Targeting Type I IFN Signaling to Promote Recovery Following Brain Trauma in Aged Animals

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 APOEe4 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.