The relationship between HIV-1 neuroinflammation, neurocognitive impairment and encephalitis pathology: A systematic review of studies investigating post-mortem brain tissue.

The activities of HIV-1 in the central nervous system (CNS) are responsible for a dysregulated neuroinflammatory response and the subsequent development of HIV-associated neurocognitive disorders (HAND). The use of post-mortem human brain tissue is pivotal for studying the neuroimmune mechanisms of CNS HIV infection. To date, numerous studies have investigated HIV-1-induced neuroinflammation in post-mortem brain tissue. However, from the commonly investigated studies in this line of research, it is not clear which neuroinflammatory markers are consistently associated with HIV neurocognitive impairment (NCI) and neuropathology (i.e., HIV-encephalitis, HIVE). Therefore, we conducted a systematic review of the association between neuroinflammation and NCI/HIVE from studies investigating post-mortem brain tissue. Our aim was to synthesise the published data to date to provide commentary on the most noteworthy markers that are associated with NCI/HIVE. PubMed, Scopus, and Web of Science databases were searched using a search protocol designed specifically for this study. Sixty-one studies were included that investigated the levels of inflammatory markers based on their gene and protein expression in association with NCI/HIVE. The findings revealed that the (1) transcript expressions of IL-1ß and TNF-α were consistently associated with NCI/HIVE, whereas CCL2 and IL-6 were commonly not associated with NCI/HIVE, (2) protein expressions of CD14, CD16, CD68, Iba-1, IL-1ß and TNF-α were consistently associated with NCI/HIVE, while CD45, GFAP, HLA-DR, IL-1 and IL-6 were commonly not associated with NCI/HIVE, and (3) gene and protein expressions of CNS IL-1ß and TNF-α were consistently associated with NCI/HIVE, while IL-6 was consistently not associated with NCI/HIVE. These markers highlight the commonly investigated markers in this line of research and elucidates the neuroinflammatory mechanisms in the HIV-1 brain that are involved in the pathophysiology of NCI/HIVE. These markers and related pathways should be investigated for the development of improved diagnostics, prognostics, and therapeutics of HAND.

Cerebral glucose hypometabolism and hypoperfusion of cingulate gyrus: an imaging biomarker of autoimmune encephalitis with psychiatric symptoms.

BACKGROUND: About 60% of autoimmune encephalitis (AE) patients present psychiatric symptoms, but the underlying mechanism remains unknown. This study examined the role of the cingulate cortex in such patients to identify predictive poor psychiatric factors. METHODS: In this study, 49 AE patients and 39 healthy controls were enrolled. AE patients were further divided into two groups based on the presence/absence of psychiatric symptoms. The ratio of the standardized uptake value (SUVR) and relative cerebral blood flow (rCBF) in different regions of the cingulate cortex were calculated through positron emission tomography-computed tomography (PET/CT) and arterial spin labeling (ASL) MRI, and the results were compared among the three groups. In addition, we followed-up on the psychiatric outcomes and identified the risk factors for poor psychiatric prognosis, focusing on the cingulate cortex. RESULTS: More than half of the AE patients (27/49) exhibited psychiatric symptoms. Agitation and thought blocking were typical psychiatric phenotypes, except for anti-glutamic acid decarboxylase 65 (GAD65) encephalitis, which mainly presented with catatonia and a depressed mood. AE patients with psychiatric symptoms experienced reduced metabolism and perfusion of the anterior cingulate cortex (ACC), midcingulate cortex (MCC), and posterior cingulate cortex (PCC). The SUVR of ACC can be used as an independent risk factor of poor psychiatric outcomes, which had an area under the ROC curve (AUC) of 0.865. CONCLUSION: Impaired cingulate cortex function in AE may be the potential mechanism of psychiatric symptoms. Hypometabolism of ACC is an independent prognostic factor predicting an unfavorable psychiatric prognosis in AE.

UNVEILING THE COMPLEX ROLE OF NF-ΚB IN ALZHEIMER'S DISEASE: INSIGHTS INTO BRAIN INFLAMMATION AND POTENTIAL THERAPEUTIC TARGETS.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and dementia. One of the major pathologies underlying AD is chronic neuroinflammation mediated by microglia and astrocytes in the brain. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway is a key regulator of inflammation and has been implicated in the neuroinflammatory processes associated with AD. This review comprehensively summarizes current findings on the complex role of NF-κB signalling in AD pathogenesis. The canonical and non-canonical NF-κB activation pathways are described, along with evidence from human studies and animal models demonstrating increased NF-κB activity in AD brains. The deleterious effects of NF-κB-mediated neuroinflammation are discussed, including the upregulation of inflammatory cytokines, chemokines, and enzymes that exacerbate neuronal damage over time. Targeting the NF-κB pathway is proposed as a promising therapeutic approach to dampen neuroinflammation in AD. Preclinical studies utilizing genetic or pharmacological inhibition of NF-κB are reviewed, and key challenges in translating these findings to clinical applications are analyzed. Overall, this review unveils the multifaceted contributions of NF-κB signalling to AD neuropathology and highlights anti-neuroinflammatory NF-κB modulation as a potential avenue for future AD treatments. Further research is warranted to fully elucidate the complex interactions between NF-κB and AD pathogenesis.

Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells.

Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction. Current treatments comprise broad immunosuppression or non-selective antibody removal. We developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells to selectively eliminate anti-NMDAR B cells and disease-causing autoantibodies. NMDAR-CAARs consist of an extracellular multi-subunit NMDAR autoantigen fused to intracellular 4-1BB/CD3ζ domains. NMDAR-CAAR T cells recognize a large panel of human patient-derived autoantibodies, release effector molecules, proliferate, and selectively kill antigen-specific target cell lines even in the presence of high autoantibody concentrations. In a passive transfer mouse model, NMDAR-CAAR T cells led to depletion of an anti-NMDAR B cell line and sustained reduction of autoantibody levels without notable off-target toxicity. Treatment of patients may reduce side effects, prevent relapses, and improve long-term prognosis. Our preclinical work paves the way for CAAR T cell phase I/II trials in NMDAR encephalitis and further autoantibody-mediated diseases.

Comprehensive analyses identify potential biomarkers for encephalitis in HIV infection.

Human immunodeficiency virus encephalitis (HIVE) is a severe neurological complication after HIV infection. Evidence shows that genetic factors play an important role in HIVE. The aim of the present study was to identify new potential therapeutic targets for HIVE. Differentially expressed gene (DEG), functional annotation and pathway, and protein-protein interaction analyses were performed to identify the hub genes associated with HIVE. Gene co-expression analysis was carried out to confirm the association between the hub genes and HIVE. Finally, the role of the hub genes in HIVE therapy was evaluated by conducting drug-gene interaction analysis. A total of 20 overlapping DEGs closely related to HIVE were identified. Functional annotation and pathway enrichment analysis indicated that the markedly enriched DEG terms included ion transport, type II interferon signaling, and synaptic signaling. Moreover, protein-protein interaction analysis revealed that 10 key HIVE-related genes were hub genes, including SCN8A, CDK5R2, GRM5, SCN2B, IFI44L, STAT1, SLC17A7, ISG15, FGF12, and FGF13. Furthermore, six hub genes were co-expressed with HIVE-associated host genes in human brain tissue. Finally, three hub genes (STAT1, ISG15, and SCN2B) interacted with several inflammation-associated drugs. These findings suggested that SCN8A, CDK5R2, GRM5, SCN2B, IFI44L, STAT1, SLC17A7, ISG15, FGF12, and FGF13 may be new targets for diagnosis and therapy of HIVE.

Downregulation of CCR5 on brain perivascular macrophages in simian immunodeficiency virus-infected rhesus macaques.

BACKGROUND: C-C chemokine receptor 5 (CCR5) is a major coreceptor for Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) cell entry; however, its role in brain pathogenesis is largely understudied. Thus, we sought to examine cell type-specific protein expression of CCR5 during SIV infection of the brain. METHODS: We examined occipital cortical tissue from uninfected rhesus macaques and SIV-infected animals with or without encephalitis using immunohistochemistry and immunofluorescence microscopy to determine the number and distribution of CCR5-positive cells. RESULTS: An increase in the number of CCR5+ cells in the brain of SIV-infected animals with encephalitis was accounted for by increased CD3+CD8+ cells expressing CCR5, but not by increased CCR5+ microglia or perivascular macrophages (PVMs), and a concurrent decrease in the percentage of CCR5+ PVMs was observed. Levels of CCR5 and SIV Gag p28 protein expression were examined on a per-cell basis, and a significant, negative relationship was established indicating decreased CCR5 expression in productively infected cells. While investigating the endocytosis-mediated CCR5 internalization as a mechanism for CCR5 downregulation, we found that phospho-ERK1/2, an indicator of clathrin-mediated endocytosis, was colocalized with infected PVMs and that macrophages from infected animals showed significantly increased expression of clathrin heavy chain 1. CONCLUSIONS: These findings show a shift in CCR5-positive cell types in the brain during SIV pathogenesis with an increase in the number of CCR5+ CD8 T cells, and downregulated CCR5 expression on infected PVMs, likely through ERK1/2-driven, clathrin-mediated endocytosis.

The association between peripheral inflammation, brain glutamate and antipsychotic response in Schizophrenia: Data from the STRATA collaboration.

Glutamate and increased inflammation have been separately implicated in the pathophysiology of schizophrenia and the extent of clinical response to antipsychotic treatment. Despite the mechanistic links between pro-inflammatory and glutamatergic pathways, the relationships between peripheral inflammatory markers and brain glutamate in schizophrenia have not yet been investigated. In this study, we tested the hypothesis that peripheral levels of pro-inflammatory cytokines would be positively associated with brain glutamate levels in schizophrenia. Secondary analyses determined whether this relationship differed according to antipsychotic treatment response. The sample consisted of 79 patients with schizophrenia, of whom 40 were rated as antipsychotic responders and 39 as antipsychotic non-responders. Brain glutamate levels were assessed in the anterior cingulate cortex (ACC) and caudate using proton magnetic resonance spectroscopy (1H-MRS) and blood samples were collected for cytokine assay on the same study visit (IL-6, IL-8, IL-10, TNF- α and IFN-γ). Across the whole patient sample, there was a positive relationship between interferon-gamma (IFN-γ) and caudate glutamate levels (r = 0.31, p = 0.02). In the antipsychotic non-responsive group only, there was a positive relationship between interleukin-8 (IL-8) and caudate glutamate (r = 0.46, p = 0.01). These findings provide evidence to link specific peripheral inflammatory markers and caudate glutamate in schizophrenia and may suggest that this relationship is most marked in patients who show a poor response to antipsychotic treatment.

The effect of neuroinflammation on the cerebral metabolism at baseline and after neural stimulation in neurodegenerative diseases.

Neuroinflammation is a reaction of nervous tissue to an attack caused by an infection, a toxin, or a neurodegenerative disease. It involves brain metabolism adaptation in order to meet the increased energy needs of glial cell activation, but the nature of these adaptations is still unknown. Increasing interest concerning neuroinflammation leads to the identification of its role in neurodegenerative diseases. Few reports studied the effect of metabolic alteration on neuroinflammation. Metabolic damage initiates a pro-inflammatory response by microglial activation. Moreover, the exact neuroinflammation effect on cerebral cell metabolism remains unknown. In this study, we reviewed systematically the neuroinflammation effect in animal models' brains. All articles showing the relationship of neuroinflammation with brain metabolism, or with neuronal stimulation in neurodegenerative diseases were considered. Moreover, this review examines also the mitochondrial damage effect in neurodegeneration diseases. Then, different biosensors are classified regarding their importance in the determination of metabolite change. Finally, some therapeutic drugs inhibiting neuroinflammation are cited. Neuroinflammation increases lymphocyte infiltration and cytokines' overproduction, altering cellular energy homeostasis. This review demonstrates the importance of neuroinflammation as a mediator of disease progression. Further, the spread of depolarization effects pro-inflammatory genes expression and microglial activation, which contribute to the degeneration of neurons, paving the road to better management and treatment of neurodegenerative diseases.

Translocator protein (TSPO)-PET as diagnostic and monitoring tool in COVID-19 related MRI-negative brainstem encephalitis: a case report.

BACKGROUND: Encephalitis and myelitis have been linked to both COVID-19 vaccination and infection, causing symptoms such as reduced consciousness, mental state alterations and seizures. Remarkably, most cases do not show significant structural alterations on MRI scans, which poses a diagnostic challenge. METHODS: We present the diagnostic workup and clinical course of a patient who developed a progressive brainstem syndrome two weeks after COVID-19 vaccination and subsequent infection. We used translocator protein (TSPO)-PET scans for the first time to investigate COVID-related neuroinflammation. RESULTS: The patient developed oculomotor disorder, dysarthria, paresthesia in all distal limbs and spastic-atactic gait. CSF analysis revealed mild lymphocytic pleocytosis with normal protein levels. Brain and spinal cord MRI scans were negative, but TSPO/PET scans showed increased microglia activity in the brainstem, which correlated with the clinical course. Steroid treatment led to clinical improvement, but relapse occurred during prednisone taper after four weeks. Plasmapheresis had no significant effect; however, complete remission was achieved with cyclophosphamide and methotrexate, with normal TSPO signal ten months after onset. CONCLUSIONS: TSPO-PET can be a valuable tool in the diagnostic and therapeutic monitoring of COVID-19-related encephalitis, particularly in cases where MRI scans are negative. Aggressive immunosuppressive therapy can lead to sustained remission.

Curcumin-dependent phenotypic transformation of microglia mediates resistance to pseudorabies-induced encephalitis.

Pseudorabies virus (PRV) causes viral encephalitis, a devastating disease with high mortality worldwide. Curcumin (CUR) can reduce inflammatory damage by altering the phenotype of microglia; however, whether and how these changes mediate resistance to PRV-induced encephalitis is still unclear. In this study, BV2 cells were infected with/without PRV for 24 h and further treated with/without CUR for 24 h. The results indicated that CUR promoted the polarization of PRV-infected BV2 cells from the M1 phenotype to the M2 phenotype and reversed PRV-induced mitochondrial dysfunction. Furthermore, M1 BV2 cell secretions induced signalling pathways leading to apoptosis in PC-12 neuronal cells, and this effect was abrogated by the secretions of M2 BV2 cells. RNA sequencing and bioinformatics analysis predicted that this phenotypic shift may be due to changes in energy metabolism. Furthermore, Western blot analysis showed that CUR inhibited the increase in AMP-activated protein kinase (AMPK) phosphorylation, glycolysis, and triacylglycerol synthesis and the reduction in oxidative phosphorylation induced by PRV infection. Moreover, the ATP levels in M2 BV2 cells were higher than those in M1 cells. Furthermore, CUR prevented the increase in mortality, elevated body temperature, slowed growth, nervous system excitation, brain tissue congestion, vascular cuffing, and other symptoms of PRV-induced encephalitis in vivo. Thus, this study demonstrated that CUR protected against PRV-induced viral encephalitis by switching the phenotype of BV2 cells, thereby protecting neurons from inflammatory injury, and this effect was mediated by improving mitochondrial function and the AMPK/NF-κB p65-energy metabolism-related pathway.

Attenuation of Alzheimer's brain pathology in 5XFAD mice by PTH1-34, a peptide of parathyroid hormone.

BACKGROUND: Alzheimer's disease (AD) and osteoporosis are two distinct diseases but often occur in the same patient. Their relationship remains poorly understood. Studies using Tg2576 AD animal model demonstrate bone deficits, which precede the brain phenotypes by several months, arguing for the independence of bone deficits on brain degeneration and raising a question if the bone deficits contribute to the AD development. To address this question, we investigated the effects of PTH1-34, a peptide of parathyroid hormone analog and a well-recognized effective anabolic therapy drug for patients with osteoporosis, on 5XFAD animal model. METHODS: 5XFAD mice, an early onset ß-amyloid (Aß)-based AD mouse model, were treated with PTH1-34 intermittently [once daily injection of hPTH1-34 (50 µg/Kg), 5 days/week, starting at 2-month old (MO) for 2-3 month]. Wild type mice (C57BL/6) were used as control. The bone phenotypes were examined by microCT and evaluated by measuring serum bone formation and resorption markers. The AD relevant brain pathology (e.g., Aß and glial activation) and behaviors were assessed by a combination of immunohistochemical staining analysis, western blots, and behavior tests. Additionally, systemic and brain inflammation were evaluated by serum cytokine array, real-time PCR (qPCR), and RNAscope. RESULTS: A reduced trabecular, but not cortical, bone mass, accompanied with a decrease in bone formation and an increase in bone resorption, was detected in 5XFAD mice at age of 5/6-month old (MO). Upon PTH1-34 treatments, not only these bone deficits but also Aß-associated brain pathologies, including Aß and Aß deposition levels, dystrophic neurites, glial cell activation, and brain inflammatory cytokines, were all diminished; and the cognitive function was improved. Further studies suggest that PTH1-34 acts on not only osteoblasts in the bone but also astrocytes in the brain, suppressing astrocyte senescence and expression of inflammatory cytokines in 5XFAD mice. CONCLUSIONS: These results suggest that PTH1-34 may act as a senolytic-like drug, reducing systemic and brain inflammation and improving cognitive function, and implicate PTH1-34's therapeutic potential for patients with not only osteoporosis but also AD.

Satureja khuzistanica Jamzad essential oil and pure carvacrol attenuate TBI-induced inflammation and apoptosis via NF-κB and caspase-3 regulation in the male rat brain.

Traumatic brain injury (TBI) causes progressive dysfunction that induces biochemical and metabolic changes that lead to cell death. Nevertheless, there is no definitive FDA-approved therapy for TBI treatment. Our previous immunohistochemical results indicated that the cost-effective natural Iranian medicine, Satureja khuzistanica Jamzad essential oil (SKEO), which consists of 94.16% carvacrol (CAR), has beneficial effects such as reducing neuronal death and inflammatory markers, as well as activating astrocytes and improving neurological outcomes. However, the molecular mechanisms of these neuroprotective effects have not yet been elucidated. This study investigated the possible mechanisms involved in the anti-inflammatory and anti-apoptotic properties of SKEO and CAR after TBI induction. Eighty-four male Wistar rats were randomly divided into six groups: Sham, TBI, TBI + Vehicle, TBI + CAR (100 and 200 mg/kg), and TBI + SKEO (200 mg/kg) groups. After establishing the "Marmarou" weight drop model, diffuse TBI was induced in the rat brain. Thirty minutes after TBI induction, SKEO & CAR were intraperitoneally injected. One day after TBI, injured rats exhibited significant brain edema, neurobehavioral dysfunctions, and neuronal apoptosis. Western blot results revealed upregulation of the levels of cleaved caspase-3, NFκB p65, and Bax/Bcl-2 ratio, which was attenuated by CAR and SKEO (200 mg/kg). Furthermore, the ELISA results showed that CAR treatment markedly prevents the overproduction of the brain pro-inflammatory cytokines, including IL-1ß, TNF-α, and IL-6. Moreover, the neuron-specific enolase (NSE) immunohistochemistry results revealed the protective effect of CAR and SKEO on post-TBI neuronal death. The current study revealed that the possible neuroprotective mechanisms of SKEO and CAR might be related to (at least in part) modulating NF-κB regulated inflammation and caspase-3 protein expression. It also suggested that CAR exerts more potent protective effects than SKEO against TBI. Nevertheless, the administration of SKEO and CAR may express a novel therapeutic approach to ameliorate TBI-related secondary phase neuropathological outcomes.

Resveratrol alleviated neuroinflammation induced by pseudorabies virus infection through regulating microglial M1/M2 polarization.

BACKGROUND: Pseudorabies virus (PRV) infections in susceptible non-porcine species trigger uncontrolled inflammations and eventually fatal encephalitis. Resveratrol (Res) has broad pharmacological functions including anti-virus, anti-inflammation, and neuroprotective. PURPOSE: We attempted to investigate the potential of Res in ameliorating PRV infection pathology in mice and decipher the mechanism of Res in treating PRV. METHODS: The mice were infected by PRV to investigate the protective effect of Res. Blood-brain barrier (BBB) permeability, H&E/Nissl/TUNEL staining, Real-time PCR and ELISA analyses were performed. Primary microglia and neuron were isolated from mice and cultured. The co-culture model of microglia and neuron was established by transwell. Immunofluorescence assay and flow cytometry were used. RESULTS: In this study, we showed that Res ameliorated brain damage by reducing BBB permeability in PRV-infected mice, and diminished the expressions of MMP-2, MMP-9 and ZO-1 in the cortex. Pathological changes of neurons by H&E/Nissl/TUNEL staining suggested that Res could alleviate neuronal lesions. Moreover, Res inhibited the expressions of pro-inflammatory factors (IL-6, TNF-α) and chemokines (CCL3, CXCL10, MCP-1), but increased the expressions of anti-inflammatory factors (IL-4, IL-10) and neurotrophic factor (TGF-ß, NGF and GDNF) in brain. In vitro cultured microglia cells, Res could suppress M1 microglia polarization and activate M2 microglia polarization. Co-culture of PRV-infected microglia with neuron cells by transwell system indicated that Res alleviated inflammatory response and neuronal apoptosis. CONCLUSION: This study provided evidence that Res could protect mice from PRV-induced encephalitis through regulation of microglia polarization and neuronal apoptosis suggesting the potential for treatment of viral encephalitis.

Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective.

Status epilepticus (SE) in humans is characterized by prolonged convulsive seizures that are generalized and often difficult to control. The current antiseizure drugs (ASDs) aim to stop seizures quickly enough to prevent the SE-induced brain inflammation, injury, and long-term sequelae. However, sole reliance on acute therapies is imprudent because prompt treatment may not always be possible under certain circumstances. The pathophysiological mechanisms underlying the devastating consequences of SE are presumably associated with neuroinflammatory reactions, where prostaglandin E2 (PGE2) plays a pivotal role. As the terminal synthase for pathogenic PGE2, the microsomal prostaglandin E synthase-1 (mPGES-1) is rapidly and robustly induced by prolonged seizures. Congenital deletion of mPGES-1 in mice is neuroprotective and blunts gliosis following chemoconvulsant seizures, suggesting the feasibility of mPGES-1 as a potential antiepileptic target. Herein, we investigated the effects of a dual species mPGES-1 inhibitor in a mouse pilocarpine model of SE. Treatment with the mPGES-1 inhibitor in mice after SE that was terminated by diazepam, a fast-acting benzodiazepine, time-dependently abolished the SE-induced PGE2 within the brain. Its negligible effects on cyclooxygenases, the enzymes responsible for the initial step of PGE2 biosynthesis, validated its specificity to mPGES-1. Post-SE inhibition of mPGES-1 also blunted proinflammatory cytokines and reactive gliosis in the hippocampus and broadly prevented neuronal damage in a number of brain areas. Thus, pharmacological inhibition of mPGES-1 by small-molecule inhibitors might provide an adjunctive strategy that can be implemented hours after SE, together with first-line ASDs, to reduce SE-provoked brain inflammation and injury.

The role of brain inflammation and abnormal brain oxygen homeostasis in the development of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE. Whilst significant strides in our understanding have been made over the years, evaluating all these mechanistic elements in vivo and showing causal association with development of HE, have been limited through the practical constraints of experimentation. Nonetheless, improvements in non-invasive assessments of different neurophysiological parameters, coupled with techniques to assess changes in inflammatory and metabolic pathways, will help provide more granular insights on these mechanisms. In this special issue we discuss some of the emerging evidence supporting the hypothesis that brain inflammation and abnormal oxygen homeostasis occur interdependently during CLD and comprise important contributors to the development of HE. This review aims at furnishing evidence for further research in brain inflammation and oxygen homeostasis as additional therapeutic targets and potentially diagnostic markers for HE.

Uncovering mechanisms of brain inflammation in Alzheimer's disease with APOE4: Application of single cell-type lipidomics.

A chronic state of unresolved inflammation in Alzheimer's disease (AD) is intrinsically involved with the remodeling of brain lipids. This review highlights the effect of carrying the apolipoprotein E ε4 allele (APOE4) on various brain cell types in promoting an unresolved inflammatory state. Among its pleotropic effects on brain lipids, we focus on APOE4's activation of Ca2+ -dependent phospholipase A2 (cPLA2) and its effects on arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid signaling cascades in the brain. During the process of neurodegeneration, various brain cell types, such as astrocytes, microglia, and neurons, together with the neurovascular unit, develop distinct inflammatory phenotypes that impact their functions and have characteristic lipidomic fingerprints. We propose that lipidomic phenotyping of single cell-types harvested from brains differing by age, sex, disease severity stage, and dietary and genetic backgrounds can be employed to probe mechanisms of neurodegeneration. A better understanding of the brain cellular inflammatory/lipidomic response promises to guide the development of nutritional and drug interventions for AD dementia.

Exercise training alters autoimmune cell invasion into the brain in autoimmune encephalomyelitis.

BACKGROUND: The mechanisms by which exercise training (ET) elicits beneficial effects on the systemic immune system and the central nervous system (CNS) in autoimmune neuroinflammation are not fully understood. OBJECTIVES: To investigate (1) the systemic effects of high-intensity continuous training (HICT) on the migratory potential of autoimmune cells; (2) the direct effects of HICT on blood-brain-barrier (BBB) properties. METHODS: Healthy mice were subjected to high-intensity continuous training (HICT) by treadmill running. The proteolipid protein (PLP) transfer EAE model was utilized to examine the immunomodulatory effects of training, where PLP-reactive lymph-node cells (LNCs) from HICT and sedentary donor mice were analyzed in vitro and transferred to naïve recipients that developed EAE. To examine neuroprotection, encephalitogenic LNCs from donor mice were transferred into HICT or sedentary recipient mice and the BBB was analyzed. RESULTS: Transfer of PLP-reactive LNCs obtained from HICT donor mice attenuated EAE severity and inflammation in recipient mice. HICT markedly inhibited very late antigen (VLA)-4 and lymphocyte function-associated antigen (LFA)-1 expression in LNCs. Transfer of encephalitogenic LNCs into HICT recipients resulted in milder EAE and attenuated CNS inflammation. HICT reduced BBB permeability and the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in CNS blood vessels. INTERPRETATION: HICT attenuates EAE development by both immunomodulatory and neuroprotective effects. The reduction in destructive CNS inflammation in EAE is attributed to systemic inhibition of autoreactive cell migratory potential, as well as reduction in BBB permeability, which are associated with reduced VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions.

Characterising murine hippocampal iron homeostasis, in relation to markers of brain inflammation and metabolism, during ageing.

Metal ions (Fe, Cu, and Zn) are essential to a healthy brain function, with the amount, localisation, and chemical form often tightly controlled. Evidence points towards loss of metal ion homeostasis within the ageing brain; in particular brain Fe accumulation appears to be a hallmark of ageing, which may place the brain at a greater risk of neurodegenerative disease. Unfortunately, the cause or consequence of altered brain metal ion homeostasis during ageing remains unknown, and there is a lack of data comparing brain metal ion homeostasis with other events of the ageing process (e.g. brain metabolism, brain inflammation). This study has utilised a multi-modal approach that incorporated: X-ray fluorescence microscopy for elemental mapping of metal ion homeostasis, Perl's Fe histochemistry, FTIR spectroscopic biochemical imaging of lactate and protein aggregates, and immuno-fluorescence analysis of markers of brain inflammation and Fe storage proteins (heavy-chain ferritin, light-chain ferritin, and mitochondrial ferritin). Interestingly, while age-related Fe accumulation was observed in corpus callosum white matter of murine (C56BL/6J) brain tissue (concomitant with elevated levels of markers of brain inflammation and altered metabolism), Fe content was not altered within the hippocampus (a decrease in total Zn within the mossy fibres was observed). Ultimately, the results of this study demonstrate an important association between elevated brain Fe and brain inflammation during natural ageing. This study also highlights that future research is required to image different chemical forms of Fe with respect to changes in brain metabolism and inflammation, as well as localising these changes to specific cell types.

Microglial STAT1-sufficiency is required for resistance to toxoplasmic encephalitis.

Toxoplasma gondii is a ubiquitous intracellular protozoan parasite that establishes a life-long chronic infection largely restricted to the central nervous system (CNS). Constant immune pressure, notably IFN-γ-STAT1 signaling, is required for preventing fatal pathology during T. gondii infection. Here, we report that abrogation of STAT1 signaling in microglia, the resident immune cells of the CNS, is sufficient to induce a loss of parasite control in the CNS and susceptibility to toxoplasmic encephalitis during the early stages of chronic infection. Using a microglia-specific genetic labeling and targeting system that discriminates microglia from blood-derived myeloid cells that infiltrate the brain during infection, we find that, contrary to previous in vitro reports, microglia do not express inducible nitric-oxide synthase (iNOS) during T. gondii infection in vivo. Instead, transcriptomic analyses of microglia reveal that STAT1 regulates both (i) a transcriptional shift from homeostatic to "disease-associated microglia" (DAM) phenotype conserved across several neuroinflammatory models, including T. gondii infection, and (ii) the expression of anti-parasitic cytosolic molecules that are required for eliminating T. gondii in a cell-intrinsic manner. Further, genetic deletion of Stat1 from microglia during T. gondii challenge leads to fatal pathology despite largely equivalent or enhanced immune effector functions displayed by brain-infiltrating immune populations. Finally, we show that microglial STAT1-deficiency results in the overrepresentation of the highly replicative, lytic tachyzoite form of T. gondii, relative to its quiescent, semi-dormant bradyzoite form typical of chronic CNS infection. Our data suggest an overall protective role of CNS-resident microglia against T. gondii infection, illuminating (i) general mechanisms of CNS-specific immunity to infection (ii) and a clear role for IFN-STAT1 signaling in regulating a microglial activation phenotype observed across diverse neuroinflammatory disease states.

A Nurr1 ligand C-DIM12 attenuates brain inflammation and improves functional recovery after intracerebral hemorrhage in mice.

We have previously reported that amodiaquine, a compound that binds to the ligand-binding domain of a nuclear receptor Nurr1, attenuates inflammatory responses and neurological deficits after intracerebral hemorrhage (ICH) in mice. 1,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) is another Nurr1 ligand that recognizes a domain of Nurr1 different from the ligand-binding domain. In the present study, mice were treated daily with C-DIM12 (50 or 100 mg/kg, p.o.) or amodiaquine (40 mg/kg, i.p.), or twice daily with 1400 W (20 mg/kg, i.p.), an inducible nitric oxide synthase (iNOS) inhibitor, from 3 h after ICH induction by microinjection of collagenase into the striatum. C-DIM12 improved the recovery of neurological function and prevented neuron loss in the hematoma, while suppressed activation of microglia/macrophages and expression of inflammatory mediators interleukin-6 and CC chemokine ligand 2. In addition, C-DIM12 as well as amodiaquine preserved axonal structures in the internal capsule and axonal transport function. We also found that C-DIM12 and amodiaquine suppressed the increases of iNOS mRNA expression after ICH. Moreover, 1400 W improved neurological function and prevented neuron loss, activation of microglia/macrophages and axonal transport dysfunction. These results suggest that suppression of iNOS induction contributes to several features of the therapeutic effects of Nurr1 ligands.