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（由申请人提供）：54 APOE等位基因的继承是迟发性AD的主要遗传危险因素。 APOE在肝X受体LXR1和LXR2的转录控制下。 LXR是控制胆固醇代谢的基因表达的转录因子。在大脑中，除了正常的神经元功能外，胆固醇的代谢对于泌尿酶活动，应用裂解，A？聚集及其从大脑的清除。最近，我们和其他人报告说，在APP转基因小鼠中，ABCA1 -LXR靶基因的缺失降低了内源性小鼠APOE水平并增加淀粉样蛋白的沉积。与APOE3载体相比，APOE4载体中AD的发病率更高，淀粉样蛋白沉积增加可能是由于这些患者观察到的APOE蛋白水平较低的结果。因此，APOE4同工型更少保护毒性A的积累？物种。可以想象的是，诸如LXR对强烈代谢信号（例如高脂饮食）的转录调控受损等其他遗传因素会影响这种风险并沉淀痴呆症的发展。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下降的有害作用至关重要。该假设基于以下观察结果：首先，我们的初步数据表明，在人类APOE靶向替换小鼠中，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）的处理，在体外和体内增加了APOE4水平，从而减少了两种同工型之间的定量差异。其次，我们和其他组的研究表明，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治疗减轻了较老的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的结果？清除率通过升高的APOE蛋白水平介导。两个具体的目的旨在检验假设：具体目的1：检查活化的LXR配体如何修改APOE3和APOE4同工型对A的影响？聚合和清除。具体目的2：表征LXR配体T0901317对APP/PS1DE9小鼠在APOE3中的AD表型的影响，而EPOE4背景喂养了正常和西方饮食。

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）

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

DOI：
10.1038/srep24048
发表时间：
2016-04-07
期刊：
Scientific reports
影响因子：
4.6
作者：
Nam KN;Mounier A;Fitz NF;Wolfe C;Schug J;Lefterov I;Koldamova R
通讯作者：
Koldamova R

ABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice.

DOI：
10.3233/jad-161056
发表时间：
2017
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
0
作者：
Fitz NF;Carter AY;Tapias V;Castranio EL;Kodali R;Lefterov I;Koldamova R
通讯作者：
Koldamova R

Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer's model mice.

DOI：
10.1038/s41598-017-04412-2
发表时间：
2017-06-27
期刊：
Scientific reports
影响因子：
4.6
作者：
Nam KN;Mounier A;Wolfe CM;Fitz NF;Carter AY;Castranio EL;Kamboh HI;Reeves VL;Wang J;Han X;Schug J;Lefterov I;Koldamova R
通讯作者：
Koldamova R

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

DOI：
10.1371/journal.pone.0172161
发表时间：
2017
期刊：
PloS one
影响因子：
3.7
作者：
Carter AY;Letronne F;Fitz NF;Mounier A;Wolfe CM;Nam KN;Reeves VL;Kamboh H;Lefterov I;Koldamova R
通讯作者：
Koldamova R

RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment.