Alzheimer’s disease (AD) and other tauopathies are neurodegenerative diseases characterised by the abnormal intracellular inclusions of hyperphosphorylated tau protein in neurons and/or glia. In AD, tau protein aggregation is accompanied by extracellular plaques of β-amyloid (Aβ) protein, protein pathologies which feature alongside prominent neuroinflammation. The innate immune response, the first line of defence against foreign pathogens, is emerging as a major contributor to the development of neurodegenerative disease. IFN-Is are soluble cytokines produced in the innate immune response which induce an antiviral transcriptional state via the regulation of several thousand ISGs. Activation of the IFN-I response is observed in the brain in AD and with age. The role of the IFN-I response in the development of Aβ protein pathology, has been well characterised, identifying Aβ as an agonist of the IFN-I pathway. Currently however, the role of IFN-I signalling in the progression of tau pathology has not been explored, and this forms the focus of this PhD thesis. My over-arching hypothesis is that the IFN-I response contributes to the development of tau pathology. I demonstrate that IFN-I promotes tau pathology in physiological cell systems and in vivo. In primary neural cultures, polyI:C, a synthetic analogue of viral nucleic acids, evoked a potent cytokine response that enhanced the seeded aggregation of tau in an IFN-I dependent manner. IFN-I induced vulnerability to seeded tau aggregation was intrinsic to neurons and could be prevented by pharmacological inhibitors. Finally, aged P301S-tau mice lacking Ifnar1, the receptor for IFN-I, had significantly reduced tau pathology compared to P301S-tau mice with intact IFN-I signalling. My results suggest that IFN-I plays a critical role in potentiating tau aggregation, identifying the IFN-I response as a potential therapeutic target in AD and other tauopathies.

Chapter 1 describes the background and rationale of this PhD thesis, including an introduction to AD, tauopathies, and innate immunity. It also contains a broad overview of inflammation in AD and the contributions of brain-resident innate immune cells, microglia, before focusing on the current understanding of the type-I IFN response in AD and tauopathies. Finally, I present the hypotheses examined in this thesis.

Chapter 2 describes the materials and methods used in this PhD thesis.

Chapter 3 describes studies conducted in primary neural cultures and organotypic hippocampal slice cultures to examine the effects of IFN-I signalling in a model of seeded tau aggregation. PolyI:C, an agonist of the IFN-I response, exacerbated the aggregation of tau in an IFN-I dependent manner. It also explores the contribution of glial cells in IFN-I driven seeded tau aggregation. Depletion of microglia and astrocytes showed that IFN-I induced vulnerability was intrinsic to neurons.

Chapter 4 describes a neuropathological investigation of tau pathology and neuroinflammation in murine models of tau pathology, including in mice with genetic depletion of IFNAR, the receptor for IFN-I. Examination of the cortical cytokine profile showed that tau pathology in P301S-tau mice was associated with an increase in proinflammatory cytokines relative to WT mice, however this was largely unaffected by the genetic depletion of IFNAR, with the exception of two IFN-I regulated cytokines. Hyperphosphorylated tau pathology, and seed-competent tau species were significantly reduced in the cerebral cortex and brainstem of aged Ifnar1^-/- P301S-tau mice relative to Ifnar1^+/+ P301S-tau mice. In contrast, microgliosis, astrogliosis, lifespan, and levels of sarcosyl insoluble tau were unchanged between groups. Cortical cytokine profile analysis was then conducted to examine neuroinflammation in a novel murine model of Aβ and tau pathology, in which Aβ, but not tau pathology, was associated with changes in the cytokine profile of ^AppNL-G-F x Mapt^P290S double KI mice.

Chapter 5 describes studies examining the effects of pharmacological inhibitors of the IFN-I response in primary neural cultures and in vivo. Both an α-IFNAR blocking antibody and a JAK1/JAK2 inhibitor, baricitinib, were able to prevent the IFN-I driven increase in seeded tau aggregation in neural cultures. Pilot studies of baricitinib administration to P301S-tau mice showed that whilst intraperitoneal administration was well tolerated, there appeared to be limited effects on ISG expression in the brain and spleen, restricting further interpretation of its effects on tau pathology.

Chapter 6 describes the key conclusions of this PhD thesis. This work suggests that there is a critical role for the IFN-I response in tau aggregation both ex vivo and in vivo, potentially identifying the IFN-I response as a therapeutic target of interest in AD and other tauopathies. Following a general discussion of how the findings relate to the current field, future directions for the work are presented.