Targeting Type I IFN signaling to promote recovery following brain trauma in aged animals

靶向 I 型干扰素信号传导促进老年动物脑外伤后的恢复

• 批准号: 10618773
• 负责人: James Paul Barrett
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618773
• 关键词: Acceleration; Address; Affect; Aging; Alleles; Alzheimer disease detection; Alzheimer' s Disease; Animal Model; Animals; Antiviral Response; Apolipoprotein E; Attenuated; Automobile Driving; Brain; Cells; Chronic; Chronic Phase; Clinical; Clinical Research; Data; Development; Disease; Disease associated microglia; Elderly; Elements; Environment; Environmental Risk Factor; Evaluation; Gene Expression; Genes; Genetic; Hour; Human; IFNAR1 gene; Impaired cognition; Impairment; Individual; Inflammation; Injury; Interferon Type I; Interferons; Intervention; Knock-out; Laboratories; Late Onset Alzheimer Disease; Microglia; Modeling; Molecular; Mus; National Institute on Aging; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurologic Deficit; Neurologic Dysfunctions; Neurological outcome; Neurons; Outcome; Pathologic; Pathway interactions; Patients; Phagocytosis; Phenotype; Play; Point Mutation; Population; Process; Publishing; Reaction; Recovery; Reporting; Research; Risk; Risk Factors; Role; Signal Transduction; TBI Patients; TREM2 gene; Tissues; Transgenic Mice; Traumatic Brain Injury; age related; age related neurodegeneration; aged; aging brain; aging population; apolipoprotein E-4; cognitive function; disease phenotype; genetic risk factor; glial activation; human model; improved; injured; model organism; mouse model; neuroinflammation; neurological recovery; neuron loss; neuropathology; neurorestoration; neurotoxic; neutralizing antibody; novel therapeutic intervention; prevent; progressive neurodegeneration; receptor; response; synergism; young adult; Acceleration; Address; Affect; Aging; Alleles; Alzheimer disease detection; Alzheimer' s Disease; Animal Model; Animals; Antiviral Response; Apolipoprotein E; Attenuated; Automobile Driving; Brain; Cells; Chronic; Chronic Phase; Clinical; Clinical Research; Data; Development; Disease; Disease associated microglia; Elderly; Elements; Environment; Environmental Risk Factor; Evaluation; Gene Expression; Genes; Genetic; Hour; Human; IFNAR1 gene; Impaired cognition; Impairment; Individual; Inflammation; Injury; Interferon Type I; Interferons; Intervention; Knock-out; Laboratories; Late Onset Alzheimer Disease; Microglia; Modeling; Molecular; Mus; National Institute on Aging; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurologic Deficit; Neurologic Dysfunctions; Neurological outcome; Neurons; Outcome; Pathologic; Pathway interactions; Patients; Phagocytosis; Phenotype; Play; Point Mutation; Population; Process; Publishing; Reaction; Recovery; Reporting; Research; Risk; Risk Factors; Role; Signal Transduction; TBI Patients; TREM2 gene; Tissues; Transgenic Mice; Traumatic Brain Injury; age related; age related neurodegeneration; aged; aging brain; aging population; apolipoprotein E-4; cognitive function; disease phenotype; genetic risk factor; glial activation; human model; improved; injured; model organism; mouse model; neuroinflammation; neurological recovery; neuron loss; neuropathology; neurorestoration; neurotoxic; neutralizing antibody; novel therapeutic intervention; prevent; progressive neurodegeneration; receptor; response; synergism; young adult

Late-Onset Alzheimer’s Disease (LOAD) is the most common human neurodegenerative disease, however, a proper understanding of the underlaying processes as well as the availability and efficacy of disease-modifying interventions is severely lacking. LOAD within the human population is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes. The strongest genetic risk factors include the 4 allele of apolipoprotein E (APOE 4) and point mutations in triggering receptor expressed on myeloid cells 2 (TREM2) locus. Clinical studies have found that traumatic brain injury (TBI) was associated with an increased risk for subsequent development of LOAD. Microglia, the principal TREM2 expressing cell population in the brain undergo a persistent shift to activated phenotypes following TBI. We hypothesize that brain trauma is an important Late-Onset Alzheimer’s Disease environmental risk factor as TBI-induced chronic microglia dysregulation/neuroinflammation is a highly effective and common trigger for the development of LOAD neuropathology with progressive tissue loss and cognitive decline. Thus, the combined effects of genetic risk factors and TBI synergize to create an efficient and accelerated LOAD phenotype. Elderly individuals are particularly vulnerable to traumatic TBI, and numerous studies report clinically worse outcomes in elderly TBI patients. The aged are also the group most affected by LOAD. Unfortunately, research on the underlying mechanisms responsible for worse outcomes in elderly TBI patients and for the potential role of brain trauma in the initiation and progression of Late-Onset Alzheimer’s Disease is limited. Microglial activation is a key secondary injury mechanism and are chronically activated for months-to-years following TBI in humans and animal models; they appear to contribute to late neurodegeneration and related neurological deficits, including Alzheimer’s disease. We have observed the presence of a specific microglia activated phenotype, disease-associated microglia (DAM) during the chronic phase of injury. Importantly, DAMs have also been observed in aged brain and age-related neurodegenerative disorders, such as Alzheimer’s disease. Our data show that TBI-induced DAM-related genes are significantly elevated in the aged brain compared to young and hypothesize that the amplification of these responses by aging may trigger Alzheimer’s neuropathology in a transgenic mouse model (APOE4/Trem2*R47H) that includes two of the most important genetic risk factors for clinical LOAD. Type I IFNs (IFN-I) are key regulators of the host anti-viral response but have also been shown to contribute to neuroinflammation during aging and neurodegenerative disorders, including Alzheimer’s disease. Our published studies showed that inhibition of IFN-I was associated with a significant reduction in neuroinflammation, neurological dysfunction and neurodegeneration after TBI. Our most recent article demonstrated excessive IFN-I gene expression in response to TBI in aged animals compared to young mice. This amplified IFN-I activity may be responsible for the enhanced neurodegeneration and exacerbated neurological outcomes in the elderly after TBI. Evidence from studies using the APOE4/Trem2*R47H mice show that even in the presence of two of the most prevalent genetic risk factors for LOAD, there is only modest evidence for Alzheimer’s Disease neuropathology. We propose that an explanation for these findings is the need for additional environmental factors which are necessary to trigger LOAD and that brain trauma plays this role in a significant number of patients. Only when both genetic and TBI elements are present the effective initiation and progression of LOAD disease processes can take place. We hypothesize that TBI-activation of IFN-I, further elevated by aging induces the DAM phenotype and associated impairments of phagocytosis triggers strong Alzheimer’s Disease neuropathology in APOE4/Trem2*R47H aged animals. We propose that inhibition of IFN-I will attenuate DAM promoting a return to restorative states such as the homeostatic phenotype that enhance neurorepair and limits the development of LOAD neurodegeneration. Specific aims include: 1) Determine if inhibition of IFN-I signaling reduces DAM phenotype, promotes neurorestorative microglia and attenuates the development of Alzheimer’s disease neurodegeneration in a model that combines priming genetic risk factors APOEε4 and Trem2*R47H with TBI; and 2) Investigate whether microglial-specific inhibition of IFN-I signaling attenuates TBI-induced Alzheimer’s disease neurodegeneration by restoring microglia neurorepair phenotypes reducing neuronal loss and limiting the age-related acceleration of these processes.

但是，晚期发作的阿尔茨海默氏病（负载）是最常见的人类神经退行性疾病，但是，严重缺乏对基础过程以及改良疾病改良干预措施的可用性和有效性的适当理解。人口内的负载是一种多基因且受环境影响的疾病，其中许多危险因素共同起作用，以产生疾病过程。强大的遗传危险因素包括4载脂蛋白E（APOE 4）的等位基因和在髓样细胞2（TREM2）基因座上表达的受体中的点突变。临床研究发现，创伤性脑损伤（TBI）与随后的负荷发展的风险增加有关。小胶质细胞，表达大脑中细胞群体的主TREM2经历了TBI后向激活的表型的持续转变。我们假设脑创伤是一个重要的晚期阿尔茨海默氏病环境危险因素，因为TBI诱导的慢性小胶质细胞失调/神经炎症是导致负载神经病理学的高度有效且常见的触发因素，其累积性组织丧失和认知能力下降。这，遗传危险因素和TBI的综合作用协同创造了有效且加速的负载表型。老年人特别容易受到创伤性TBI的攻击，许多研究报告说，古老的TBI患者的临床结果较差。老年人也是受负载影响最大的组。不幸的是，对造成古老TBI患者预后差的基本机制以及脑创伤在晚期阿尔茨海默氏病的倡议和进展中的潜在作用的研究是有限的。 小胶质细胞激活是一种关键的继发性损伤机制，在人类和动物模型中TBI之后，长期激活了一个月。它们似乎有助于神经退行性的晚期和相关的神经系统缺陷，包括阿尔茨海默氏病。我们已经观察到在慢性损伤期间存在特定的小胶质细胞活化表型，与疾病相关的小胶质细胞（DAM）。重要的是，在老年大脑和与年龄有关的神经退行性疾病（例如阿尔茨海默氏病）中也观察到大坝。我们的数据表明，与年轻人相比，老年大脑中TBI诱导的与大脑相关的基因显着升高，并假设通过衰老对这些反应进行扩增可能会触发阿尔茨海默氏症的神经病理学在转基因小鼠模型（APOE4/trem2*r47H）中，其中包括临床载荷的两个最重要的遗传风险因素。 I型IFN（IFN-I）是宿主抗病毒反应的关键调节剂，但也已证明在包括阿尔茨海默氏病在内的衰老和神经退行性疾病期间有助于神经炎症。我们发表的研究表明，对IFN-I的抑制与TBI后神经炎症，神经功能障碍和神经变性的显着降低有关。我们最近的文章表明，与年轻小鼠相比，年龄动物中TBI的IFN-I基因表达过多。这种扩增的IFN-I活性可能导致TBI后的神经变性增强和加剧的神经系统结局。 使用APOE4/TREM2*R47H小鼠的研究的证据表明，即使存在两个最普遍的负载遗传危险因素，也只有阿尔茨海默氏病神经病理学的适度证据。我们建议对这些发现的解释是需要触发负荷所必需的其他环境因素，并且脑创伤在大量患者中起着这种作用。只有当存在遗传和TBI元素时，才有有效的倡议和负荷疾病过程的进展。 我们假设IFN-I的TBI激活通过衰老而进一步提高了吞噬作用的大坝表型和相关的损害，诱导了APOE4/TREM2*R47H年龄动物的强烈阿尔茨海默氏病神经病理。我们建议抑制IFN-I会减弱大坝，以促进恢复恢复状态，例如增强神经卫星的体内平衡表型，并限制了负载神经变性的发展。 具体目的包括：1）确定对IFN-I信号传导的抑制是否减少了大坝的表型，促进神经抑制小胶质细胞并减弱在结合启动遗传风险因素APOEε4和TREM2*R47H与TBI的模型中，降低了阿尔茨海默氏病神经变性的发展； 2）研究IFN-I信号传导的小胶质细胞特异性抑制是否会减弱TBI诱导的阿尔茨海默氏病神经退行性变性，通过恢复小胶质细胞神经培养表型减少神经元损失并限制了这些过程年龄相关的加速度。