Abrogation of type-I interferon signalling alters the microglial response to Aβ1–42

Abstract

Neuroinflammation and accompanying microglial dysfunction are now appreciated to be involved in Alzheimer's disease (AD) pathogenesis. Critical to the process of neuroinflammation are the type-I interferon (IFN) family of cytokines. Efforts to phenotypically characterize microglia within AD identify distinct populations associated with type-I IFN signalling, yet how this affects underlying microglial function is yet to be fully elucidated. Here we demonstrate that Aβ 1-42 exposure increases bioactive levels of type-I IFN produced by primary microglia alongside increased expression of type-I IFN related genes. primary microglia isolated from brains of App swe PS1 ΔE9 mice with ablated type-I IFN signalling show an increased phagocytic ability to uptake FITC-Aβ 1-42 . Correlative assessment of plaque sizes in aged App swe PS1 ΔE9 mice with abrogated type-I IFN signalling show unchanged deposition levels. Microglia from these mice did however show alterations in morphology. This data further highlights the role of type-I IFN signalling within microglia and identifies a role in phagocytosis. As such, targeting both microglial and global type-I IFN signalling presents as a novel therapeutic strategy for AD management.Alzheimer's disease (AD) is now recognised as the most common form of dementia and is now estimated to be the 5 th largest cause of death globally 1 . AD has been classically characterised by its two hallmark pathologies, neurofibrillary tangles composed of hyper phosphorylated tau, and extracellular senile plaques composed of amyloid beta (Aβ). The immune response to these pathologies, neuroinflammation is now appreciated to be involved in disease progression. Regulated forms of neuroinflammation are viewed as protective, and indeed required for homeostatic function. In contrast, a dysregulated form of this process is present in AD 2 . This dysregulated form is now recognised as a contributor to AD pathogenesis.Fundamental to this neuroinflammation are microglia, the resident innate immune cells within the central nervous system (CNS). Critically, microglia mount the initial neuroinflammatory response and further maintain it 3 . Upon recognition of noxious stimuli, microglia release a number of cytokines including interleukin (IL) 1β, IL6, and tumor necrosis factor alpha (TNFα) to create an inflammatory microenvironment 4 . This is seen in conjunction with chemokine secretion to recruit additional microglia. Microglia also have a number of roles outside immune-related functions. In particular, microglia are often viewed as macrophages of the CNS due to a shared hierarchal lineage and roles in phagocytosis 5 .Due to diverse roles, microglia adopt a number of varied phenotypes with differential corresponding functions throughout the CNS. As such, large efforts have been made to better phenotypically characterize microglia under both normal and AD settings, primarily through transcriptomic-based approaches 6,7 . In the 5× familial AD mouse model, a single cell ribonucleic acid (RNA) -seq approach was used t...

Type I interferon responsive microglia shape cortical development and behavior

“…Furthermore, we identify and characterize a distinct IFITM3+ microglial subset in situ that associates with Aβ plaques in the 5xFAD model of Alzheimer’s disease. This is consistent with multiple reports of IFN-I involvement in aging and Alzheimer’s disease 67,76,89,90,116,117 , and suggests potential roles for an IFN-I induced cell state in regulating Aβ deposition. Determining the mechanisms of microglial engulfment during cortical development and in pathology may enable therapeutics to target specific phases of the phagocytic cycle while preserving microglial homeostatic function.…”

Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression

“…Our refined analyses of microglia-associated changes at different stages of tauopathy suggest that early immune activation is accompanied by immune suppression, likely driven by the activation of IFN-β, and we provide multiple analyses supporting this model. Recent experimental data show that IFN receptor blockade reduces sustained microgliosis and synaptic clearance ( Roy et al, 2020 ), and IFN treatment inhibits microglial phagocytosis ( Mudò et al, 2019 ) and release of pro-inflammatory cytokines ( Moore et al, 2020 ). Here, we provide complementary evidence that IFN-β may also suppress genes involved in microglial immune clearance (NAct; including Il1b , CD74 , IL27ra , B2m , Fcer1g , Cd14 , Ptprc , Tlr2 , Trem2 , Cd68 , and Cxcr4 ) and drive genes that function in early immune suppression (NSupp; PD-L1 , Isg15 , Tgfbr2 , Usp18 , and Zc3h12a ; Mao et al, 2017 ).…”

Interferon-Driven Immune Dysregulation in Down Syndrome: A Review of the Evidence

“…Nucleic acid-containing amyloid fibrils can lead to microglial activation, microgliosis, and synapse loss. [89][90][91] Studies in the IFN-R knockout model have suggested that the IFN pathway plays a key role in the neuroinflammatory network in Alzheimer's disease. Future studies to identify the potential clinical and biological risk factors, such as interferon score, for early-onset Alzheimer's disease in DS will be beneficial not only to individuals with DS, but to society as a whole (Figure 3).…”