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.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and ...microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the
LGALS3
gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.
Activated microglia can phagocytose dying, stressed, or excess neurons and synapses via the phagocytic receptor Mer tyrosine kinase (MerTK). Galectin-3 (Gal-3) can cross-link surface glycoproteins by ...binding galactose residues that are normally hidden below terminal sialic acid residues. Gal-3 was recently reported to opsonize cells via activating MerTK. We found that LPS-activated BV-2 microglia rapidly released Gal-3, which was blocked by calcineurin inhibitors. Gal-3 bound to MerTK on microglia and to stressed PC12 (neuron-like) cells, and it increased microglial phagocytosis of PC12 cells or primary neurons, which was blocked by inhibition of MerTK. LPS-activated microglia exhibited a sialidase activity that desialylated PC12 cells and could be inhibited by Tamiflu, a neuraminidase (sialidase) inhibitor. Sialidase treatment of PC12 cells enabled Gal-3 to bind and opsonize the live cells for phagocytosis by microglia. LPS-induced microglial phagocytosis of PC12 was prevented by small interfering RNA knockdown of Gal-3 in microglia, lactose inhibition of Gal-3 binding, inhibition of neuraminidase with Tamiflu, or inhibition of MerTK by UNC569. LPS-induced phagocytosis of primary neurons by primary microglia was also blocked by inhibition of MerTK. We conclude that activated microglia release Gal-3 and a neuraminidase that desialylates microglial and PC12 surfaces, enabling Gal-3 binding to PC12 cells and their phagocytosis via MerTK. Thus, Gal-3 acts as an opsonin of desialylated surfaces, and inflammatory loss of neurons or synapses may potentially be blocked by inhibiting neuraminidases, Gal-3, or MerTK.
Neither any neuroprotective drug has been shown to be beneficial in improving the outcome of severe traumatic brain injury (TBI) nor has any prophylactically-induced moderate hypothermia shown any ...beneficial effect on outcome in severe TBI, despite the optimism generated by preclinical studies. This contrasts with the paradox that hypothermia still is the most powerful neuroprotective method in experimental models because of its ability to influence the multiple biochemical cascades that are set in motion after TBI. The aim of this short review is to highlight the most recent developments concerning the pathophysiology of severe TBI, to review new data on thermoregulation and induced hypothermia, the regulation of core and brain temperature in mammals and the multiplicity of effects of hypothermia in the pathophysiology of TBI. Many experimental studies in the last decade have again confirmed that moderate hypothermia confers protection against ischemic and non-ischemic brain hypoxia, traumatic brain injury, anoxic injury following resuscitation after cardiac arrest and other neurological insults. Many posttraumatic adverse events that occur in the injured brain at a cellular and molecular level are highly temperature-sensitive and are thus a good target for induced hypothermia. The basic mechanisms through which hypothermia protects the brain are clearly multifactorial and include at least the following: reduction in brain metabolic rate, effects on cerebral blood flow, reduction of the critical threshold for oxygen delivery, blockade of excitotoxic mechanisms, calcium antagonism, preservation of protein synthesis, reduction of brain thermopooling, a decrease in edema formation, modulation of the inflammatory response, neuroprotection of the white matter and modulation of apoptotic cell death. The new developments discussed in this review indicate that, by targeting many of the abnormal neurochemical cascades initiated after TBI, induced hypothermia may modulate neurotoxicity and, consequently, may play a unique role in opening up new therapeutic avenues for treating severe TBI and improving its devastating effects. Furthermore, greater understanding of the pathophysiology of TBI, new data from both basic and clinical research, the good clinical results obtained in randomized clinical trials in cardiac arrest and better and more reliable cooling methods have given hypothermia a second chance in treating TBI patients. A critical evaluation of hypothermia is therefore mandatory to elucidate the reasons for previous failures and to design further multicenter randomized clinical trials that would definitively confirm or refute the potential of this therapeutic modality in the management of severe traumatic brain injuries.
Microglia are resident brain macrophages, which can cause neuronal loss when activated in infectious, ischemic, traumatic, and neurodegenerative diseases. Caspase-8 has both prodeath and prosurvival ...roles, mediating apoptosis and/or preventing RIPK1-mediated necroptosis depending on cell type and stimulus. We found that inflammatory stimuli (LPS, lipoteichoic acid, or TNF-α) caused an increase in caspase-8 IETDase activity in primary rat microglia without inducing apoptosis. Inhibition of caspase-8 with either Z-VAD-fmk or IETD-fmk resulted in necrosis of activated microglia. Inhibition of caspases with Z-VAD-fmk did not kill non-activated microglia, or astrocytes and neurons in any condition. Necrostatin-1, a specific inhibitor of RIPK1, prevented microglial caspase inhibition-induced death, indicating death was by necroptosis. In mixed cerebellar cultures of primary neurons, astrocytes, and microglia, LPS induced neuronal loss that was prevented by inhibition of caspase-8 (resulting in microglial necroptosis), and neuronal death was restored by rescue of microglia with necrostatin-1. We conclude that the activation of caspase-8 in inflamed microglia prevents their death by necroptosis, and thus, caspase-8 inhibitors may protect neurons in the inflamed brain by selectively killing activated microglia.
Background: Caspase-8 signaling can mediate apoptosis or survival depending on the cellular context.
Results: Inflamed microglia survive because of caspase-dependent suppression of RIPK1-mediated necroptosis for survival.
Conclusion: Caspase inhibition rescues neurons by triggering necroptosis of neurotoxic inflamed microglia.
Significance: We demonstrate a novel neuroprotective mechanism of caspase inhibitors, namely killing of neurotoxic microglia by necroptosis.
Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the ...central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPARγ agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPARγ agonists. Leriglitazone is a novel, blood-brain barrier (BBB)-penetrant PPARγ agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPARγ in physiology and pathophysiology in the CNS, describe the mechanism of action of PPARγ agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases.
Traumatic brain injury (TBI) is currently a major cause of morbidity and poor quality of life in Western society, with an estimate of 2.5 million people affected per year in Europe, indicating the ...need for advances in TBI treatment. Within the first 24 h after TBI, several inflammatory response factors become upregulated, including the lectin galectin-3. In this study, using a controlled cortical impact (CCI) model of head injury, we show a large increase in the expression of galectin-3 in microglia and also an increase in the released form of galectin-3 in the cerebrospinal fluid (CSF) 24 h after head injury. We report that galectin-3 can bind to TLR-4, and that administration of a neutralizing antibody against galectin-3 decreases the expression of IL-1β, IL-6, TNFα and NOS2 and promotes neuroprotection in the cortical and hippocampal cell populations after head injury. Long-term analysis demonstrated a significant neuroprotection in the cortical region in the galectin-3 knockout animals in response to TBI. These results suggest that following head trauma, released galectin-3 may act as an alarmin, binding, among other proteins, to TLR-4 and promoting inflammation and neuronal loss. Taking all together, galectin-3 emerges as a clinically relevant target for TBI therapy.
Microglia are implicated in neurodegeneration, potentially by phagocytosing neurons, but it is unclear how to block the detrimental effects of microglia while preserving their beneficial roles. The ...microglial P2Y6 receptor (P2Y6R) – activated by extracellular UDP released by stressed neurons – is required for microglial phagocytosis of neurons. We show here that injection of amyloid beta (Aβ) into mouse brain induces microglial phagocytosis of neurons, followed by neuronal and memory loss, and this is all prevented by knockout of P2Y6R. In a chronic tau model of neurodegeneration (P301S TAU mice), P2Y6R knockout prevented TAU-induced neuronal and memory loss. In vitro, P2Y6R knockout blocked microglial phagocytosis of live but not dead targets and reduced tau-, Aβ-, and UDP-induced neuronal loss in glial-neuronal cultures. Thus, the P2Y6 receptor appears to mediate Aβ- and tau-induced neuronal and memory loss via microglial phagocytosis of neurons, suggesting that blocking this receptor may be beneficial in the treatment of neurodegenerative diseases.
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•P2Y6R knockout prevents microglial phagocytosis of stressed-but-viable cells•P2Y6R knockout does not alter microglial phagocytosis of healthy or dead cells•P2Y6R knockout prevents microglial phagocytosis of neurons induced by Aβ in vivo•P2Y6R knockout reduces neuronal loss and memory deficits induced by Aβ or Tau in mice
Puigdellívol et al. find that the knockout of the microglial P2Y6 receptor, required for microglial engulfment of neurons, prevents neuronal and memory loss in two different mouse models of neurodegeneration, suggesting that neuronal loss in neurodegeneration is due to microglia eating neurons, which may be prevented by blocking the P2Y6 receptor.
Objective
This study aimed to assess the association of somatic depressive symptoms (SDS), cognitive/emotional depressive symptoms (C-EDS), and antidepressant treatment on mortality due to cancer and ...other causes in a community cohort.
Methods
A community-based sample recruited in 1995, 2000, and 2005 aged between 35 and 75 years was examined in two waves and followed for a median of 6.7 years. SDS and C-EDS phenotypes were assessed using the Patient Health Questionnaire-9. Medication used by participants was collected. Deaths and their causes were registered during follow-up. Cox proportional hazard models stratified by sex were performed to determine the association between depressive phenotypes and mortality.
Results
The cohort consisted of 5,646 individuals (53.9% women) with a mean age of 64 years (SD = 11.89). During the follow-up, 392 deaths were recorded, of which 27.8% were due to cancer. C-EDS phenotype was associated with an increased risk of cancer mortality in both men (HR = 2.23; 95% CI = 1.11–4.44) and women (HR = 3.69; 95% CI = 1.69–8.09), and SDS was significantly associated with non-cancer mortality in men (HR = 2.16; 95 CI % = 1.46–3.18). Selective serotonin reuptake inhibitors (SSRIs) were significantly associated with both cancer (HR = 2.78; 95% CI = 1.10–6.98) and non-cancer mortality (HR = 2.94; 95% CI = 1.76–4.90) only in the male population.
Conclusion
C-EDS phenotype was related to an increased risk of cancer mortality at 6 years. In addition, the use of SSRIs in the male population was associated with cancer and all-cause mortality.
Abstract
Inflammation may contribute to multiple brain pathologies. One cause of inflammation is lipopolysaccharide/endotoxin (LPS), the levels of which are elevated in blood and/or brain during ...bacterial infections, gut dysfunction and neurodegenerative diseases, such as Parkinson’s disease. How inflammation causes neuronal loss is unclear, but one potential mechanism is microglial phagocytosis of neurons, which is dependent on the microglial P2Y
6
receptor. We investigated here whether the P2Y
6
receptor was required for inflammatory neuronal loss. Intraperitoneal injection of LPS on 4 successive days resulted in specific loss of dopaminergic neurons (measured as cells staining with tyrosine hydroxylase or NeuN) in the
substantia nigra
of wild-type mice, but no neuronal loss in cortex or hippocampus. This supports the hypothesis that neuronal loss in Parkinson’s disease may be driven by peripheral LPS. By contrast, there was no LPS-induced neuronal loss in P2Y
6
receptor knockout mice. In vitro, LPS-induced microglial phagocytosis of cells was prevented by inhibition of the P2Y
6
receptor, and LPS-induced neuronal loss was reduced in mixed glial–neuronal cultures from P2Y
6
receptor knockout mice. This supports the hypothesis that microglial phagocytosis contributes to inflammatory neuronal loss, and can be prevented by blocking the P2Y
6
receptor, suggesting that P2Y
6
receptor antagonists might be used to prevent inflammatory neuronal loss in Parkinson’s disease and other brain pathologies involving inflammatory neuronal loss.
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