Neuroinflammatory Biomarkers in Cerebrospinal Fluid From 106 Patients With Recent-Onset Depression Compared With 106 Individually Matched Healthy Control Subjects.

BACKGROUND: Neuroinflammation has been linked to depression; however, neuroinflammatory biomarkers in the cerebrospinal fluid (CSF) have not previously been thoroughly investigated in a large group of patients with recent-onset depression compared with healthy control subjects. METHODS: We conducted an individually matched case-control study comparing patients with recent-onset depression (ICD-10: F32) to control subjects. Primary outcomes were CSF white cell count (WCC), CSF-to-serum albumin ratio, CSF total protein, and immunoglobulin G (IgG) index. Secondary outcomes were CSF WCC differential count and CSF neutrophil-to-lymphocyte, CSF-to-serum IgG, and CSF-to-plasma glucose ratios. Linear models adjusting for sex and age were applied. RESULTS: We included 106 patients with recent-onset depression (84.0% outpatients) and 106 healthy control subjects. Patients had 18% higher CSF WCC relative to control subjects (relative mean difference [MD]: 1.18; 95% CI: 1.02-1.40; p = .025). CSF WCC differed with depression symptomatology (p = .034), and patients with severe depression (n = 29) had 43% higher CSF WCC relative to control subjects (MD: 1.43; 95% CI: 1.13-1.80, p = .003). Two (1.9%) patients and no controls (0.0%) had CSF WCC above the normal range (>5 × 106/L). No significant differences between groups were observed regarding CSF-to-serum albumin ratio (MD: 1.07; 95% CI: 0.97-1.18; p = .191), CSF total protein (MD: 1.01; 95% CI: 0.94-1.09; p = .775), or IgG index (MD: 1.05; 95% CI: 0.97-1.15; p = .235). Regarding secondary outcomes, the proportion of CSF neutrophils was lower among patients (MD: 0.22; 95% CI: 0.08-0.59; p = .003) relative to control subjects, whereas the remaining outcomes were not significantly different (all p > .06). CONCLUSIONS: Patients had higher CSF WCC relative to control subjects, indicating increased neuroimmunologic activation, particularly for severe depression.

Value of Thyroid Peroxidase Antibodies in Neuroimmune Diseases: Analysis of Interference During Treatment with Intravenous Immunoglobulins.

OBJECTIVE: The absence of specific markers can make the diagnosis of neuroimmune disorders difficult, making other biomarkers such as thyroid peroxidase antibodies (TPO-Abs) more relevant. Laboratory tests are susceptible to interference, especially those tests performed using immunoassay techniques. The effect of treatment with human intravenous immunoglobulin (IVIG) on the results of TPO-Abs assays has not been previously characterized. MATERIALS AND METHODS: We analyzed TPO-Abs levels in 170 children monitored in the neuroimmune disease department of a tertiary hospital. We analyzed the characteristics of patients with increased TPO-Abs values and compared their progress with and without treatment. RESULTS: We found that 97% of patients with elevated TPO-Abs had received IVIG. After withdrawal from IVIG, a mean TPO-Abs decrease of 62.5% at 1 month was observed. The IVIG drug preparation was found to contain 1176 U/mL of TPO-Abs. An interferogram confirmed interference. CONCLUSION: It is advisable to measure levels of TPO-Abs before starting immunotherapy and remain vigilant regarding possible interference in the event of unsubstantiated elevations of this analyte.

Predictive effects of admission white blood cell counts and hounsfield unit values on delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Neuroinflammatory response is deemed the primary pathogenesis of delayed cerebral ischemia (DCI) caused by aneurysmal subarachnoid hemorrhage (aSAH). Both white blood cell (WBC) count and Hounsfield Unit (HU) are gradually considered can reflect inflammation in DCI. This study aims to identify the relationship between WBC count and HU value and investigate the effects of both indicators in predicting DCI after aSAH. METHODS: We enrolled 109 patients with aSAH admitted within 24 h of onset in our study. A multivariate logistic regression analysis was used to evaluate the admission WBC count, HU value, and combined WBC-HU associated with DCI. The receiver operating characteristic curve and area under the curve (AUC) were used to determine thresholds and detect the predictive ability of these predictors. These indicators were also compared with the established inflammation markers. RESULTS: Thirty-six (33%) patients developed DCI. Both WBC count and HU value were strongly associated with the admission glucose level (ρ = .303, p = .001; ρ = .273, p = .004), World Federation of Neurosurgical Societies grade (ρ = .452, p < .001; ρ = .578; p < .001), Hunt-Hess grade (ρ = .450, p < .001; ρ = .510, p < .001), and modified Fisher scale score (ρ = .357, p < .001; ρ = .330, p < .001). After controlling these public variables, WBC count (ρ = .300, p = .002) positively correlated with HU value. An early elevated WBC (odds ratio [OR] 1.449, 95% confidence interval [CI]: 1.183-1.774, p < .001) count and HU value (OR 1.304, 95%CI: 1.149-1.479, p < .001) could independently predict the occurrence of DCI. However, only these patients with both WBC count and HU value exceeding the cut-off points (OR 36.89, 95%CI: 5.606-242.78, p < .001) were strongly correlated with DCI. Compared with a single WBC count (AUC 0.811, 95%CI: 0.729-0.892, p < .001) or HU value (AUC 0.869, 95%CI: 0.803-0.936, p < .001), the combined WBC-HU (AUC 0.898, 95%CI: 0.839-0.957, p < .001) demonstrated a better ability to predict the occurrence of DCI. Inspiringly, the prediction performance of these indicators outperformed the established inflammatory markers. CONCLUSION: An early elevated WBC count and HU value could independently predict DCI occurrence between 4 and 30 days after aSAH. Furthermore, WBC count was positively correlated with HU value, and the combined WBC-HU demonstrated a superior prediction ability for DCI development compared with the individual indicator.

Vanishing tumefactive ANCA-associated hypertrophic pachymeningitis: A case report.

We report a case of a 59-year-old man with hypertrophic pachymeningitis (HP), initially presenting as a tumefactive lesion that disappeared spontaneously. He developed headache and left abducens nerve palsy 2 years before admission, and cerebral magnetic resonance imaging (MRI) revealed a round mass lesion. Meningioma was initially considered, but the lesion disappeared spontaneously along with the symptoms. However, 6 months before admission, left abducens nerve palsy reappeared. Repeated MRI revealed multiple intracranial tumefactive lesions. HP was diagnosed based on the pathological analysis of the biopsied specimen. HP can appear as a vanishing tumor, and pathological evaluation is essential for a precise diagnosis. If spontaneous disappearance of tumefactive intracranial lesions is encountered, the possibility of HP should be considered.

Markers of Neuroinflammation in the Serum of Prepubertal Children with Fetal Alcohol Spectrum Disorders.

BACKGROUND: Fetal Alcohol Spectrum Disorders (FASD) are the manifestation of the damage caused by alcohol consumption during pregnancy. Children with Fetal Alcohol Syndrome (FAS), the extreme FASD manifestation, show both facial dysmorphology and mental retardation. Alcohol consumed during gestational age prejudices brain development by reducing, among others, the synthesis and release of neurotrophic factors and neuroinflammatory markers. Alcohol drinking also induces oxidative stress. HYPOTHESIS/OBJECTIVE: The present study aimed to investigate the potential association between neurotrophins, neuroinflammation, and oxidative stress in 12 prepubertal male and female FASD children diagnosed as FAS or partial FAS (pFAS). METHODS: Accordingly, we analyzed, in the serum, the level of BDNF and NGF and the oxidative stress, as Free Oxygen Radicals Test (FORT) and Free Oxygen Radicals Defense (FORD). Moreover, serum levels of inflammatory mediators (IL-1α, IL-2, IL-6, IL-10, IL-12, MCP-1, TGF-ß, and TNF-α) involved in neuroinflammatory and oxidative processes have been investigated. RESULTS: We demonstrated low serum levels of NGF and BDNF in pre-pubertal FASD children with respect to healthy controls. These changes were associated with higher serum presence of TNF- α and IL-1α. Quite interestingly, an elevation in the FORD was also found despite normal FORT levels. Moreover, we found a potentiation of IL-1α, IL-2, IL-10, and IL-1α1 in the analyzed female compared to male children. CONCLUSION: The present investigation shows an imbalance in the peripheral neuroimmune pathways that could be used in children as early biomarkers of the deficits observed in FASD.

Salivary GFAP as a potential biomarker for diagnosis of mild cognitive impairment and Alzheimer's disease and its correlation with neuroinflammation and apoptosis.

Glial fibrillary acidic protein (GFAP) is the main constituent of the astrocytic cytoskeleton, overexpressed during reactive astrogliosis-a hallmark of Alzheimer's Disease (AD). GFAP and established biomarkers of neurodegeneration, inflammation, and apoptosis have been determined in the saliva of amnestic-single-domain Mild Cognitive Impairment (MCI) (Ν = 20), AD (Ν = 20) patients, and cognitively healthy Controls (Ν = 20). Salivary GFAP levels were found significantly decreased in MCI and AD patients and were proven an excellent biomarker for discriminating Controls from MCI or AD patients. GFAP levels correlate with studied biomarkers and Aß42, IL-1ß, and caspase-8 are its main predictors.

Ocular Motor Abnormalities in Anti-IgLON5 Disease.

Objective: Anti-IgLON5 disease forms an interface between neuroinflammation and neurodegeneration and includes clinical phenotypes that are often similar to those of neurodegenerative diseases. An early diagnosis of patients with anti-IgLON5 disease and differentiation from neurodegenerative diseases is necessary and may have therapeutic implications. Methods: In our small sample size study we investigated oculomotor function as a differentiating factor between anti-IgLON5 disease and neurodegenerative disorders. We examined ocular motor and vestibular function in four patients suffering from anti-IgLON5 disease using video-oculography (VOG) and a computer-controlled rotational chair system (sampling rate 60 Hz) and compared the data with those from ten age-matched patients suffering from progressive supranuclear palsy (PSP) and healthy controls (CON). Results: Patients suffering from anti-IgLON5 disease differed from PSP most strikingly in terms of saccade velocity and accuracy, the presence of square wave jerks (SWJ) (anti-IgLON5 0/4 vs. PSP 9/10) and the clinical finding of supranuclear gaze palsy (anti-IgLON5 1/4). The presence of nystagmus, analysis of smooth pursuit eye movements, VOR and VOR suppression was reliable to differentiate between the two disease entities. Clear differences in all parameters, although not always significant, were found between all patients and CON. Discussion: We conclude that the use of VOG as a tool for clinical neurophysiological assessment can be helpful in differentiating between patients with PSP and patients with anti-IgLON5 disease. VOG could have particular value in patients with suspected PSP and lack of typical Parkinson's characteristics. future trials are indispensable to assess the potential of oculomotor function as a biomarker in anti-IgLON5 disease.

Soluble triggering receptor expressed on myeloid cells-1 as a serum biomarker of early neurologic deterioration and prognosis in acute supratentorial intracerebral hemorrhage.

BACKGROUND: Triggering receptor expressed on myeloid cells-1 (TREM-1) participates in neuroinflammation. We intended to ascertain whether serum soluble TREM-1 (sTREM-1) could be utilized as a biomarker of inflammation, severity, early neurologic deterioration (END) and outcome after primary intracerebral hemorrhage (ICH). METHODS: Serum sTREM-1 levels were gauged in 104 ICH patients and 104 healthy controls. END was diagnosed when the National Institutes of Health Stroke Scale (NIHSS) score increased ≥ 4 points or death between admission and 24 h after admission. Patients with a modified Rankin scale score of > 2 at 3 months were considered to have poor outcome. RESULTS: As compared to controls, patients exhibited significantly elevated serum sTREM-1 levels (median: 309.0 vs 67.9 pg/ml). Serum sTREM-1 concentrations were intimately correlated with NIHSS score (r = 0.574), hematoma volume (r = 0.554), blood leukocyte count (r = 0.529) and serum C-reactive protein concentrations (r = 0.509). Serum sTREM-1 concentrations > 309.0 pg/ml independently predicted END and poor outcome with odds ratio values of 4.054 and 4.721 respectively. Serum sTREM-1 concentrations distinguished END and poor outcome with areas under receiver operating characteristic curve of 0.789 and 0.813 respectively. CONCLUSION: Serum sTREM-1 may represent a promising inflammatory biomarker for assessment of severity and prediction of END and poor outcome after ICH.

Fas/FasL Contributes to HSV-1 Brain Infection and Neuroinflammation.

The Fas/FasL pathway plays a key role in immune homeostasis and immune surveillance. In the central nervous system (CNS) Fas/FasL is involved in axonal outgrowth and adult neurogenesis. However, little is known about the role of the Fas/FasL pathway in herpes encephalitis. In this study, we used a neuropathogenic clinical strain of herpes simplex virus type 1 (HSV-1) to explore infection-induced inflammation and immune responses in the mouse brain and the role of Fas/FasL in antiviral CNS immunity. HSV-1 CNS infection induced the infiltration of Fas- FasL-bearing monocytes and T cells in the brain and also to an up-regulation of Fas and FasL expression on resident astrocytes and microglia within infected sites. Upon infection, Fas- and FasL-deficient mice (lpr and gld) were partially protected from encephalitis with a decreased morbidity and mortality compared to WT mice. Fas/FasL deficiency promoted cell-mediated immunity within the CNS. Fas receptor stimulation abrogated HSV-1 induced activation and inflammatory reactions in microglia from WT mice, while lack of Fas or FasL led to a more pronounced activation of monocytes and microglia and also to an enhanced differentiation of these cells into a pro-inflammatory M1 phenotype. Furthermore, the specific immune system was more efficient in Fas- and FasL-deficient mice with significantly higher numbers of infiltrating HSV-1-specific cytotoxic T cells in the brain. Our data indicate that the Fas/FasL pathway leads to excessive neuroinflammation during HSV-1 infection, which is associated with a diminished anti-viral response and an excessive neuroinflammation.

Tannic acid protects aged brain against cerebral hypoperfusion via modulation of Nrf2 and inflammatory pathways.

Current study purposed to investigate the neuroprotective effects of Tannic Acid (TA) on mild chronic cerebral hypoperfusion model in rats. Male Wistar rats were subjected to permanent Unilateral Common Carotid Artery Occlusion (UCCAO), followed by TA treatment (0.05% w/v) in drinking water for one month. Nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO-1), heme oxygenase-1 (HO-1), factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, blood triglyceride, blood glucose, and liver enzymes' activity were detected after the experimental period. Also, behavioral tests, hematoxylin and eosin (H&E) staining, and PET scan were performed after treatment. Post-treatment of TA improved locomotion and memory function (P < 0.001), and reduced neural cell death (P < 0.001) in the treatment group compared to UCCAO rats. Furthermore, long-term TA treatment significantly increased the levels of Nrf2 (P < 0.001), NQO-1 (P < 0.001), and HO-1 (P < 0.001) in the hippocampus of the treatment group compared to the UCCAO group. TA consumption in the treatment group applied its anti-inflammatory effects via reducing the activity of NF-κB and TNF-α in comparison with the UCCAO group (P < 0.001 for both). Blood triglyceride, blood glucose, and liver enzymes did not change considerably in the groups (P > 0.05). The current results indicate that long-term post-treatment of TA exhibits protective effects against memory deficit and motor dysfunction. The cellular mechanism of TA in hypoperfused rats might be associated with the activation of antioxidant pathways, especially the Nrf2 pathway, and suppressing inflammatory factors like NF-κB and TNF-α.

Placental Macrophages Demonstrate Sex-Specific Response to Intrauterine Inflammation and May Serve as a Marker of Perinatal Neuroinflammation.

Preterm birth (PTB) is considered to be one of the most frequent causes of neonatal death. Prompt and effective measures to predict adverse fetal outcome following PTB are urgently needed. Placenta macrophages are a critical immune cell population during pregnancy, phenotypically divided into M1 and M2 subsets. An established mouse model of intrauterine inflammation (IUI) was applied. Placenta (labyrinth) and corresponding fetal brain were harvested within 24 hours post injection (hpi). Flow cytometry, Western blot, real-time qPCR, and regular histology were utilized to examine the cytokines, macrophage polarization, and sex-specificity. Placental exposure to LPS led to significantly reduced labyrinth thickness compared to PBS-exposed controls as early as 3 hpi, accompanied by apoptosis and necrosis. Pro-inflammatory M1 markers, Il-1ß, and iNOS, and anti-inflammatory M2 marker Il-10 increased significantly in placentas exposed to IUI. Analysis of flow cytometry revealed that fetal macrophages (Hofbauer cell, HBCs) were mostly M1-like and that maternal inter-labyrinth macrophages (MIM) were M2-like in their features in IUI. Male fetuses displayed significantly decreased M2-like features in HBCs at 3 and 6 hpi, while female fetuses showed significant increase in M2-like features in MIM at 3 and 6 hpi. Furthermore, there was a significant correlation between the frequency of HBCs and corresponding microglial marker expression at 3 and 6 hpi. Placental macrophages demonstrated sex-specific features in response to IUI. Specifically, HBCs may be a potential biomarker for fetal brain injury at preterm birth.

TNF-α Increase in a Cohort of Depressive Patients.

Background: The model of neuroinflammation has been proposed as a possible explanation of depression. Investigations of serum levels of tumor necrosis factor-α (TNF-α) in depressed patients have previously shown contradictory results of increased and decreased levels of TNF-α during the treatment of depression. Methods: We compared the serum levels of TNF-α in two cohorts of patients suffering from depression (ICD-10 criteria): one cohort from a psychotherapeutic unit (n = 18), where patients were treated with Cognitive Behavioral Analysis System of Psychotherapy (CBASP), and the other cohort from a psychiatric day care unit (n = 16). Both cohorts were investigated at the beginning and at the end of treatment. The intensity of depression was measured by means of the Beck Depression Inventory, 2nd edition (BDI-II) at both time points. Results: We observed a statistically significant increase of TNF-α in the psychotherapeutic unit at time point 2 compared to time point 1 (T = -14.71, p < 0.001), but not in the psychiatric day care unit. In both cohorts, BDI-II scores at time point 2 were significantly decreased compared to time point 1 (psychiatric day care unit: T = 3.32, p = 0.005; psychotherapeutic unit: T = 6.22, p < 0.001). There was a significant correlation in the psychotherapeutic unit at time point 2 (r = -0.682, p = 0.02). Conclusion: As TNF-α was increased at time point 2 in the psychotherapeutic unit but not in patients of the psychiatric day care unit, we propose the different durations of pretreatments in both cohorts and the associated processes of neuroinflammation as a possible explanation for our results. The lack of information about the time course of TNF-α in depression could in general explain the huge variety of TNF-α levels in different cohorts of depressed patients reported in the literature.

Efficient roles of miR-146a in cellular and molecular mechanisms of neuroinflammatory disorders: An effectual review in neuroimmunology.

Known as one of the most sophisticated systems of the human body, the nervous system consists of neural cells and controls all parts of the body. It is closely related to the immune system. The effects of inflammation and immune reactions have been observed in the pathogenesis of some neurological disorders. Defined as the gene expression regulators, miRNAs participate in cellular processes. miR-146a is a mediator in the neuroimmune system, leaving substantial effects on the homeostasis of immune and brain cells, neuronal identities acquisition, and immune responses regulation in the nervous system. Its positive efficiency has been proven in modulating inflammatory reactions, hemorrhagic complications, and pain. Moreover, the miR-146a targets play a key role in the pathogenesis of these illnesses. Based on the performance of its targets, miR-146a can have various effects on the disease progress. The abnormal expression/function of miR-146a has been reported in neuroinflammatory disorders. There is research evidence that this molecule qualifies as a desirable biomarker for some disorders and can even be a therapeutic target. This study aims to provide a meticulous review regarding the roles of miR-146a in the pathogenesis and progression of several neuroinflammatory disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, temporal lobe epilepsy, ischemic stroke, etc. The study also considers its eligibility for use as an ideal biomarker and therapeutic target in these diseases. The awareness of these mechanisms can facilitate the disease management/treatment, lead to patients' amelioration, improve the quality of life, and mitigate the risk of death.

GW9508 ameliorates cognitive dysfunction via the external treatment of encephalopathy in Aß1-42 induced mouse model of Alzheimer's disease.

The functions and mechanisms of GPR40 receptor to ameliorating the Alzheimer's disease (AD) by external treatment of encephalopathy remain unknown. In present study, the typical Aß1-42 induced mice model was applied to explore the functions and mechanisms of GPR40 receptor by external treatment of encephalopathy in AD. GPR40 agonist GW9508 and antagonist GW1100 were given by i.g injection to activate/inhibit the GPR40 receptor respectively in the gut of AD mouse which illustrated the function and mechanism of GPR40 receptor in ameliorating AD symptoms by external treatment of encephalopathy. A series of behavioral experiments were used to investigate the cognitive function and memory ability of mice, while molecular biology experiments such as Western blot, ELISA, flow cytometry were used to detect the corresponding changes of signaling pathways. The results revealed that intragastric administrated GW9508 could significantly ameliorate cognitive deficits of AD mouse, up-regulate the expression levels of gut-brain peptides both in blood circulation and hypothalamus thus up-regulate the expression levels of α-MSH in hypothalamus, while the negative autophagy-related proteins and inflammation-related proteins were down-regulated correspondingly. Meanwhile, GW9508 could also inhibit the pathological process of neuroinflammation in microglia. GW1100 reversed the effects of GW9508 significantly. These results suggested that GPR40 was an underlying therapeutic target for the external treatment of encephalopathy related to AD and GPR40 agonist could be explored as the emerging AD therapeutic drug.

Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease.

The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.

Ciprofloxacin and dexamethasone in combination attenuate S. aureus induced brain abscess via neuroendocrine-immune interaction of TLR-2 and glucocorticoid receptor leading to behavioral improvement.

Staphylococcus aureus induced brain abscess is a critical health concern throughout the developing world. The conventional surgical intervention could not regulate the abscess-induced brain inflammation. Thus further study over the alternative therapeutic strategy for treating a brain abscess is of high priority. The resident glial cells recognize the invading S. aureus by their cell surface Toll-like receptor-2 (TLR-2). Glucocorticoid receptor (GR) was known for its immunosuppressive effects. In this study, an attempt had been taken to utilize the functional relationship or cross-talking between TLR-2 and GR during the pathogenesis of brain abscesses. Here, the combination of an antibiotic (i.e. ciprofloxacin) and dexamethasone was used to regulate the brain inflammation either in TLR-2 or GR blocking condition. We were also interested to figure out the possible impact of alternative therapy on behavioral impairments. The results indicated that combination treatment during TLR-2 blockade significantly reduced the bacterial burden and abscess area score in the infected brain. However, marked improvements were observed in anxiety, depression-like behavior, and motor co-ordination. The combination treatment after TLR-2 blocking effectively scavenged free radicals (H2O2, superoxide anion, and NO) through modulating antioxidant enzyme activities that ultimately control S. aureus induced glial reactivity possibly via up-regulating GR expression. The exogenous dexamethasone might regulate the GR expression in the brain by increasing the corticosterone concentration and the GC-GR mediated signaling. Therefore, this in-vivo study demonstrates the possible regulatory mechanism of bacterial brain abscess that involved TLR-2 and GR as a part of neuroendocrine-immune interaction.

STC1 ameliorates cognitive impairment and neuroinflammation of Alzheimer's disease mice via inhibition of ERK1/2 pathway.

OBJECTIVE: To investigate the regulatory role of STC1 (Stanniocalcin-1) mediated ERK1/2 pathway in cognitive impairment and neuroinflammation of Alzheimer's disease (AD). METHODS: WT mice and STC1 Tg mice (transgenic overexpression of STC1) were used to establish AD models to perform behavioral test by Morris water maze. Hippocampal cell apoptosis was quantified by TUNEL staining, the levels of inflammatory cytokines in serum and hippocampal tissues determined by ELISA, as well as oxidative stress-related factors detected by corresponding testing kits, and protein expression of STC1 and ERK1/2 pathway measured by Western blotting. RESULTS: Compared with WT Sham group, WT AD mice had prolonged escape latency, decreased crossing platform times, increased hippocampal cell apoptosis with up-regulated inflammatory cytokines and oxidative stress-related factors, as well as increased STC1 and ERK1/2 pathway-related molecules. By contrast, STC1 Tg AD mice showed shortened escape latency, increased crossing platform times than WT AD mice, and they also exhibited the decreased apoptosis index and inflammatory cytokines, alleviated oxidative stress-injury, down-regulated protein expression of ERK1/2 pathway, and up-regulated the protein expression of STC1 and UCP2. CONCLUSION: STC1 overexpression could alleviate oxidative stress-induced injury, reduce neuroinflammation, improve cognitive function to play a neuro-protective role by inhibiting ERK1/2 signaling pathway.

Lipocalin 2 regulates iron homeostasis, neuroinflammation, and insulin resistance in the brains of patients with dementia: Evidence from the current literature.

Dementia accompanied by memory loss is considered one of the most common neurodegenerative diseases worldwide, and its prevalence is gradually increasing. Known risk factors for dementia include genetic background, certain lifestyle and dietary patterns, smoking, iron overload, insulin resistance, and impaired glucose metabolism in the brain. Here, we review recent evidence on the regulatory role of lipocalin 2 (LCN2) in dementia from various perspectives. LCN2 is a neutrophil gelatinase-associated protein that influences diverse cellular processes, including the immune system, iron homeostasis, lipid metabolism, and inflammatory responses. Although its functions within the peripheral system are most widely recognized, recent findings have revealed links between LCN2 and central nervous system diseases, as well as novel roles for LCN2 in neurons and glia. Furthermore, LCN2 may modulate diverse pathological mechanisms involved in dementia. Taken together, LCN2 is a promising therapeutic target with which to address the neuropathology of dementia.

Extracellular vesicles in neuroinflammation: Pathogenesis, diagnosis, and therapy.

Extracellular vesicles (EVs) are bilayer membrane vesicles and act as key messengers in intercellular communication. EVs can be secreted by both neurons and glial cells in the central nervous system (CNS). Under physiological conditions, EVs contribute to CNS homeostasis by facilitating omnidirectional communication among CNS cell populations. In response to CNS injury, EVs mediate neuroinflammatory responses and regulate tissue damage and repair, thereby influencing the pathogenesis, development, and/or recovery of neuroinflammatory diseases, including CNS autoimmune diseases, neurodegenerative diseases, stroke, CNS traumatic injury, and CNS infectious diseases. The unique ability of EVs to pass through the blood-brain barrier further confers them an important role in the bidirectional communication between the CNS and periphery, and application of EVs enables the diagnosis, prognosis, and therapy of neuroinflammatory diseases in a minimally invasive manner.