THE ROLE OF SULFATIDES IN ALZHEIMER'S DISEASE

描述(由申请人提供)： 阿尔茨海默病(AD)是老年痴呆症最常见的原因。脂类转运体载脂蛋白E(ApoE)的e4等位基因与AD发病早、发病风险高有关，从而强调了血脂改变在AD发病机制中的重要性。然而，载脂蛋白E介导的脂流改变在AD发病机制中的作用尚不清楚。硫脂是髓鞘中的一种特殊的膜脂成分，对神经元的功能是必不可少的。我们最近证实：(1)在非常轻微的AD中，硫脂含量急剧下降；(2)CMS中的硫脂含量受载脂蛋白E的调节；以及(3)人脑脊液中硫脂(与CMS中的载脂蛋白E相关)和淀粉样β1-42(Abeta42)的含量高度相关。因此，我们认为载脂蛋白/脂蛋白相关的硫脂特异性地促进Abeta与载脂蛋白E颗粒的结合，以实现正常的清除。然而，在发生Abeta积聚的病理条件下，含有硫脂的apoE相关脂蛋白促进Abeta42聚集，这可能形成Abeta进一步沉积的成核部位。此外，由于加速的内吞过程，AA/apoE/硫脂复合体的代偿性清除增加导致硫脂耗竭。这一假设将利用我们开发的三个独立的模型进行验证，这些模型用于研究载脂蛋白E亚型、Abeta多肽和硫脂之间的特定相互作用。首先，我们将利用一个已定义的囊泡模型系统，在宿主磷脂基质中以硫脂为客体，通过质谱仪(硫脂和Aβ质量)、ELISA(载脂蛋白E含量)和核磁共振光谱(Aβ纤维生成)来研究apoE/Abeta/硫脂特异性相互作用的动力学。其次，我们将使用少突胶质细胞(中枢神经系统中硫脂的细胞来源)作为细胞培养模型，以确定硫脂/载脂蛋白E/Aβ相互作用在调节Aβ清除和硫脂运输中的重要性。最后，我们将利用转基因小鼠来研究硫脂与载脂蛋白E变体的详细相互作用，并验证调节硫脂运输和Abeta清除的显著分子相互作用。综上所述，这些研究结果将探索SU！fatides/apoE/Abeta的具体相互作用，并解决导致极早期阿尔茨海默病硫脂丢失和Abeta聚集的分子机制(S)，从而为AD的发病机制提供洞察力，并为AD治疗寻找新的靶点。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the aging population. The importance of lipid alterations in AD pathogenesis has been underscored by the demonstration that the e4 allele of the lipid transporter apolipoprotein E (apoE) is associated with an earlier onset and a higher risk for AD. However, the effects of apoE-mediated alterations of lipid flux in AD pathogenesis are unknown. Sulfatides are specialized integral membrane lipid constituents in the myelin sheath which are essential for neuronal function. We have recently demonstrated that (1) sulfatide content precipitously drops in very mild AD, (2) CMS sulfatide content is modulated by apoE, and (3) the contents of sulfatides {which are associated with apoE in the CMS) and amyloid-beta..1-42 (Abeta42) are highly correlated in human cerebrospinal fluid. Accordingly, we propose that apoE/lipoprotein associated sulfatides specifically facilitate Abeta binding to the apoE particles for normal clearance. However, under pathological conditions where Abeta accumulation occurs, apoEassociated lipoproteins containing sulfatides facilitate Abeta42 aggregation which may form nucleation sites for further Abeta deposition. Furthermore, increased compensatory clearance of Aa/apoE/sulfatide complexes due to an accelerated endocytotic process results in sulfatide depletion. This hypothesis will be tested utilizing three independent models we have developed to study specific interactions, among apoE isoforms, Abeta peptides, and sulfatides. First, we will utilize a defined vesicular model system containing sulfatides as guest in a host phospholipid matrix to examine the kinetics of apoE/Abeta/sulfatide specific interactions by mass spectrometry (sulfatide and Abeta mass), ELISA (apoE content), and NMR spectroscopy (Abeta fibrillogenesis). Second, we will use oligodendrocytes (the cellular source of sulfatides in the CNS) as a cell culture model to identify the importance of sulfatide/apoE/Abeta interactions in modulating Abeta clearance and sulfatide trafficking. Finally, we will utilize transgenic mice to examine the detailed interactions of sulfatides with apoE variants and to verify the salient molecular interactions which modulate sulfatide trafficking and Abeta clearance. Collectively, the results of the proposed studies will explore the specific interactions of su!fatides/apoE/Abeta and address the molecular mechanism(s) leading to sulfatide loss and Abeta aggregation in very early Alzheimer's disease, thereby, providing insight into AD pathogenesis and identifying novel targets for AD treatment.