Towards understanding the role of immune regulation of Apolipoprotein E function in Alzheimer's disease proteostasis

了解载脂蛋白 E 功能的免疫调节在阿尔茨海默氏病蛋白质稳态中的作用

• 批准号: 10363732
• 负责人: PARAMITA CHAKRABARTY
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363732
• 关键词: AD transgenic mice; Address; Affect; Age; Alleles; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Antigen-Antibody Complex; Apolipoprotein E; Behavioral; Binding; Biological; Brain; CX3CL1 gene; Cell-Free System; Code; Cognition; Complex; Coupled; Data; Deposition; Disease; E protein; Genes; Genotype; Gliosis; Goals; Human; Immune; Immune signaling; Immunologic Receptors; Impairment; Inflammatory; Innate Immune System; Interleukin-10; Interleukin-10 Overexpression; Interleukin-4; Knock-out; Knowledge; Literature; Maps; Mediating; Microglia; Modeling; Molecular Chaperones; Mus; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Phagocytosis; Phenotype; Physiological; Play; Pre-Clinical Model; Property; Prosencephalon; Protein Isoforms; Proteins; Recombinant adeno-associated virus (rAAV); Reporting; Research Design; Research Personnel; Rodent Model; Role; Senile Plaques; Series; Signal Pathway; Signal Transduction; Study models; System; Systems Biology; Tauopathies; Technology; Testing; Therapeutic; Time; Toll-like receptors; Transgenic Mice; Transgenic Organisms; Ursidae Family; Work; antagonist; apolipoprotein E-2; base; cognitive function; cohort; cytokine; design; efficacy testing; experience; experimental study; genetic risk factor; genomic locus; immune activation; immunomodulatory strategy; immunoregulation; inhibition of autophagy; insight; interest; interleukin-10 receptor; link protein; mouse model; pre-clinical; proteostasis; receptor; risk variant; systematic review; tau Proteins; tool; transcriptomics; uptake; β-amyloid burden

The goal of our proposal is to determine the role of the master regulatory cytokine, Interleukin 10 (IL10), in regulating proteostasis in mouse models of Alzheimer’s disease (AD) in an Apolipoprotein E (ApoE) isoform dependent manner. Our proposal addresses two key questions that are relevant to understanding of AD pathogenesis: (1) how does immune pathways interact with and modulate the function of AD risk genes, such as APOE and (2) can we harness this knowledge to disrupt the IL-10/APOE axis and achieve therapeutic benefits in AD-relevant mouse models? Our preliminary data has shown that the anti-inflammatory cytokine Interleukin (IL)-10, has unexpected negative effect on Aβ and tau proteostasis in transgenic mouse models of AD. This demonstrates a complex interplay between innate immunity and proteostasis in AD type neurodegenerative diseases, an interaction we call immunoproteostasis. The mechanism(s) underlying such immunoproteostasis leading to neurodegenerative pathology in AD remain unknown; studying the mechanisms underlying immunoproteostasis can enable us to design immunobiotherapies targeting such signaling pathways. We have observed that overexpression of IL-10 in APP transgenic mice worsens Aβ plaque pathology and cognitive functions via an ApoE-dependent mechanism. Mechanistically, we could attribute the negative effects of IL-10 on Aβ proteostasis to synergistic effects of decreased Aβ phagocytosis by microglia, increased endogenous ApoE expression and enhanced accumulation of ApoE in insoluble amyloid plaques. In our study, the increased level of insoluble ApoE was plaque-associated, consistent with mouse ApoE functioning as a pathological chaperone for Aβ aggregates. Blocking IL-10 signaling using the soluble decoy receptor against IL-10 abrogated this effect and reduced brain amyloid plaque burden. We observed similar ApoE dependent effects on tau proteostasis following IL-10 overexpression in two independent mouse models of tauopathy. Essentially, IL-10 accelerated tauopathy and reduced time to survival in JNPL3 mice; it also promoted forebrain neurodegeneration and tauopathy in the rTg4510 mice. While this was an unexpected phenotype, we provide preliminary data that ApoE specifically interacts with fibrillar tau in a cell free system, which could partially explain the proteostasis, though other mechanisms, such as autophagy inhibition also need to be considered. Guided by these robust preliminary data, we will undertake the following specific aims: Aim 1. Assess whether APOE genotype affects IL10-induced proteostasis in APP mice and evaluate whether interaction of human APOE isoforms with Aβ aggregates alters microglial clearance of insoluble Aβ. We will test the effects of IL- 10 immunoproteostasis on amyloid plaque deposition in an APP transgenic mouse expressing human APOE protein (2 or 3 or 4) and provide mechanistic insights into APOE-dependent microglial uptake and clearance of aggregated Aβ. We expect that promoting expression of the protective APOE2 isoform will have beneficial effects while APOE4 induction will have harmful effects. Aim2. Determine the effects of an AAV-delivered soluble IL-10 receptor decoy (sIL10R1) strategy in APP, tau and non- transgenic mice. Given that IL-10 worsens proteostasis and AD-relevant phenotype in mouse models of Aβ and tau, herein, we will test the efficacy of a decoy receptor strategy against IL-10. By blocking IL-10 signaling, we expect the decoy receptor strategy to be a potentially translatable disease modifying therapy against both Aβ and tau proteostasis. Aim3. Replicate and extend our studies of IL-10 overexpression as a driver of tau pathology. Herein, using the AAV toolkit, and systems biology approach, we propose to reproduce our observations of IL-10/APOE-dependent proteostasis phenotype in a well-controlled and behaviorally-characterized tau transgenic cohort and further provide insights into possible mechanisms underlying such amyloidogenic properties of the IL-10/APOE axis. The strength of this proposal lies in the teamwork between a new investigator with continuing commitment to studying the neuroimmune axis in mouse models of AD and an established investigator with experience in creating transgenic AD mouse models. We expect that this proposal will enhance our knowledge of the complex immune signaling cascades in AD proteostasis and uncover translatable immune decoy receptor strategies targeting APOE-regulated proteostasis.

我们建议的目标是确定主调节细胞因子白细胞介素10（IL 10）在调节细胞凋亡中的作用。 在阿尔茨海默氏病（AD）小鼠模型中以载脂蛋白E（ApoE）同种型依赖性方式进行蛋白质稳态。 我们的建议解决了与理解AD发病机制相关的两个关键问题：（1）免疫如何影响AD的发病机制？ 通路与AD风险基因（如APOE）相互作用并调节其功能，（2）我们能否利用这一点 破坏IL-10/APOE轴并在AD相关小鼠模型中获得治疗益处的知识？ 我们的初步数据表明，抗炎细胞因子白细胞介素（IL）-10，具有意想不到的负面影响 对AD转基因小鼠模型中Aβ和tau蛋白质稳定的影响。这表明了先天性的 AD型神经退行性疾病中的免疫和蛋白稳态，我们称之为免疫蛋白稳态的相互作用。的 导致AD中神经变性病理学的这种免疫蛋白抑制的潜在机制仍然未知; 研究免疫蛋白抑制的潜在机制可以使我们能够设计针对这些免疫蛋白抑制的免疫生物疗法。 信号通路 我们已经观察到APP转基因小鼠中IL-10的过度表达会损害Aβ斑块的病理学和认知功能， 通过ApoE依赖性机制发挥作用。从机制上讲，我们可以将IL-10对Aβ的负面影响归因于 蛋白质抑制对小胶质细胞Aβ吞噬作用降低、内源性ApoE表达增加的协同作用 并增强ApoE在不溶性淀粉样斑块中的积累。在我们的研究中，不溶性ApoE水平的增加 与斑块相关，与小鼠ApoE作为Aβ聚集体的病理性伴侣的功能一致。阻挡 使用针对IL-10的可溶性诱饵受体的IL-10信号传导消除了这种作用并减少了脑淀粉样斑块 负担我们观察到在两个小鼠中IL-10过表达后，ApoE对tau蛋白抑制的依赖性作用相似。 tau蛋白病的独立小鼠模型。从本质上讲，IL-10加速了JNPL 3中的tau蛋白病并缩短了生存时间。 它还促进rTg 4510小鼠的前脑神经变性和tau蛋白病。虽然这是一个意想不到的 表型，我们提供了初步数据，ApoE特异性地与纤维状tau蛋白在无细胞系统中相互作用， 可以部分解释蛋白质稳态，但其他机制，如自噬抑制也需要 考虑了在这些可靠的初步数据的指导下，我们将实现以下具体目标： 目标1。评估APOE基因型是否影响APP小鼠中IL 10诱导的蛋白质稳态， 人APOE亚型与Aβ聚集体的结合改变了小胶质细胞对不溶性Aβ的清除。我们将测试IL- 10在表达人APOE蛋白的APP转基因小鼠中对淀粉样蛋白斑沉积的免疫蛋白抑制（2或 3或4），并提供了APOE依赖性小胶质细胞摄取和清除聚集Aβ的机制见解。我们 预期促进保护性APOE 2亚型的表达将具有有益的效果，而APOE 4诱导 会产生有害影响 目标2。确定AAV递送的可溶性IL-10受体诱饵（sIL 10 R1）策略在APP、tau和非IL-10受体中的作用。 转基因小鼠鉴于IL-10在Aβ和tau的小鼠模型中破坏蛋白质稳态和AD相关表型， 在此，我们将测试针对IL-10的诱饵受体策略的效力。通过阻断IL-10信号传导，我们预期 诱饵受体策略是一种潜在的针对Aβ和tau蛋白酶抑制的可转化疾病修饰疗法。 目标3。复制和扩展我们的研究IL-10过表达作为tau病理学的驱动因素。在此，使用AAV 工具包和系统生物学方法，我们建议重现我们对IL-10/APOE依赖性蛋白质稳态的观察 在良好控制和行为表征的tau转基因组中的表型，并进一步提供了对以下方面的见解： IL-10/APOE轴的淀粉样蛋白生成特性的潜在可能机制。 这个建议的力量在于一个新的研究者与持续致力于研究之间的团队合作 AD小鼠模型中的神经免疫轴和具有创建转基因AD经验的既定研究者 小鼠模型。我们希望这一提议将增强我们对免疫系统中复杂免疫信号级联的认识。 AD蛋白质稳态和发现针对APOE调节的蛋白质稳态的可翻译免疫诱饵受体策略。

项目成果

Combination of Aβ Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition.

Aβ 抑制和大脑先天免疫激活的结合显着减弱淀粉样斑块沉积。

• DOI: 10.1016/j.ajpath.2017.08.010
• 发表时间: 2017
• 期刊: The American journal of pathology
• 作者: Verbeeck,Christophe;Carrano,Anna;Chakrabarty,Paramita;Jankowsky,JoannaL;Das,Pritam
• 通讯作者: Das,Pritam

Ifngr1 and Stat1 mediated canonical Ifn-γ signaling drives nigrostriatal degeneration.

• DOI: 10.1016/j.nbd.2017.11.007
• 发表时间: 2018-03
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Strickland MR;Koller EJ;Deng DZ;Ceballos-Diaz C;Golde TE;Chakrabarty P
• 通讯作者: Chakrabarty P

Generation and characterization of new monoclonal antibodies targeting the PHF1 and AT8 epitopes on human tau.

• DOI: 10.1186/s40478-017-0458-0
• 发表时间: 2017-07-31
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Strang KH;Goodwin MS;Riffe C;Moore BD;Chakrabarty P;Levites Y;Golde TE;Giasson BI
• 通讯作者: Giasson BI

Impact of APOE genotype on prion-type propagation of tauopathy.

• DOI: 10.1186/s40478-022-01359-y
• 发表时间: 2022-04-19
• 期刊: ACTA NEUROPATHOLOGICA COMMUNICATIONS
• 影响因子: 7.1
• 作者: Williams, Tristan;Ruiz, Alejandra Jolie;Ruiz, Angelica Maria;Vo, Quan;Tsering, Wangchen;Xu, Guilian;McFarland, Karen;Giasson, Benoit, I;Sullivan, Patrick;Borchelt, David R.;Chakrabarty, Paramita
• 通讯作者: Chakrabarty, Paramita

Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy.

• DOI: 10.1186/s40478-023-01581-2
• 发表时间: 2023-06-19
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1