Liver X Receptors as Therapeutic Targets in Alzheimer?s Disease

描述(申请人提供)：阿尔茨海默氏症的特征是A？肽在大脑中积累和沉积，导致突触功能紊乱和神经元丢失，这是该疾病典型的认知丧失的基础。A？可以通过细胞内和细胞外的作用以及A？的外流进入外周循环而从大脑中清除。因此，促进A型肝炎清除的治疗策略具有特殊的意义和重要性。 对家族性阿尔茨海默病的遗传分析已经确立了APP的加工和A？产生在疾病发病机制中的中心地位。载脂蛋白E的一种异构体(ApoE4)已被证明可显著增加晚发性AD的风险，然而，这种作用的机制尚不清楚。载脂蛋白是大脑中主要的载脂蛋白，由星形胶质细胞在新生的高密度脂蛋白(HDL)样颗粒中分泌，该颗粒通过将脂类添加到ApoE中组装而成，ApoE起到支撑高密度脂蛋白形成的作用。载脂蛋白E的脂化是通过ABC转运蛋白ABCA1将磷脂和胆固醇转移到载脂蛋白E来实现的。重要的是，ApoE与ApoE结合强烈，与未脂化的ApoE相比，脂化形式的ApoE与ApoE的相互作用能力更强。重要的是，载脂蛋白E的脂化程度决定了它与Aβ的相互作用是导致多肽从大脑中清除，还是形成纤维并沉积到斑块中。现在有令人信服的实验证据表明，ApoE的脂化作用有利于A？肽从大脑中清除。因此，增加高脂形式载脂蛋白E丰度的治疗药物在减轻疾病发病机制方面可能是有用的。 ApoE和ABCA1的表达受II型核受体--肝X受体(LXR)的协调调节。LXRs是配体激活的转录因子，与这些基因(以及其他脂代谢基因)的启动子结合，当被激活时，会刺激脂化形式的ApoE水平增加。我们报道，用LXR激动剂GW3965治疗1岁大的表达HAPP的Tg2576小鼠后，A？肽水平和斑块负荷显著降低(&gt；50%)。我们推测，这种效应是由于增强了从大脑中清除蛋白水解性Aé多肽的能力。我们向i)提出建议。建立预防和逆转AD动物模型中AD相关病理发展所需的治疗条件，II)。通过检查缺乏LXRa和LXR的AD小鼠模型，明确确定LXRs在A代谢中的作用，验证这些受体作为AD的治疗靶点，以及III)。目的：探讨LXR激动剂促进蛋白水解肽降解的分子机制。

DESCRIPTION (provided by applicant): Alzheimer's disease is characterized by the accumulation and deposition of A¿ peptides within the brain, leading to perturbation in synaptic function and neuronal loss that underlies the loss of cognition that typifies the disease. A¿ can be cleared from the brain by proteinases, acting both intracellularly and extracellularly, as well as the efflux of A¿ into the peripheral circulation. Thus, therapeutic strategies that facilitate A¿ clearance are of particular interest and importance. Genetic analysis of familial forms of AD has established the centrality of APP processing and A¿ production to disease pathogenesis. An isoform of Apolipoprotein E (apoE4) has been shown to confer dramatically increased risk for late onset AD, however, the mechanisms subserving this effect are unclear. ApoE is the principal apolipoprotein in the brain and is secreted from astrocytes within a nascent high density lipoprotein (HDL)-like particle that is assembled by the addition of lipids to ApoE, which acts to scaffold HDL formation. The lipidation of ApoE is carried out by the action of the ABC transporter ABCA1 that transfers both phospholipids and cholesterol to ApoE. Importantly, ApoE binds avidly to A¿ peptides, and lipidated forms of ApoE exhibit a greater capacity to interact with A¿ compared to unlipidated ApoE. Importantly, the degree of ApoE lipidation governs whether its interaction with A¿ leads to clearance of the peptides from the brain, or alternatively to form fibrils and be deposited into plaques. There is now compelling experimental evidence that ApoE lipidation favors the clearance of A¿ peptides from the brain. It follows that therapeutic agents that increase the abundance of highly lipidated forms of ApoE may be of utility in attenuating disease pathogenesis. The expression of both ApoE and ABCA1 are coordinately regulated by the type II nuclear receptor, liver X receptor (LXR). LXRs are ligand activated transcription factors which bind to the promoters of these (and other genes of lipid metabolism) and when activated stimulate an increase in the levels of lipidated forms of ApoE. We report that treatment of 1 year old hAPP-expressing Tg2576 mice with the LXR agonist GW3965 results in a significant (>50%) reduction in A¿ peptide levels and plaque load. We postulate that this effect is due to the enhanced ability to proteolytically clear A¿ peptides from the brain. We propose to i). to establish the therapeutic conditions required to prevent and reverse the development of AD-related pathology in an animal model of AD, ii). to definitively establish the role of LXRs in A¿ metabolism by examination of murine models of AD lacking LXRa and LXR¿, validating these receptors as therapeutic targets in AD, and iii). to ascertain the molecular mechanisms through which the LXR agonists facilitate the proteolytic degradation of A¿ peptides.