Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.

Intronic G4C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly (GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS, we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1ß, and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits, and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.

Anxiolytic effects of NLRP3 inflammasome inhibition in a model of chronic sleep deprivation.

Sleep deprivation is a form of stress that provokes both inflammatory responses and neuropsychiatric disorders. Because persistent inflammation is implicated as a physiological process in anxiety disorders, we investigated the contributions of NLRP3 inflammasome signaling to anxiety and anxiolytic properties of flavanol diets in a model of chronic sleep deprivation. The results show a flavanol-rich dietary preparation (FDP) exhibits anxiolytic properties by attenuating markers of neuroimmune activation, which included IL-1ß upregulation, NLRP3 signaling, and microglia activation in the cortex and hippocampus of sleep-deprived mice. Production of IL-1ß and NLRP3 were critical for both anxiety phenotypes and microglia activation. Individual FDP metabolites potently inhibited IL-1ß production from microglia following stimulation with NLRP3-specific agonists, supporting anxiolytic properties of FDP observed in models of sleep deprivation involve inhibition of the NLRP3 inflammasome. The study further showed sleep deprivation alters the expression of the circadian gene Bmal1, which critically regulated NLRP3 expression and IL-1ß production.

Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets.

Dysfunctional immune activity is a physiological component of both Alzheimer's disease (AD) and major depressive disorder (MDD). The extent to which altered immune activity influences the development of their respective cognitive symptoms and neuropathologies remains under investigation. It is evident, however, that immune activity affects neuronal function and circuit integrity. In both disorders, alterations are present in similar immune networks and neuroendocrine signalling pathways, immune responses persist in overlapping neuroanatomical locations, and morphological and structural irregularities are noted in similar domains. Epidemiological studies have also linked the two disorders, and their genetic and environmental risk factors intersect along immune-activating pathways and can be synonymous with one another. While each of these disorders individually contains a large degree of heterogeneity, their shared immunological components may link distinct phenotypes within each disorder. This review will therefore highlight the shared immune pathways of AD and MDD, their overlapping neuroanatomical features, and previously applied, as well as novel, approaches to pharmacologically manipulate immune pathways, in each neurological condition. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping pathomechanisms, neurobehavioral features, and genetic etiologies. Individuals diagnosed with either disorder exhibit symptoms within a clinical spectrum. Symptoms of ALS involve neuromusculature deficits, reflecting upper and lower motor neurodegeneration, while the primary clinical features of FTD are behavioral and cognitive impairments, reflecting frontotemporal lobar degeneration. An intronic G4C2 hexanucleotide repeat expansion (HRE) within the promoter region of chromosome 9 open reading frame 72 (C9orf72) is the predominant monogenic cause of both ALS and FTD. While the heightened risk to develop ALS/FTD in response to C9orf72 expansions is well-established, studies continue to define the precise mechanisms by which this mutation elicits neurodegeneration. Studies show that G4C2 expansions undergo repeat-associated non-ATG dependent (RAN) translation, producing dipeptide repeat proteins (DRPs) with varying toxicities. Accumulation of DRPs in neurons, in particular arginine containing DRPs, have neurotoxic effects by potently impairing nucleocytoplasmic transport, nucleotide metabolism, lysosomal processes, and cellular metabolic pathways. How these pathophysiological effects of C9orf72 expansions engage and elicit immune activity with additional neurobiological consequences is an important line of future investigations. Immunoreactive microglia and elevated levels of peripheral inflammatory cytokines noted in individuals with C9orf72 ALS/FTD provide evidence that persistent immune activation has a causative role in the progression of each disorder. This review highlights the current understanding of the cellular, proteomic and genetic substrates through which G4C2 HREs may elicit detrimental immune activity, facilitating region-specific neurodegeneration in C9orf72 mediated ALS/FTD. We in particular emphasize interactions between intracellular pathways induced by C9orf72 expansions and innate immune inflammasome complexes, intracellular receptors responsible for eliciting inflammation in response to cellular stress. A further understanding of the intricate, reciprocal relationship between the cellular and molecular pathologies resulting from C9orf72 HREs and immune activation may yield novel therapeutics for ALS/FTD, which currently have limited treatment strategies.

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders.

The production of inflammatory proteins by the innate immune system is a tightly orchestrated procedure that allows the body to efficiently respond to exogenous and endogenous threats. Recently, accumulating evidence has indicated that disturbances in the inflammatory response system not only provoke autoimmune disorders, but also can have deleterious effects on neuronal function and mental health. As inflammation in the brain is primarily mediated by microglia, there has been an expanding focus on the mechanisms through which these cells initiate and propagate neuroinflammation. Microglia can enter persistently active states upon their initial recognition of an environmental stressor and are thereafter prone to elicit amplified and persistent inflammatory responses following subsequent exposures to stressors. A recent focus on why primed microglia cells are susceptible to environmental insults has been the NLRP3 inflammasome. Its function within the innate immune system is regulated in such a manner that supports a role for the complex in gating neuroinflammatory responses. The activation of NLRP3 inflammasome in microglia results in the cleavage of zymogen inflammatory interleukins into functional forms that elicit a number of consequential effects in the local neuronal environment. There is evidence to support the principle that within primed neuroimmune systems a lowered threshold for NLRP3 activation can cause persistent neuroinflammation or the amplified production of inflammatory cytokines, such as IL-1ß and IL-18. Over the course of an individual's lifetime, persistent neuroinflammation can subsequently lead to the pathophysiological signatures that define psychological disorders. Therefore, targeting the NLRP3 inflammasome complex may represent an innovative and consequential approach to limit neuroinflammatory states in psychiatric disorders, such as major depressive disorder.