Physiology and Pathophysiology of Apolipoprotein E receptor-2 splicing in Alzheimer's disease

阿尔茨海默病中载脂蛋白 E 受体 2 剪接的生理学和病理生理学

• 批准号: 10076307
• 负责人: Joachim J Herz
• 金额: $ 39.72万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10076307
• 关键词: Affect; Age; Alleles; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Behavior; Biological Assay; Brain; Carrier Proteins; Cholesterol; Cognition; Cognitive deficits; Endosomes; Event; Functional disorder; Gene Expression; Gene Family; Genes; Homeostasis; Human; Impairment; Intervention; LDL-Receptor Related Protein 1; Ligands; Low Density Lipoprotein Receptor; Luciferases; Mediating; Memory; Memory Loss; Mus; Neurons; Neurotransmitters; Pathogenesis; Peripheral; Physiological; Physiology; Protein Isoforms; Proteins; RNA Splicing; Receptor Activation; Regulation; Reporting; Role; Signal Transduction; Source; Synapses; Testing; Trademark; VLDL receptor; Variant; amyloid formation; amyloid precursor protein processing; animation; apolipoprotein E receptor 2; apolipoprotein E-4; extracellular; fear memory; glycosylation; high risk; human old age (65+); member; neurotransmission; novel therapeutics; prevent; progressive neurodegeneration; receptor; synaptic function; trafficking

PROJECT SUMMARY According to the most recent Alzheimer's Association report, 2015 Alzheimer's Disease Facts and Figures, one out of nine Americans over the age of 65 has Alzheimer's Disease (AD) and an estimated 40-65% of them carry at least one copy of the ε4 allele of gene for a cholesterol transport protein, apolipoprotein E (ApoE). Despite being one of the highest risk factors for AD (second only to age), the mechanism by which ApoE4 increases AD occurrence is unknown. ApoE transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein (LDL) receptor gene family. Some of these ApoE receptors, i.e. LRP1, Apoer2, VLDL receptor (Vldlr), and Lrp4, are intrinsic components of central and peripheral synapses, where they serve as essential regulators of neurotransmission through cytoplasmic signaling and neurotransmitter trafficking. The progressive neurodegeneration in AD first presents as memory loss brought on by synaptic dysfunction. Amyloid-β (Aβ), the central component in the trademark plaques that build up in the brains of people with AD, are a product of the amyloid precursor protein, APP, and a likely source of this early dysfunction. We have shown previously that Aβ-induced synaptic suppression can be prevented through ApoE receptor activation and ApoE4 selectively impairs this synaptoprotective function by sequestering the ApoE receptor, Apoer2. Apoer2, an essential CNS ApoE receptor, is endogenously expressed in multiple alternatively spliced forms, indicating a physiological need for functionally diverse forms of the receptor. We have found that differential splicing of an extracellular O-glycosylation domain dramatically alters Apoer2 abundance, synaptic function and fear memory. Apoer2 can also modify the formation of Aβ through multiple interactions with APP that effect APP processing. Therefore, understanding the regulation and function of Apoer2 is central to understanding the mechanisms by which ApoE4 causes synaptic dysfunction in AD. Accumulating evidence has identified Apoer2 as a key regulator of synaptic homeostasis. In this application, we propose to investigate the consequences of the two main physiological splicing events of Apoer2 on gene expression, protein interactions, behavior and cognition. In Aim 1 we will employ Apoer2- deficient mice and mice expressing various splice forms of Apoer2 to explore how Apoer2 regulates gene expression. In Aim 2, we will explore the protein interactome of these Apoer2 isoforms and probe how the various ApoE isoforms affect their trafficking and signaling, as well as their ability to regulate APP processing. In Aim 3, we will explore how endogenous Apoer2 splice variants modify behavior and cognition and how they affect cognitive deficits in mice with human ApoE isoforms or Aβ-overproduction.

项目摘要 根据最新的阿尔茨海默氏症协会报告，2015年阿尔茨海默氏症的事实和数字， 在65岁以上的美国人中，九分之一的人患有阿尔茨海默病（AD）， 携带胆固醇转运蛋白载脂蛋白E（ApoE）基因ε4等位基因的至少一个拷贝。 尽管是AD的最高风险因素之一（仅次于年龄），但ApoE 4 AD发生率增加未知。ApoE通过ApoE受体将胆固醇转运到神经元， 低密度脂蛋白（LDL）受体基因家族的成员。这些ApoE受体中的一些，即LRP 1， Apoer 2、VLDL受体（Vldlr）和Lrp 4是中枢和外周突触的内在组分，其中 它们通过细胞质信号传导和神经递质作为神经传递的重要调节剂 贩卖人口 AD的进行性神经退行性变首先表现为突触损伤引起的记忆丧失， 功能障碍β淀粉样蛋白（Aβ）是在老年人大脑中形成的标志性斑块的中心成分， 患有AD的人，是淀粉样前体蛋白APP的产物，也是这种早期疾病的可能来源。 功能障碍我们以前已经证明，Aβ诱导的突触抑制可以通过ApoE来预防， 受体激活和ApoE 4通过隔离ApoE选择性地损害这种突触保护功能 受体Apoer 2. Apoer 2是一种必需的CNS ApoE受体，在多种细胞中内源性表达， 选择性剪接形式，表明对受体功能多样形式的生理需要。我们 已经发现细胞外O-糖基化结构域的差异剪接显著改变Apoer 2 丰度、突触功能和恐惧记忆。Apoer 2还可以通过多种途径修饰Aβ的形成。 与APP的交互影响APP处理。因此，了解的调节和功能 Apoer 2是理解ApoE 4导致AD中突触功能障碍的机制的核心。 越来越多的证据表明Apoer 2是突触稳态的关键调节因子。在这 应用，我们建议调查的两个主要的生理剪接事件的后果， Apoer 2对基因表达、蛋白质相互作用、行为和认知的影响。在目标1中，我们将使用Apoer 2- 缺陷小鼠和表达Apoer 2各种剪接形式的小鼠，以探索Apoer 2如何调节基因 表情在目标2中，我们将探索这些Apoer 2亚型的蛋白质相互作用组，并探索它们如何与Apoer 2亚型相互作用。 各种ApoE同种型影响它们的运输和信号传导以及它们调节APP加工的能力。 在目标3中，我们将探讨内源性Apoer 2剪接变异体如何改变行为和认知，以及它们如何影响行为和认知。 影响人类ApoE亚型或Aβ过度产生小鼠的认知缺陷。

项目成果

Biolistic transfection and expression analysis of acute cortical slices.

急性皮质切片的基因枪转染和表达分析。

• DOI: 10.1016/j.jneumeth.2020.108666
• 发表时间: 2020
• 期刊: Journal of neuroscience methods
• 影响因子: 3
• 作者: Hamad,MohammadIK;Daoud,Solieman;Petrova,Petya;Rabaya,Obada;Jbara,Abdalrahim;Melliti,Nesrine;Stichmann,Sarah;Reiss,Gebhard;Herz,Joachim;Förster,Eckart
• 通讯作者: Förster,Eckart

ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease.

• DOI: 10.1016/j.tem.2016.12.001
• 发表时间: 2017-04
• 期刊: Trends in endocrinology and metabolism: TEM
• 作者: Lane-Donovan C;Herz J
• 通讯作者: Herz J

Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer's disease.

逆转 ApoE4 诱导的循环阻滞作为阿尔茨海默病的新型预防方法。

• DOI: 10.7554/elife.40048
• 发表时间: 2018
• 期刊: eLife
• 影响因子: 7.7
• 作者: Xian,Xunde;Pohlkamp,Theresa;Durakoglugil,MuratS;Wong,ConnieH;Beck,JürgenK;Lane-Donovan,Courtney;Plattner,Florian;Herz,Joachim
• 通讯作者: Herz,Joachim

Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases.

循环 Reelin 可促进急性和长期 COVID-19 病例的炎症并调节疾病活动。

• DOI: 10.3389/fimmu.2023.1185748
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Calvier, Laurent;Drelich, Aleksandra;Hsu, Jason;Tseng, Chien-Te;Mina, Yair;Nath, Avindra;Kounnas, Maria Z.;Herz, Joachim
• 通讯作者: Herz, Joachim

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia.

• DOI: 10.1016/j.chembiol.2017.06.010
• 发表时间: 2017-07-20
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: She A;Kurtser I;Reis SA;Hennig K;Lai J;Lang A;Zhao WN;Mazitschek R;Dickerson BC;Herz J;Haggarty SJ
• 通讯作者: Haggarty SJ