Alleviating lysosomal lipid defects in ADRD by blocking cholesterol storage

家长津贴行政补充建议摘要 “通过阻断胆固醇储存来缓解ADRD患者的溶酶体脂质缺陷” 该实验室的长期目标是生产基于胆固醇代谢的疗法，以 治疗AD和ADRD。血管性痴呆(VAD)是一种ADRD，是第二种最常见的 美国老年痴呆症后的痴呆症。VaD的病因是复杂的，但与 血脂异常、动脉粥样硬化、中风和糖尿病。动脉粥样硬化的特点是 巨噬细胞和平滑肌中胆固醇、胆固醇酯和其他脂类的积聚 动脉壁内的细胞。酰基辅酶A：胆固醇酰基转移酶1(ACAT1)是一种酶 将胆固醇转化为胆固醇酯以储存在所有细胞中，包括巨噬细胞 肌肉细胞，以及大脑中的小胶质细胞和神经元。我们的实验室一直在研究 ACAT1已经几十年了。我们和其他人在小鼠模型中证明了这一点，抑制ACAT1 有益于几种疾病，包括动脉粥样硬化、饮食引起的肥胖和阿尔茨海默病。 载脂蛋白是一种脂蛋白，在体内和大脑中运输胆固醇和其他类脂。载脂蛋白3 是主要的等位基因。载脂蛋白E4是一个次要等位基因，是阿尔茨海默病的主要遗传风险因素；它也是一种遗传风险 卒中相关VAD的因子。希望能制造出部分概括的动物模型 VaD的基本特征，使候选药物(S)可以在临床前水平进行测试。 然而，目前还没有ApoE亚型的动脉粥样硬化相关的VaD小鼠模型 具体方式可供选择。为了开始填补这一空白，我们在补充请求中建议 制作这样一个模型，我们称之为athero/E3和athero/E4小鼠。 化合物F是一种临床批准的小分子ACAT1抑制剂，最初旨在治疗 动脉粥样硬化，但被放弃，因为化合物F在减少动脉粥样硬化方面不如他汀类药物有效 男性的血清胆固醇水平。F对血脑屏障是否具有通透性尚不清楚。我们 已经开发了纳米颗粒平台，并表明存在于该纳米颗粒中的F是可渗透的 血脑屏障。我们还表明，在给小鼠注射IP后，纳米颗粒F有效地 在体细胞和脑细胞中抑制ACAT1。在补充要求中，我们建议使用 纳米粒F用于治疗西方饮食诱导的athero/E3和athero/E4小鼠。

ABSTRACT of the administrative supplement proposal for the parent grant “Alleviating lysosomal lipid defects in ADRD by blocking cholesterol storage” The long-term goal of this laboratory is to produce cholesterol metabolism-based therapeutics to treat AD and ADRDs. Vascular dementia (VaD), an ADRD, is the second most common form of dementia after AD in the US. The etiology of VaD is complex, but is closely associated with dyslipidemia, atherosclerosis, stroke, and diabetes. Atherosclerosis is characterized by accumulation of cholesterol, cholesteryl esters and other lipids in macrophages and smooth muscle cells within the arterial walls. Acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1) is an enzyme that converts cholesterol to cholesterol esters for storage in all cells, including macrophages, smooth muscle cells, as well as microglia and neurons in the brain. Our laboratory has been working on ACAT1 for several decades. We and others demonstrated that in mouse models, inhibiting ACAT1 benefit several diseases, including atherosclerosis, diet induced obesity, and AD. ApoE is a lipoprotein that transports cholesterol and other lipids in the body and in the brain. Apoe3 is the major allele. Apoe4, a minor allele, is a major genetic risk factor for AD; it is also a genetic risk factor for stroke associated VaD. It is desirable to produce animal models that partially recapitulate the essential features of VaD, such that candidate drug(s) can be tested at the preclinical level. However, at present, no mouse model for atherosclerosis associated VaD in ApoE isoform specific manner is available. To begin to fill this void, in the supplement request, we propose to produce such a model, and we refer it as the Athero/E3 and Athero/E4 mice. Compound F is a clinically approved small molecule ACAT1 inhibitor, originally intended to treat atherosclerosis, but was abandoned because compound F was not as efficient as statin in reducing serum cholesterol levels in men. Whether F was permeable to blood brain barrier was unknown. We have developed a nanoparticle platform and showed that F present in this nanoparticle is permeable to blood brain barrier. We have also shown that after IP injections to mice, nanoparticle F efficiently inhibited ACAT1 in body cells and in brain cells. In the supplement request, we propose to use nanoparticle F to treat the Athero/E3 and Athero/E4 mice under Western diet.