THE ROLE OF SULFATIDES IN ALZHEIMER'S DISEASE

描述（由申请人提供）： 阿尔茨海默病（AD）是老年人痴呆症的最常见原因。脂质转运蛋白载脂蛋白E（apoE）的e4等位基因与AD的早期发病和高风险相关，这一事实强调了脂质改变在AD发病机制中的重要性。然而，载脂蛋白E介导的脂质流动的改变在AD发病机制的影响是未知的。硫酸脂是髓鞘中的一种特殊的膜脂质成分，对神经元的功能至关重要。我们最近已经证明，（1）在非常轻度的AD中，硫苷脂含量急剧下降，（2）CMS硫苷脂含量受apoE调节，以及（3）硫苷脂（其与CMS中的apoE相关）和淀粉样蛋白-β的含量。1-42（A β 42）在人类脑脊液中高度相关。因此，我们认为apoE/脂蛋白相关的硫苷脂特异性地促进Abeta与apoE颗粒的结合以进行正常清除。然而，在发生Abeta积聚的病理条件下，含有硫苷脂的apoE相关脂蛋白促进Abeta 42聚集，这可能形成进一步Abeta沉积的成核位点。此外，Aa/apoE/硫苷脂复合物的补偿清除率增加，由于加速的内吞过程导致硫苷脂消耗。这一假设将利用三个独立的模型进行测试，我们已经开发出研究特定的相互作用，载脂蛋白E亚型，Abeta肽，和硫苷脂。首先，我们将利用一个定义的囊泡模型系统中的主机磷脂基质中含有作为客人的硫苷脂检查载脂蛋白E/Abeta/硫苷脂特异性相互作用的动力学质谱法（硫苷脂和Abeta质量），ELISA（载脂蛋白E含量），和NMR光谱（Abeta纤维）。第二，我们将使用少突胶质细胞（在中枢神经系统中的硫苷脂的细胞来源）作为细胞培养模型，以确定在调节A β清除和硫苷脂运输的硫苷脂/载脂蛋白E/A β相互作用的重要性。最后，我们将利用转基因小鼠来研究硫苷脂与apoE变体的详细相互作用，并验证调节硫苷脂运输和Abeta清除的显著分子相互作用。总的来说，拟议的研究结果将探讨苏的具体相互作用！fatides/apoE/Abeta，并解决了在极早期阿尔茨海默病中导致硫苷脂损失和Abeta聚集的分子机制，从而提供了对AD发病机制的深入了解，并确定了AD治疗的新靶点。

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.