Explore the vast range of titles available.

Key Points Microglia are involved in the communication of systemic inflammation to the brain Microglia become primed by systemic inflammation or neurodegeneration The exaggerated response of primed microglia to systemic inflammation contributes to the pathogenesis of neurodegenerative disease Modulation of systemic inflammation offers novel strategies in the prevention and therapy of neurodegenerative disease As a response to accumulation of debris and abnormally folded proteins during neurodegeneration, microglia multiply and adopt a chronically activated state. This process, referred to as priming, makes microglia susceptible to a secondary inflammatory stimulus, often arising from a systemic disorder with an inflammatory component, such as diabetes. Primed microglia react to the secondary inflammatory stimulus with an exaggarated response, which can further exacerbate neurodegeneration. Under physiological conditions, the number and function of microglia—the resident macrophages of the CNS—is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state—a process referred to as priming. Studies using preclinical animal models have shown that priming of microglia is driven by changes in their microenvironment and the release of molecules that drive their proliferation. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component. The concept of microglial priming, and the subsequent exaggerated response of these cells to secondary systemic inflammation, opens the way to treat neurodegenerative diseases by targeting systemic disease or interrupting the signalling pathways that mediate the CNS response to systemic inflammation. Both lifestyle changes and pharmacological therapies could, therefore, provide efficient means to slow down or halt neurodegeneration.

Microglia, the resident immune cells of the central nervous system (CNS), play an important role in CNS homeostasis during development, adulthood and ageing. Their phenotype and function have been widely studied, but most studies have focused on their local interactions in the CNS. Microglia are derived from a particular developmental niche, are long-lived, locally replaced and form a significant part of the communication route between the peripheral immune system and the CNS; all these components of microglia biology contribute to maintaining homeostasis. Microglia function is tightly regulated by the CNS microenvironment, and increasing evidence suggests that disturbances, such as neurodegeneration and ageing, can have profound consequences for microglial phenotype and function. We describe the possible biological mechanisms underlying the altered threshold for microglial activation, also known as ‘microglial priming’, seen in CNS disease and ageing and consider how priming may contribute to turning immune-to-brain communication from a homeostatic pathway into a maladaptive response that contributes to symptoms and progression of diseases of the CNS.

Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation.

Systemic infection or inflammation gives rise to signals that communicate with the brain and leads to changes in metabolism and behaviour collectively known as sickness behaviour. In healthy young individuals, these changes are normally transient with no long-term consequences. The microglia are involved in the immune to brain signalling pathways. In the aged or diseased brain, the microglia have a primed phenotype as a consequence of changes in their local microenvironment. Systemic inflammation impacts on these primed microglia and switches them from a relatively benign to an aggressive phenotype with the enhanced synthesis of pro-inflammatory mediators. Recent evidence suggests that systemic inflammation contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and may accelerate disease progression. The normal homeostatic role that microglia play in signalling about systemic infections and inflammation becomes maladaptive in the aged and diseased brain and this offers a route to therapeutic intervention. Prompt treatment of systemic inflammation or blockade of signalling pathways from the periphery to the brain may help to slow neurodegeneration and improve the quality of life for individuals suffering from chronic neurodegenerative disease.

The immune-system–brain interface is a crucial route for communication between the brain in health and disease and environmental pathogens and toxins. Can systemic infections and inflammation associated with chronic neurodegenerative diseases exacerbate symptoms and drive the progression of neurodegeneration? It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration.

Protein misfolding is common across many neurodegenerative diseases, with misfolded proteins acting as seeds for \"prion-like\" conversion of normally folded protein to abnormal conformations. A central hypothesis is that misfolded protein accumulation, spread, and distribution are restricted to specific neuronal populations of the central nervous system and thus predict regions of neurodegeneration. We examined this hypothesis using a highly sensitive assay system for detection of misfolded protein seeds in a murine model of prion disease. Misfolded prion protein (PrP) seeds were observed widespread throughout the brain, accumulating in all brain regions examined irrespective of neurodegeneration. Importantly, neither time of exposure nor amount of misfolded protein seeds present determined regions of neurodegeneration. We further demonstrate two distinct microglia responses in prion-infected brains: a novel homeostatic response in all regions and an innate immune response restricted to sites of neurodegeneration. Therefore, accumulation of misfolded prion protein alone does not define targeting of neurodegeneration, which instead results only when misfolded prion protein accompanies a specific innate immune response.

Background Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against overactivity of the immune system. In this study, we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection. Methods Mice were given repeated doses of lipopolysaccharide (LPS) or a single injection of live Salmonella typhimurium . Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry. To assess priming of the innate immune response in the brain, mice were infected with Salmonella typhimurium and subsequently challenged with a focal unilateral intracerebral injection of LPS. Results Repeated systemic LPS challenges resulted in increased brain IL-1β, TNF-α and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1β and IL-12 levels in Salmonella typhimurium -infected mice increased over three weeks, with high interferon-γ levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS four weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice. Conclusions These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have a profound effect on the onset and/or progression of pre-existing neurodegenerative disease.

In neuroscience it is a technical challenge to identify and follow the temporal and spatial distribution of cells as they differentiate. We hypothesised that RGB marking, the tagging of individual cells with unique hues resulting from simultaneous expression of the three basic colours red, green and blue, provides a convenient toolbox for the study of the CNS anatomy at the single-cell level. Using γ-retroviral and lentiviral vector sets we describe for the first time the in-vivo multicolour RGB marking of neurons in the adult brain. RGB marking also enabled us to track the spatial and temporal fate of neural stem cells in the adult brain. The application of different viral envelopes and promoters provided a useful approach to track the generation of neurons vs. glial cells at the neurogenic niche, allowing the identification of the prominent generation of new astrocytes to the striatum. Multicolour RGB marking could serve as a universal and reproducible method to study and manipulate the CNS at the single-cell level, in both health and disease.

Prion diseases are fatal neurodegenerative diseases of the CNS that are associated with the accumulation of misfolded cellular prion protein. There are several different strains of prion disease defined by different patterns of tissue vacuolation in the brain and disease time course, but features of neurodegeneration in these strains have not been extensively studied. Our previous studies using the prion strains ME7, 79A and 22L showed that infected mice developed behavioural deficits in the same sequence and temporal pattern despite divergent end-stage neuropathology. Here the objective was to address the hypothesis that synaptic loss would occur early in the disease in all three strains, would precede neuronal death and would be associated with the early behavioural deficits. C57BL/6 mice inoculated with ME7, 79A, or 22L-infected brain homogenates were behaviourally assessed on species typical behaviours previously shown to change during progression and euthanised when all three strains showed statistically significant impairment on these tasks. A decrease in labelling with the presynaptic marker synaptophysin was observed in the stratum radiatum of the hippocampus in all three strains, when compared to control animals. Negligible cell death was seen by TUNEL at this time point. Astrocyte and microglial activation and protease resistant prion protein (PrP(Sc)) deposition were assessed in multiple brain regions and showed some strain specificity but also strongly overlapping patterns. This study shows that despite distinct pathology, multiple strains lead to early synaptic degeneration in the hippocampus, associated with similar behavioural deficits and supports the idea that the initiation of synaptic loss is a primary target of the misfolded prion agent.

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer's disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signaling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease.