中无脂蛋白的sAβ显著降低，表明阿尔茨海默病患者脑与脑脊液中无脂蛋白sAβ的清除受损，这是阿尔茨海默病的一个病理步骤。我们还发现，褪黑素的施用部分抑制了预期的a β-淀粉样变性的时间依赖性升高，减少了蛋白质的异常硝化，并增加了AD转基因小鼠模型的存活率。为了阐明褪黑激素在AD发病机制中的潜在生理作用，我们监测了这种激素对转基因小鼠a β清除的影响。值得注意的是，褪黑素具有上调大脑中Aβ清除的能力。这些结果提示褪黑素可以作为AD的疾病调节剂。少

To assess whether lipoproteins are physiologically able to balance and modulate the sAβ homeostasis in vivo, soluble Aβ levels in lipoprotein-depleted plasma were measured as a function of age in normal controls, Alzheimer's disease (AD) patients, and Down's syndrome (DS) cases. The reshaping of sAβ homeostasis, in particular the sAβ42-lipoprotein interaction, takes place over normal-60s, whereas mild AD patients appear to have impaired this anti-amyloidogenic mechanism resulting in a significant increase of lipoprotein-free sAβ42. Similar loss of function takes place in Down's syndrome patients. Lipoprotein-free sAβ remains significantly elevated from the presymptomatic through the symptomatic stages of the disease, and declines with the progression of the AD-like pathology. The dissociation of sAβ from lipoprotein-particles also occurs in brain parenchyma and the presence of soluble dimeric lipoprotein-free Aβ prior to its parenchymal deposition in AD brains would support the hypothe … More sis that functionally declined lipoproteins may be major determinants in the production of metabolic conditions leading to higher levels of sAβ species and cerebral amyloidosis. These data was corroborated with the analysis of pooled CSF soluble Aβ in normal control individual and AD via size-exclusion chromatography and ELISA. Lipoprotein-free sAβ in CSF was significantly decreased in AD, indicating that brain to CSF clearance of Lipoprotein-free sAβ can be impaired in AD and its failure, a pathological step in AD pathology.We also found that the administration of melatonin partially inhibited the expected time-dependent-elevation of Aβ-amyloidosis, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice model of AD. To clarify a potential physiological role of melatonin in AD pathogenesis, we have monitored the effect of this hormone on Aβ clearance in transgenic mice. It is relevant to note that melatonin has ability to upregulate Aβ clearance out of the brain. These results presented here suggest that melatonin can be explored as disease-modifying agents in AD. Less