LXR and human ApoE isoform effects on AD phenotype: in vitro and in vivo models

LXR 和人 ApoE 亚型对 AD 表型的影响：体外和体内模型

基本信息

批准号：
8850760
负责人：
RADOSVETA KOLDAMOVA
金额：
$ 35.53万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850760
关键词：
Address Affect Agonist Alleles Alzheimer&apos s Disease Amyloid Amyloid deposition Apolipoprotein E Brain Cholesterol Cholesterol Homeostasis Clinical Research Complex Data Dementia Deposition Development Diet Disease Progression Epidemiologic Studies Exercise Fatty acid glycerol esters Future Gene Expression Gene Proteins Gene Targeting Genetic Health Human Impaired cognition In Vitro Incidence Intervention Knowledge Late Onset Alzheimer Disease Lead Life Style Ligands Link Liver Mediating Memory Metabolic Metabolism Mus Neurofibrillary Tangles Neurons Obesity Passive Immunization Pathogenesis Patients Prevention strategy Prevention therapy Protein Isoforms Proteins Reporting Research Risk Risk Factors Role Seeds Senile Plaques Signal Transduction Testing Transcriptional Regulation Transgenic Mice Treatment Efficacy Up-Regulation Wild Type Mouse abeta accumulation amyloid pathology apolipoprotein E-3 apolipoprotein E-4 base behavior test cognitive performance design disease phenotype feeding genetic risk factor in vivo in vivo Model lipoprotein cholesterol novel therapeutics receptor research study response secretase therapy design transcription factor

项目摘要

DESCRIPTION (provided by applicant): The inheritance of 54 allele of APOE is a major genetic risk factor for late-onset AD. APOE is under the transcriptional control of Liver X receptors, LXR1 and LXR2. LXR are transcription factors that control the expression of genes involved in cholesterol metabolism. In brain, in addition to normal neuronal function, cholesterol metabolism is of utmost importance for secretase activities, APP cleavage, A? aggregation and its clearance from the brain. Recently we, and others, reported that deletion of Abca1 - an LXR target gene, in APP transgenic mice decreases endogenous mouse ApoE level and increases amyloid deposition. Compared with APOE3 carriers, higher incidence of AD and increased amyloid deposition in APOE4 carriers might be a result of lower ApoE protein levels observed in these patients. Thus, ApoE4 isoform provides less protection against the accumulation of toxic A? species. It is conceivable that additional genetic factors such as impaired transcriptional regulation by LXR in response to strong metabolic signals, like high fat diet, influence this risk and precipitate the development of dementia. We hypothesize that transcriptional control of ApoE by LXR is critical for ameliorating the detrimental effect of ApoE4 isoform on amyloid deposition and cognitive decline. The hypothesis is based on the following observations: First, our preliminary data demonstrate that in human ApoE targeted replacement mice, ApoE4 protein levels are lower than ApoE3 and this correlates with increased amyloid load. In addition, treatment with the synthetic LXR ligand, T0901317 (T0), increases ApoE4 levels in vitro and in vivo thus reducing the quantitative differences between the two isoforms. Second, studies from our and other groups indicated that treatment of APP transgenic mice with T0 increases ApoE protein level and inhibits A? deposition. Third, our recent study demonstrated that T0 treatment alleviates the deleterious effects of high fat diet on amyloid deposition and cognitive decline in older APP23 mice suggesting that the effect of T0 on AD phenotype is a result of facilitated A? clearance mediated through increased ApoE protein level. Two Specific aims are designed to test the hypothesis: Specific aim 1: To examine how the activated LXR ligands modify the effect of ApoE3 and ApoE4 isoforms on A? aggregation and clearance. Specific aim 2: To characterize the effects of LXR ligand T0901317 on AD phenotype in APP/PS1dE9 mice on ApoE3 and EpoE4 background fed normal and Western type of diets.

描述（申请人提供）：APOE 54等位基因的遗传是迟发性AD的主要遗传危险因素。 APOE 受肝脏 X 受体 LXR1 和 LXR2 的转录控制。 LXR 是控制胆固醇代谢相关基因表达的转录因子。在大脑中，除了正常的神经元功能外，胆固醇代谢对于分泌酶活性、APP 裂解、A?聚集及其从大脑中的清除。最近，我们和其他人报道了 APP 转基因小鼠中 LXR 靶基因 Abca1 的缺失会降低小鼠内源性 ApoE 水平并增加淀粉样蛋白沉积。与 APOE3 携带者相比，APOE4 携带者 AD 发生率较高，淀粉样蛋白沉积增加，可能是由于这些患者中观察到的 ApoE 蛋白水平较低。因此，ApoE4 同工型对有毒 A? 积累的保护作用较小。物种。可以想象的是，其他遗传因素，例如 LXR 响应强代谢信号（如高脂肪饮食）的转录调节受损，会影响这种风险并加速痴呆的发展。我们假设 LXR 对 ApoE 的转录控制对于改善 ApoE4 同工型对淀粉样蛋白沉积和认知能力下降的有害影响至关重要。该假设基于以下观察：首先，我们的初步数据表明，在人 ApoE 靶向替代小鼠中，ApoE4 蛋白水平低于 ApoE3，这与淀粉样蛋白负荷增加相关。此外，用合成 LXR 配体 T0901317 (T0) 处理可增加体外和体内 ApoE4 水平，从而减少两种异构体之间的数量差异。其次，我们和其他小组的研究表明，用 T0 治疗 APP 转基因小鼠会增加 ApoE 蛋白水平并抑制 A？沉积。第三，我们最近的研究表明，T0 治疗减轻了高脂肪饮食对老年 APP23 小鼠淀粉样蛋白沉积和认知能力下降的有害影响，这表明 T0 对 AD 表型的影响是促进 A？通过增加 ApoE 蛋白水平介导的清除。设计了两个具体目标来检验该假设：具体目标 1：检查激活的 LXR 配体如何改变 ApoE3 和 ApoE4 亚型对 A？聚集和清除。具体目标 2：在正常和西方饮食喂养的 ApoE3 和 EpoE4 背景下，表征 LXR 配体 T0901317 对 APP/PS1dE9 小鼠 AD 表型的影响。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity.

贝沙罗汀激活的类视黄醇 X 受体调节神经元分化和树突复杂性。

DOI：
发表时间：
2015-08-26
期刊：
影响因子：
0
作者：
Mounier, Anais;Georgiev, Danko;Nam, Kyong Nyon;Fitz, Nicholas F;Castranio, Emilie L;Wolfe, Cody M;Cronican, Andrea A;Schug, Jonathan;Lefterov, Iliya;Koldamova, Radosveta
通讯作者：
Koldamova, Radosveta

RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of Aβ oligomers.

在小鼠大脑中发现的 RXR 控制调节网络抵消了 Aβ 寡聚体的有害影响。

DOI：
发表时间：
2016-04-07
期刊：
影响因子：
4.6
作者：
Nam, Kyong Nyon;Mounier, Anais;Fitz, Nicholas F;Wolfe, Cody;Schug, Jonathan;Lefterov, Iliya;Koldamova, Radosveta
通讯作者：
Koldamova, Radosveta

ATP-binding cassette transporter A1: from metabolism to neurodegeneration.

ATP 结合盒转运蛋白 A1：从新陈代谢到神经变性。

DOI：
发表时间：
2014-12
期刊：
影响因子：
6.1
作者：
Koldamova, Radosveta;Fitz, Nicholas F;Lefterov, Iliya
通讯作者：
Lefterov, Iliya

Opposing effects of Apoe/Apoa1 double deletion on amyloid-β pathology and cognitive performance in APP mice.

Apoe/Apoa1 双缺失对 APP 小鼠淀粉样蛋白-β 病理学和认知表现的相反影响。

DOI：
10.1093/brain/awv293
发表时间：
2015-10-28
期刊：
Brain : a journal of neurology
影响因子：
0
作者：
N. Fitz;Victor Tapias;Andrea A Cronican;Emilie L. Castranio;Muzamil Saleem;A. Carter;M. Lefterova;I. Lefterov;R. Koldamova
通讯作者：
R. Koldamova

Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice.

肝脏 X 受体激动剂治疗显着影响 APOE3 和 APOE4 Abca1 单倍体缺陷小鼠的表型和转录组。

DOI：
发表时间：
2017
期刊：
影响因子：
3.7
作者：
Carter, Alexis Y;Letronne, Florent;Fitz, Nicholas F;Mounier, Anais;Wolfe, Cody M;Nam, Kyong Nyon;Reeves, Valerie L;Kamboh, Hafsa;Lefterov, Iliya;Koldamova, Radosveta
通讯作者：
Koldamova, Radosveta