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

晚发性阿尔茨海默病(LOAD)是人类最常见的神经退行性疾病，但对其发病过程以及疾病干预措施的有效性和有效性尚缺乏正确的认识。人类人口中的负荷是一种多基因和受环境影响的疾病，有许多危险因素共同作用，产生疾病过程。最大的遗传危险因素包括载脂蛋白E的4等位基因(4)和髓系细胞表达的受体2(TREM2)基因座的点突变。临床研究发现，创伤性脑损伤(TBI)与随后发生LOAD的风险增加有关。小胶质细胞是脑内表达TREM2的主要细胞群，在脑损伤后经历持续的向激活表型的转变。我们假设脑创伤是迟发性阿尔茨海默病的重要环境风险因素，因为脑损伤引起的慢性小胶质细胞调节失调/神经炎症是导致进行性组织丢失和认知功能下降的负荷神经病理的高效和常见的触发因素。因此，遗传风险因素和脑外伤的综合作用共同创造了一种有效和加速的负荷表型。老年人特别容易受到创伤性脑损伤的影响，许多研究报告称，老年脑外伤患者的临床预后较差。老年人也是受负荷影响最大的群体。不幸的是，关于老年脑外伤患者预后较差的潜在机制以及脑损伤在迟发性阿尔茨海默病的发生和发展中的潜在作用的研究有限。 在人类和动物模型中，小胶质细胞的激活是一个关键的继发性损伤机制，在脑损伤后几个月到几年内长期激活；它们似乎导致晚期神经退行性变和相关的神经功能障碍，包括阿尔茨海默病。我们观察到一种特殊的小胶质细胞激活表型，疾病相关小胶质细胞(DAM)在慢性损伤阶段的存在。重要的是，在老年脑和与年龄相关的神经退行性疾病，如阿尔茨海默病中也观察到了水坝。我们的数据显示，与年轻人相比，脑损伤诱导的DAM相关基因在老年人中显著升高，并假设这些反应的放大可能在转基因小鼠模型(APOE4/TREM2*R47H)中引发阿尔茨海默病神经病理，该模型包括临床负荷的两个最重要的遗传风险因素。 I型干扰素(IFN-I)是宿主抗病毒反应的关键调节因子，但也被证明在衰老过程中导致神经炎症和神经退行性疾病，包括阿尔茨海默病。我们已发表的研究表明，抑制干扰素-I与脑创伤后神经炎症、神经功能障碍和神经变性的显著减少有关。我们最新的文章显示，与年轻小鼠相比，老年动物在脑损伤后过量表达干扰素-I基因。这种被放大的干扰素-I活性可能是老年人脑外伤后神经退行性变加剧和神经预后恶化的原因。 使用APOE4/TREM2*R47H小鼠进行的研究的证据表明，即使存在两个最常见的负荷遗传风险因素，也只有少量证据表明阿尔茨海默病的神经病理。我们认为，对这些发现的解释是，需要额外的环境因素来触发负荷，而脑损伤在相当数量的患者中扮演着这种角色。只有当遗传因素和脑损伤因素同时存在时，才能有效地启动和发展负荷性疾病过程。 我们假设，在APOE4/TREM2*R47H老年动物中，干扰素-I的TBI激活，随着年龄的增加，进一步升高，诱导了DAM表型和相关的吞噬功能障碍，触发了强烈的阿尔茨海默病神经病理。我们认为，抑制干扰素-I将减轻DAM，促进恢复状态的恢复，如促进神经修复并限制负荷性神经变性的发展的动态平衡表型。 具体目标包括：1)在一个结合了启动遗传风险因子APOEε4和TREM2*R47H与脑损伤的模型中，确定抑制干扰素-I信号是否减少了DAM的表型、促进了神经恢复性的小胶质细胞和延缓了阿尔茨海默病神经变性的发展；以及2)研究小胶质细胞特异性抑制干扰素-I信号是否通过恢复小胶质细胞神经修复表型、减少神经元损失和限制这些过程的年龄相关加速来减轻脑损伤所致的阿尔茨海默病神经变性。

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.