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.

项目总结 根据阿尔茨海默氏症协会的最新报告，2015年阿尔茨海默病事实和数据， 每九个65岁以上的美国人中就有一个患有阿尔茨海默病(AD)，其中估计有40%-65%的人患有阿尔茨海默氏症 携带至少一份胆固醇运输蛋白载脂蛋白E(εE)基因的载脂蛋白4等位基因。 尽管是AD的最高风险因素之一(仅次于年龄)，但ApoE4的机制 增加AD的发生是未知的。载脂蛋白E通过载脂蛋白E受体将胆固醇输送到神经元，而载脂蛋白E受体 低密度脂蛋白(LDL)受体基因家族的成员。这些载脂蛋白E受体中的一些，即LRP1， ApoER2、VLDL受体和Lrp4是中枢和外周突触的固有成分，其中 它们通过细胞质信号和神经递质作为神经传递的基本调节器。 贩卖人口。 阿尔茨海默病的进行性神经变性首先表现为突触引起的记忆丧失 功能障碍。淀粉样蛋白-β(Aβ)，是在大脑中积聚的商标斑块的中心成分 阿尔茨海默病患者是淀粉样前体蛋白APP的产物，可能是这种早期疾病的来源 功能障碍。我们以前已经证明，β诱导的突触抑制可以通过载脂蛋白E来防止 受体激活和载脂蛋白E4通过隔离载脂蛋白E选择性地损害这种突触保护功能 受体ApoER2。ApoER2是一种重要的中枢ApoE受体，在多种组织中均有内源性表达。 另一种剪接形式，表明生理上需要功能多样的受体形式。我们 发现细胞外O-糖基化结构域的差异剪接显著改变ApoER2 丰富性、突触功能和恐惧记忆。ApoER2还可以通过多个途径改变β的形成 影响应用程序处理的与应用程序的交互。因此，理解规则和功能 ApoER2是理解ApoE4导致AD突触功能障碍的机制的核心。 越来越多的证据表明，ApoER2是突触内稳态的关键调节因子。在这 应用，我们建议调查两个主要的生理剪接事件的后果 ApoER2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，我们将采用ApoER2- ApoER2基因缺陷小鼠和表达不同剪接形式的小鼠探讨ApoER2对基因的调控 表情。在目标2中，我们将探索这些ApoER2亚型的蛋白质相互作用组，并探索ApoER2亚型如何 不同的载脂蛋白E亚型影响它们的运输和信号传递，以及它们调节APP处理的能力。 在目标3中，我们将探索内源性ApoER2剪接变体如何改变行为和认知，以及它们是如何 影响人类载脂蛋白E亚型或Aβ过度产生的小鼠的认知缺陷。

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