Recent advances in the mechanisms of neuroinflammation and their roles in neurodegeneration
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Abstract Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.
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A large body of experimental evidence suggests that neuroinflammation is a key pathological event triggering and perpetuating the neurodegenerative process associated with many neurological diseases. Therefore, different stimuli, such as lipopolysaccharide (LPS), are used to model neuroinflammation associated with neurodegeneration. By acting at its receptors, LPS activates various intracellular molecules, which alter the expression of a plethora of inflammatory mediators. These factors, in turn, initiate or contribute to the development of neurodegenerative processes. Therefore, LPS is an important tool for the study of neuroinflammation associated with neurodegenerative diseases. However, the serotype, route of administration, and number of injections of this toxin induce varied pathological responses. Thus, here, we review the use of LPS in various models of neurodegeneration as well as discuss the neuroinflammatory mechanisms induced by this toxin that could underpin the pathological events linked to the neurodegenerative process.
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Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency. Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1β expression in brain and cerebrospinal fluid from MS patients. Collectively, these data reveal a critical role for A20 in the control of microglia activation and neuroinflammation.
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The innate immune response is thought to exert a dichotomous role in the brain. Indeed, although molecules of the innate immune response can promote repair mechanisms, during neuroinflammatory processes many harmful mediators are also released. Signs
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Experimental studies of neuroinflammation in Alzheimer’s disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture human brain microglia in high purity for experimental studies were discussed. These methods were employed to isolate human microglia for investigation of a number of features of neuroinflammation, including activation phenotypes, neurotoxicity, responses to abnormal aggregated proteins such as amyloid beta, phagocytosis, and the effects of aging and disease on microglia cellular properties. In recent years, interest in human microglia and neuroinflammation has been renewed due to the identification of inflammation-related AD genetic risk factors, in particular the triggering receptor expressed on myeloid cells (TREM)-2. Because of the difficulties in developing effective treatments for AD, there has been a general need for greater understanding of the functions of microglia in normal and AD brains. While most experimental studies on neuroinflammation have employed rodent microglia, this review considered the role of human microglia in experimental studies. This review focused on the development of in vitro methodology for the culture of postmortem human microglia and the key findings obtained from experimental studies with these cells.
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Does neuroinflammation promote neurodegeneration? Does neurodegeneration promote neuroinflammation? Or, is the answer to both questions, yes? These questions have proven challenging to answer in patients with typical age-related neurodegenerative diseases in whom the onset of neuroinflammation and neurodegeneration are largely unknown. Patients recovering from diseases associated with abrupt-onset neuroinflammation, including rare forms of antibody-mediated encephalitis (AME) and common complications of novel coronavirus disease 2019 (COVID-19), provide a unique opportunity to untangle the relationship between neuroinflammation and neurodegeneration. This review explores the lessons learned from patients with AME and COVID-19.Persistent cognitive impairment is increasingly recognized in patients recovering from AME or COVID-19, yet the drivers of impairment remain largely unknown. Clinical observations, neuroimaging and biofluid biomarkers, and pathological studies imply a link between the severity of acute neuroinflammation, subsequent neurodegeneration, and disease-associated morbidity.Data from patients with AME and COVID-19 inform key hypotheses that may be evaluated through future studies incorporating longitudinal biomarkers of neuroinflammation and neurodegeneration in larger numbers of recovering patients. The results of these studies may inform the contributors to cognitive impairment in patients with AME and COVID-19, with potential diagnostic and therapeutic applications in patients with age-related neurodegenerative diseases.
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Purpose of review Does neuroinflammation promote neurodegeneration? Does neurodegeneration promote neuroinflammation? Or, is the answer to both questions, yes ? These questions have proven challenging to answer in patients with typical age-related neurodegenerative diseases in whom the onset of neuroinflammation and neurodegeneration are largely unknown. Patients recovering from diseases associated with abrupt-onset neuroinflammation, including rare forms of antibody-mediated encephalitis (AME) and common complications of novel coronavirus disease 2019 (COVID-19), provide a unique opportunity to untangle the relationship between neuroinflammation and neurodegeneration. This review explores the lessons learned from patients with AME and COVID-19. Recent findings Persistent cognitive impairment is increasingly recognized in patients recovering from AME or COVID-19, yet the drivers of impairment remain largely unknown. Clinical observations, neuroimaging and biofluid biomarkers, and pathological studies imply a link between the severity of acute neuroinflammation, subsequent neurodegeneration, and disease-associated morbidity. Summary Data from patients with AME and COVID-19 inform key hypotheses that may be evaluated through future studies incorporating longitudinal biomarkers of neuroinflammation and neurodegeneration in larger numbers of recovering patients. The results of these studies may inform the contributors to cognitive impairment in patients with AME and COVID-19, with potential diagnostic and therapeutic applications in patients with age-related neurodegenerative diseases.
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