The endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer ...membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid β and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer's disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer's disease. Intestinal permeability increases early in Parkinson's disease, and injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson's disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.
It was previously thought that neurons were phagocytosed only when dead or dying. However, it is increasingly clear that viable synapses, dendrites, axons and whole neurons can be phagocytosed alive ...(defined here as neurophagy), and this may contribute to a wide range of developmental, physiological and pathological processes. Phagocytosis of live synapses, dendrites and axons by glia contributes to experience‐dependent sculpting of neuronal networks during development, but excessive phagocytosis of synapses may contribute to pathology in Alzheimer's disease, schizophrenia and ageing. Neurons can expose phosphatidylserine or calreticulin, which act as ‘eat me’ signals provoking phagocytosis via microglial receptors, whereas sialylation of neuronal surfaces acts as a ‘don't eat me’ signal that inhibits phagocytosis and desialylation can provoke phagocytosis. Opsonins, such as complement components and apolipoproteins, are released during inflammation and enhance engulfment. Phagocytosis of neurons is seen in multiple human diseases, but it is as yet unclear whether inhibition of phagocytosis will be beneficial in treating neurological diseases. Here we review the signals regulating glial phagocytosis of live neurons and synapses, and the involvement of this phagocytosis in development and disease.
Microglia or astrocytes can phagocytose neurons or their processes, thereby sculpting neuronal circuits during development. However, inflammation may drive excessive phagocytosis of otherwise‐viable synapses, dendrites, myelin or neurons during brain disease.
After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as 'selective neuronal loss', and in ...brain areas remote from, but connected to, the infarct, known as 'secondary neurodegeneration'. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release "find-me" signals such as ATP, (ii) expose "eat-me" signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons.
Living too long Brown, Guy C
EMBO reports,
02/2015, Letnik:
16, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Longer lifespans, often ending with multiple diseases, threaten the viability of social and health systems. Rather than prolonging life further, research and funding should focus on increasing the ...quality of life in old age.
Neuronal Cell Death Fricker, Michael; Tolkovsky, Aviva M; Borutaite, Vilmante ...
Physiological reviews,
04/2018, Letnik:
98, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate or be replaced. The concept ...of cell death used to be simple as there were just two or three types, so we just had to work out which type was involved in our particular pathology and then block it. However, we now know that there are at least a dozen ways for neurons to die, that blocking a particular mechanism of cell death may not prevent the cell from dying, and that non-neuronal cells also contribute to neuronal death. We review here the mechanisms of neuronal death by intrinsic and extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic cell death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, and mitochondrial permeability transition. We next explore the mechanisms of neuronal death during development, and those induced by axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity and oxytosis), loss of connected neurons, aggregated proteins and the unfolded protein response, oxidants, inflammation, and microglia. We then reassess which forms of cell death occur in stroke and Alzheimer's disease, two of the most important pathologies involving neuronal cell death. We also discuss why it has been so difficult to pinpoint the type of neuronal death involved, if and why the mechanism of neuronal death matters, the molecular overlap and interplay between death subroutines, and the therapeutic implications of these multiple overlapping forms of neuronal death.
How microglia kill neurons Brown, Guy C; Vilalta, Anna
Brain research,
12/2015, Letnik:
1628, Številka:
Pt B
Journal Article
Recenzirano
Abstract Microglia are resident brain macrophages that become inflammatory activated in most brain pathologies. Microglia normally protect neurons, but may accidentally kill neurons when attempting ...to limit infections or damage, and this may be more common with degenerative disease as there was no significant selection pressure on the aged brain in the past. A number of mechanisms by which activated microglia kill neurons have been identified, including: (i) stimulation of the phagocyte NADPH oxidase (PHOX) to produce superoxide and derivative oxidants, (ii) expression of inducible nitric oxide synthase (iNOS) producing NO and derivative oxidants, (iii) release of glutamate and glutaminase, (iv) release of TNFα, (v) release of cathepsin B, (vi) phagocytosis of stressed neurons, and (vii) decreased release of nutritive BDNF and IGF-1. PHOX stimulation contributes to microglial activation, but is not directly neurotoxic unless NO is present. NO is normally neuroprotective, but can react with superoxide to produce neurotoxic peroxynitrite, or in the presence of hypoxia inhibit mitochondrial respiration. Glutamate can be released by glia or neurons, but is neurotoxic only if the neurons are depolarised, for example as a result of mitochondrial inhibition. TNFα is normally neuroprotective, but can become toxic if caspase-8 or NF-κB activation are inhibited. If the above mechanisms do not kill neurons, they may still stress the neurons sufficiently to make them susceptible to phagocytosis by activated microglia. We review here whether microglial killing of neurons is an artefact, makes evolutionary sense or contributes in common neuropathologies and by what mechanisms. This article is part of a Special Issue entitled SI: Neuroprotection.
Cell death by phagocytosis Brown, Guy C
Nature reviews. Immunology,
02/2024, Letnik:
24, Številka:
2
Journal Article
Recenzirano
Cells can die as a consequence of being phagocytosed by other cells - a form of cell death that has been called phagotrophy, cell cannibalism, programmed cell removal and primary phagocytosis. ...However, these are all different manifestations of cell death by phagocytosis (termed 'phagoptosis' for short). The engulfed cells die as a result of cytotoxic oxidants, peptides and degradative enzymes within acidic phagolysosomes. Cell death by phagocytosis was discovered by Metchnikov in the 1880s, but was neglected until recently. It is now known to contribute to developmental cell death in nematodes, Drosophila and mammals, and is central to innate and adaptive immunity against pathogens. Cell death by phagocytosis mediates physiological turnover of erythrocytes and other leucocytes, making it the most abundant form of cell death in the mammalian body. Immunity against cancer is also partly mediated by macrophage phagocytosis of cancer cells, but cancer cells can also phagocytose host cells and other cancer cells in order to survive. Recent evidence indicates neurodegeneration and other neuropathologies can be mediated by microglial phagocytosis of stressed neurons. Thus, despite cell death by phagocytosis being poorly recognized, it is one of the oldest, commonest and most important forms of cell death.
Microglia, the brain's professional phagocytes, can remove dead and dying neurons as well as synapses and the processes of live neurons. However, we and others have recently shown that microglia can ...also execute neuronal death by phagocytosing stressed-but-viable neurons - a process that we have termed phagoptosis. In this Progress article, we discuss evidence suggesting that phagoptosis may contribute to neuronal loss during brain development, inflammation, ischaemia and neurodegeneration.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Phagoptosis, also called primary phagocytosis, is a recently recognised form of cell death caused by phagocytosis of viable cells, resulting in their destruction. It is provoked by exposure of ...‘eat-me’ signals and/or loss of ‘don’t-eat-me’ signals by viable cells, causing their phagocytosis by phagocytes. Phagoptosis mediates turnover of erythrocytes, neutrophils and other cells, and thus is quantitatively one of the main forms of cell death in the body. It defends against pathogens and regulates inflammation and immunity. However, recent results indicate that inflamed microglia eat viable brain neurons in models of neurodegeneration, and cancer cells can evade phagocytosis by expressing a ‘don’t-eat-me’ signal, suggesting that too much or too little phagoptosis can contribute to pathology. This review provides an overview of the molecular signals that regulate phagoptosis and the physiological and pathological circumstances in which it has been observed.