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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer&apos 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

项目摘要

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.

我们建议的目的是确定主调节细胞因子白介素10（IL10）在调节中的作用阿尔茨海默氏病小鼠模型（AD）中的蛋白质症（APOE蛋白E（APOE）同工型依赖性方式。我们的建议解决了与对AD发病机理的理解有关的两个关键问题：（1）免疫如何途径与APOE等AD风险基因的功能相互作用并调节（2）我们可以利用这一点在与AD相关的小鼠模型中破坏IL-10/APOE轴并实现治疗益处的知识？我们的初步数据表明，抗炎细胞因子白介素（IL）-10具有意外的负面影响在AD的转基因小鼠模型中，Aβ和Tau蛋白抑制作用。这证明了先天的复杂相互作用 AD型神经退行性疾病中的免疫学和蛋白质症，我们称为免疫蛋白抑制剂。这这种免疫蛋白抑制性的机制导致AD中的神经退行性病理仍然未知；研究免疫抑制性的机制可以使我们能够设计针对此类的免疫疗法信号通路。我们已经观察到APP转基因小鼠中IL-10的过表达会使Aβ斑块病理和认知恶化通过APOE依赖机制的功能。从机械上讲，我们可以归因于IL-10对Aβ的负面影响小胶质细胞降低Aβ吞噬作用的蛋白质静态作用，内源性APOE表达增加并增强了APOE在不溶性淀粉样斑块中的积累。在我们的研究中，无法解决的APOE水平增加与斑块相关，与小鼠APOE作为Aβ骨料的病理伴侣一致。阻塞使用固体诱饵受体对IL-10的IL-10信号传导废除了这种作用，并减少了脑淀粉样蛋白负担。我们观察到IL-10在两个 tauopathy的独立小鼠模型。本质上，IL-10加速了tauopathy，并减少了在JNPL3中生存的时间小鼠；它还促进了RTG4510小鼠中的前脑神经变性和tauopathy。虽然这是一个意外的表型，我们提供了APOE在无细胞系统中与Fibrillar Tau专门相互作用的初步数据，该数据尽管其他机制（例如自噬抑制）也需要部分解释蛋白质的病经过考虑的。在这些强大的初步数据的指导下，我们将实现以下具体目标： AIM 1。评估APOE基因型是否影响APP小鼠中IL10诱导的蛋白抑制性并评估是否相互作用具有Aβ聚集体的人ApoE同工型改变了不溶性Aβ的小胶质清除率。我们将测试IL-的影响 10在表达人apoE蛋白的APP转基因小鼠中淀粉样菌斑沉积的免疫蛋白抑制剂（2或 3或4），并提供有关依赖APOE的小胶质细胞摄取和骨料Aβ清除率的机械见解。我们预计促进受保护的APOE2同工型的表达将产生有益的作用，而APOE4诱导会产生有害影响。 AIM2。确定APP，TAU和非 - 转基因小鼠。鉴于IL-10在Aβ和TAU的小鼠模型中恶化了蛋白质和与AD相关的表型，在此，我们将测试针对IL-10的诱饵受体策略的效率。通过阻止IL-10信令，我们期望诱饵受体策略是针对Aβ和TAU蛋白质症的一种潜在可翻译疾病的疾病。 AIM3。复制并扩展我们对IL-10过表达的研究，作为TAU病理的驱动力。此处使用AAV 工具包和系统生物学方法，我们建议复制我们对IL-10/apoE依赖性蛋白质的观察结果在良好控制和行为特征的Tau转基因队列中的表型，并进一步提供了见解 IL-10/APOE轴的这种淀粉样蛋白生成特性的可能机制。该提议的优势在于新调查员之间的团队合作，并继续致力于学习 AD小鼠模型和具有创建转基因AD经验的既定研究者的神经免疫轴鼠标模型。我们希望该提案将增强我们对复杂免疫信号级联的了解 AD Proteostasis和针对APOE调节蛋白质的可翻译免疫系列受体策略。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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.