Effects of electroconvulsive shock on neuro-immune responses: Does neuro-damage occur?

Electroconvulsive therapy (ECT) is one of the most effective treatments for treatment-resistant depression. However, this treatment may produce memory impairment. The mechanisms of the cognitive adverse effects are not known. Neuroimmune response is related to the cognitive deficits. By reviewing the available animal literature, we examined the glia activation, inflammatory cytokines, neuron oxidative stress responses, and neural morphological changes following electroconvulsive shock (ECS) treatment. The studies showed that ECS activates microglia, upregulates neuro-inflammatory cytokines, and increases oxidative stress responses. But these effects are rapid and may be transient. They normalize as ECS treatment continues, suggesting endogenous neuroprotection may be mobilized. The transient changes are well in line with the clinical observations that ECT usually does not cause significant long-lasting retrograde amnesia. The longitudinal studies will be particularly important to explore the dynamic changes of neuroplasticity following ECT (Jonckheere et al., 2018). Investigating the neuroplasticity changes in animals that suffered chronic stress may also be crucial to giving support to the translation of preclinical research.

Stiff person spectrum disorders: An illustrative case series of their phenotypic and antibody diversity.

Stiff person spectrum disorders (SPSD) are a broad group of immune-mediated disorders. Clinical presentations include classical stiff person syndrome (SPS), focal SPS, and progressive encephalomyelitis with rigidity and myoclonus (PERM). The most frequently associated antibodies are anti-GAD65, anti-GlyR, anti-amphiphysin, and anti-DPPX. Immunotherapy is the primary treatment modality. We present an illustrative case series of three patients: anti-GlyR antibody-mediated PERM presenting as rapidly progressive dementia; anti-amphiphysin antibody-mediated SPS; and SPS presentation with anti-Zic4 antibodies, spasmodic laryngeal stridor and fluctuating eyelid ptosis. Clinical characteristics, CSF findings, neurophysiological features, adequate immunological assays and a high suspicion index are essential for prompt diagnosis and management.

Herpes Simplex Virus Type-1 Infection: Associations with Inflammation and Cognitive Aging in Relation to Schizophrenia.

Most persons experience cognitive decline as they grow older. The term "cognitive aging," coined to describe milder varieties of cognitive decline, is likely to be due to multiple causes. Persistent or repeated infections of the central nervous system (whether subclinical or diagnosable) can cause damage to neurons directly or indirectly through inflammation resulting in incremental neuronal damage, thus eroding cognitive reserve. This possibility has not been considered widely. We evaluated the data linking persistent infection with herpes simplex virus type 1 (HSV-1) and cognitive aging by applying the Bradford Hill criteria. Despite inherent problems in establishing causal relations for chronic disorders, our analyses suggest plausible links. These studies are pertinent for patients with schizophrenia, who are particularly vulnerable due to disorder-related cognitive impairment. Further investigations are warranted to test a causal hypothesis, particularly prospective studies and intervention studies.

1-Methylnicotinamide attenuates lipopolysaccharide-induced cognitive deficits via targeting neuroinflammation and neuronal apoptosis.

Alzheimer's disease (AD) is a neurodegenerative disease that affects cognition and behavior. The neuroinflammatory response in the brain is an important pathological characteristic in AD. In this study, we investigated the neuroprotective effects of 1-Methylnicotinamide (MNA), known as the main metabolite of nicotinamide, on reducing lipopolysaccharide (LPS)-induced cognitive deficits via targeting neuroinflammation and neuronal apoptosis. We found that the mice treated with LPS exhibited cognitive deficits in the novel object recognition, Morris water maze and Y-maze avoidance tests. However, intragastric administration of MNA (100 or 200 mg/kg) for 3 weeks significantly attenuated LPS-induced cognitive deficits in mice. Importantly, MNA treatment suppressed the protein expression of nuclear factor-kappa B p65 (NF-κB p65), pro-inflammatory cytokines (TNF-α, IL-6) and decreased the activation of microglia and astrocytes in the hippocampus and frontal cortex of LPS-induced mice. In addition, MNA treatment suppressed neuronal apoptosis by reducing the number of TUNEL-positive cells, caspase-3 activation and increasing the level of Bcl-2/Bax ratio in the hippocampus and frontal cortex. These findings indicate that MNA could be a potential neuroprotective drug in neurodegenerative diseases such as AD.

Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity, Attenuates Cognitive Deficits in APP/PS1 Mice.

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease (AD). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD-like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 between the APP/PS1 mice and the age-matched wild type (WT) mice at different stages of development using western blot and RT-qPCR. The hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice was higher than that of the WT mice starting from 6 months to 10 months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time-dependent manner. The spatial learning and memory deficit from the 8-month-old APP/PS1 mice was observed in the Y-maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra-hippocampal injection of AAV-TIPE2 into APP/PS1 mice resulted in an improvement of learning and memory and reduced expression of inflammatory cytokines, such as TNF-α, IL-6 and IL-1ß, and increased expression of anti-inflammatory cytokines, such as IL-10 and Arg-1. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the pathogenesis of Alzheimer's disease, and overexpression of TIPE2 attenuates cognitive deficits in APP/PS1 mice, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits. Graphical Abstract .

Alpha lipoic acid and metformin alleviates experimentally induced insulin resistance and cognitive deficit by modulation of TLR2 signalling.

BACKGROUND: Obesity is commonly found to be co-morbid with type 2 Diabetes Mellitus. In obese diabetic patients, TLR-2 receptor induced inflammation leads to the development of insulin resistance (IR). Furthermore, the IR is considered to be the most important cause for promoting cognitive decline which is evident in brain of patients with Alzheimer's disease related dementia (ADRD). METHODS: In this study, the effect of α-lipoic acid (ALA) has been examined in rodent model of zymosan induced insulin resistance and cognitive deficits, targeting at TLR-2 signalling. TLR-2 agonist, Zymosan initiates inflammatory cascade, resulting in IR and cognitive dysfunction. Zymosan (50 mg/kg ip) was given to mice on 1st, 8th, 15th and 22nd day to induce IR which was confirmed by hyperglycaemia, hyperinsulinemia, hyperlipidimea, increased glycated haemoglobin and HOMA-IR. Further the cognitive performance was assessed in Morris water maze revealing cognitive deficit in zymosan treated mice. RESULTS: Daily treatment with ALA for 28 days (50, 100, 200 mg/kg, ip) significantly improved insulin sensitivity and cognitive performance in mice by decreasing insulin resistance, corticosterone, IL-6 levels, acetylcholinesterase enzyme activity and oxidative stress in liver, cortex and hippocampus. ALA also increased adiponectin level and reduced body weight. Combination of ALA (100 mg/kg, ip) with metformin (100 mg/kg, ip) exhibited a potentiating effect in improving cognitive performance and insulin signalling. CONCLUSION: The findings of the study supported the hypothesis that TLR-2 induced inflammation leads to insulin resistance and cognitive impairment and provides an evidence for the therapeutic effect of ALA in IR and ADRD patients.

Combination of chick embryo and nutrient mixture prevent D-galactose-induced cognitive deficits, immune impairment and oxidative stress in aging rat model.

Aging is spontaneous and inevitable processes that lead to changes in biological systems. The present paper was designed to investigate the anti-aging roles of chick embryo (CE) and nutrient mixture (NM) in aging rats. Aging was induced by administration of D-galactose (D-gal, 500 mg/kg/day for 90 days). CE and NM were administered to aging rats through different dose gavage once a day. Cognitive function assessment was performed using the Morris water maze test. At the end of experiment, serum and tissues were collected for immunity and antioxidation function. The organs and tissues were excised for histological study. The results demonstrated that CE plus NM was superior treatment to improve the histopathologic changes and reverse learning and memory impairment of the aging rats. CE plus NM also increased the spleen and thymus index as well as splenocyte proliferation, and reversed inflammatory cytokine levels. In addition, the biochemical index showed that CE plus NM could improve the antioxidant enzyme activity of the aging rats, decrease lipofuscin (LF) and glutamate content. CE plus NM also inhibited the activation of TLR4/NF-κB pathway stimulated by LPS in splenic B lymphocytes. Overall, these results seem to be implying that CE plus NM was used as potentially natural supplement or functional food for preventing aging.

A year-long immune profile of the systemic response in acute stroke survivors.

Stroke is a leading cause of cognitive impairment and dementia, but the mechanisms that underlie post-stroke cognitive decline are not well understood. Stroke produces profound local and systemic immune responses that engage all major innate and adaptive immune compartments. However, whether the systemic immune response to stroke contributes to long-term disability remains ill-defined. We used a single-cell mass cytometry approach to comprehensively and functionally characterize the systemic immune response to stroke in longitudinal blood samples from 24 patients over the course of 1 year and correlated the immune response with changes in cognitive functioning between 90 and 365 days post-stroke. Using elastic net regularized regression modelling, we identified key elements of a robust and prolonged systemic immune response to ischaemic stroke that occurs in three phases: an acute phase (Day 2) characterized by increased signal transducer and activator of transcription 3 (STAT3) signalling responses in innate immune cell types, an intermediate phase (Day 5) characterized by increased cAMP response element-binding protein (CREB) signalling responses in adaptive immune cell types, and a late phase (Day 90) by persistent elevation of neutrophils, and immunoglobulin M+ (IgM+) B cells. By Day 365 there was no detectable difference between these samples and those from an age- and gender-matched patient cohort without stroke. When regressed against the change in the Montreal Cognitive Assessment scores between Days 90 and 365 after stroke, the acute inflammatory phase Elastic Net model correlated with post-stroke cognitive trajectories (r = -0.692, Bonferroni-corrected P = 0.039). The results demonstrate the utility of a deep immune profiling approach with mass cytometry for the identification of clinically relevant immune correlates of long-term cognitive trajectories.

T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis.

Hypertension is considered the major modifiable risk factor for the development of cognitive impairment. Because increased blood pressure is often accompanied by an activation of the immune system, the concept of neuro-inflammation gained increasing attention in the field of hypertension-associated neurodegeneration. Particularly, hypertension-associated elevated circulating T-lymphocyte populations and target organ damage spurred the interest to understanding mechanisms leading to inflammation-associated brain damage during hypertension. The present study describes sphingosine-1-phosphate (S1P) as major contributor to T-cell chemotaxis to the brain during hypertension-associated neuro-inflammation and cognitive impairment. Using Western blotting, flow cytometry and mass spectrometry approaches, we show that hypertension stimulates a sphingosine kinase 1 (SphK1)-dependent increase of cerebral S1P concentrations in a mouse model of angiotensin II (AngII)-induced hypertension. The development of a distinct S1P gradient between circulating blood and brain tissue associates to elevated CD3+ T-cell numbers in the brain. Inhibition of S1P1-guided T-cell chemotaxis with the S1P receptor modulator FTY720 protects from augmentation of brain CD3 expression and the development of memory deficits in hypertensive WT mice. In conclusion, our data highlight a new approach to the understanding of hypertension-associated inflammation in degenerative processes of the brain during disease progression.

Gene expression changes related to immune processes associate with cognitive endophenotypes of schizophrenia.

Schizophrenia is a heterogeneous disorder characterized by a spectrum of symptoms and many different underlying causes. Thus, instead of using the broad diagnosis, intermediate phenotypes can be used to possibly decrease the underlying complexity of the disorder. Alongside the classical symptoms of delusions and hallucinations, cognitive deficits are a core feature of schizophrenia. To increase our understanding of the biological processes related to these cognitive deficits, we performed a genome-wide gene expression analysis. A battery of 14 neuropsychological tests was administered to 844 individuals from a Finnish familial schizophrenia cohort. We grouped the applied neuropsychological tests into five factors for further analysis. Cognitive endophenotypes, whole blood mRNA, genotype, and medication use data were studied from 47 individuals. Expression level of several RNA probes were significantly associated with cognitive performance. The factor representing Verbal Working Memory was associated with altered expression levels of 11 probes, of which one probe was also associated with a specific sub-measure of this factor (WMS-R Digit span backward). While, the factor Processing speed was related to one probe, which additionally associated among 55 probes with a specific sub-measure of this factor (WAIS-R Digit symbol). Two probes were associated with the measure recognition memory performance. Enrichment analysis of these differentially expressed probes highlighted immunological processes. Our findings are in line with genome-wide genetic discoveries made in schizophrenia, suggesting that immunological processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1ß replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1ß synthesis. Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1ß but direct hippocampal action of IL-1ß causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

Cognitive impairment, event-related potentials and immunological status in patients with systemic lupus erythematosus.

BACKGROUND: Cognitive impairment (CI) is a frequent problem in lupus patients, regardless of their overt neuropsychiatric (NP) involvement. OBJECTIVES: The aim of our study was to test cognitive abilities in systemic lupus erythematosus (SLE) patients by means of neuropsychological testing and event-related potentials (ERPs), and to search for their cognitive abilities correlations with a wide range of auto-antibodies. MATERIAL AND METHODS: A total of 37 SLE patients were subjected to a battery of neuropsychological tests, recommended by the American College of Rheumatology (ACR), and to ERPs. They were also tested for a wide range of auto-antibodies (anti-cardiolipin (aCL), anti-ß2-glycoprotein I (anti-ß2-GPI), lupus anticoagulant, anti-dsDNA, anti-nucleosome, anti-ribosomal P (anti-Rib-P), anti-ganglioside, anti-Ro/SS-A, and anti-La/SS-B. RESULTS: Cognitive impairment was found in 35% of patients, mostly with NP SLE (NPSLE), and was associated with higher disease activity, measured by the SLE Disease Activity Index (SLEDAI), and with a longer duration of central nervous system (CNS) involvement. There were no differences in the immunological status between CI patients and those without cognitive decline, but some antibodies were correlated with worse results in certain neuropsychological tests (anti-dsDNA and worse results of Rey Complex Figure Test - RCFTc for copying and RCFTr for recall, and of verbal fluency test (VFT); aCL IgG and worse results in Digit Span (DS) and in RCFTc). Event-related potentials showed prolonged N200 and P300 latencies in SLE patients in comparison to controls, but no differences were found between SLE and NPSLE patients. Mean P300 latency was significantly longer in patients without anti-nucleosome antibodies. CONCLUSIONS: Event-related potentials can be used as a complementary tool in assessing CI in SLE patients. The immunological status of patients with CI did not differ from that of patients without cognitive problems.

NEUROPSYCHOBIOLOGICAL MECHANISMS OF AFFECTIVE AND COGNITIVE DISORDERS IN THE CHORNOBYL CLEAN-UP WORKERS TAKING INTO ACCOUNT THE SPECIFIC GENE POLYMORPHISMS. / NEIROPSYKhOBIOLOGIChNI MEKhANIZMY AFEKTYVNYKh I KOGNITYVNYKh ROZLADIV V UChASNYKIV LIKVIDATsIÏ NASLIDKIV AVARIÏ NA ChORNOBYL'S'KII AES Z URAKhUVANNIaM POLIMORFIZMU GENIV.

Relevance of the present work is determined by the considerable prevalence of both affective and cognitive disor-ders in the victims due to the Chornobyl accident, the pathogenesis of which is insufficiently studied.Objective is to identify the neuropsychiobiological mechanisms of the formation of the remote affective and cog-nitive disorders following exposure to ionizing radiation taking into account the specific gene polymorphisms.Design, object and methods of research. The retrospective and prospective cohort study with the external andinternal control groups. The randomized sample of the male participants in liquidation of the consequences of theaccident (Chornobyl clean-up workers, liquidators) at the Chornobyl nuclear power plant (ChNPP) in 1986-1987(n = 198) recruited from the Clinico-epidemiological registry (CER) of NRCRM aged 39-87 (M ± SD: 60.0-8.5 years)with the external irradiation dose ranged 0.6-5900.0 mSv (M ± SD: 456.0 ± 760.0 mSv) was examined. The compar-ison group (n = 110) consisted of the unexposed patients of the Radiation Psychoneurology Department with thecorresponding age and sex (the external control group). The internal control group included the liquidators irradi-ated at doses < 50.0 mSv (n = 42). The standard diagnostic neuropsychiatric scales, psychodiagnostic questionnairesand tests, neuropsychological methods (including the Wechsler Adult Intelligence Scale (WAIS) with premorbid IQ(pre-IQ) assessment), neuropsychiatric and psychophysiological methods (quantitative EEG (qEEG) and the audito-ry cognitive evoked potentials (Event-Related Potentials, ERP) were applied. The genotypes of the serotonin trans-porter gene SLC6A4 were determined by the 5_HTTLPR and rs25531 polymorphisms. The methods of descriptive and vari-ation statistics, non-parametric criteria, regression-correlation analysis, survival analysis by Kaplan - Meier and riskanalysis were used.Results. Cerebrovascular diseases, organic mental and depressive disorders, mainly of radiation-stress-relatednature, prevail among the liquidators. The overall risk of neuropsychiatric pathology increases (Pv < 0.001) with theirradiation dose. The verbal memory and learning are impaired, as well as the full IQ is reduced at the expense of theverbal one. The frequency of both mild cognitive impairment and dementia is risen. The cognitive impairment atdoses > 0.3 Sv is dose-dependent (r = 0.4-0.7; p = 0.03-0.003). Affective disorders (depression) and neurocogni-tive deficit are more severe at higher doses of irradiation (> 50 mSv). In the left posterior temporal region(Wernicke's area) the qEEG indices changes become dose-dependent at doses greater than 0.25-0.3 Sv. The dis-turbed brain information processes lateralized to the Wernicke's area are observed even at doses > 50 mSv. The car-riers of intermediate and low-level genotypes (LА/S, LА/LG, LG/LG, LG/S, S/S) of the serotonin transporter gene SLC6A4have more depressive disorders, especially severe ones, and tend to have more frequent and severe cognitive andstress-related disorders.The debut of depressive disorders in the carriers of the intermediate and low-activity genotypes occurs much earli-er (Log-Rank Test = 4.43, p = 0.035) in comparison with the carriers of the high-performance genotype LА/ LА.Conclusions. The radiation-induced dysfunction of the cortico-limbic system in the left dominant hemisphere ofthe human brain with a specific involvement of the hippocampus is considered to be the key cerebral basis of post-radiation organic brain damage. The association of genotypes by 5_HTTLPR and rs25531 polymorphisms of the SLC6A4gene with affective and cognitive disorders suggests the presence of neuropsychobiological features of these dis-orders associated with ionizing radiation depending on the certain gene polymorphisms.

Recent advancements toward therapeutic vaccines against Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by protein aggregates of amyloid ß (Aß) and tau. These proteins have normal physiological functions, but in AD, they undergo a conformational change and aggregate as toxic oligomeric and fibrillar species with a high ß-sheet content. AREAS COVERED: Active and passive immunotherapeutic approaches are among the most attractive methods for targeting misfolded Aß and tau. Promising preclinical testing of various immunotherapeutic approaches has yet to translate to cognitive benefits in human clinical trials. Knowledge gained from these past failures has led to the development of second-generation Aß-active immunotherapies, anti-Aß monoclonal antibodies targeting a wide array of Aß conformations, and to a number of immunotherapies targeting pathological tau. This review covers the more recent advances in vaccine development for AD from 2016 to present. EXPERT COMMENTARY: Due to the complex pathophysiology of AD, greatest clinical efficacy will most likely be achieved by concurrently targeting the most toxic forms of both Aß and tau.

Naringenin ameliorates learning and memory impairment following systemic lipopolysaccharide challenge in the rat.

Systemic inflammation following infection is usually associated with long-term complications including cognitive deficit and dementia. Neuroinflammation and cognitive decline are also main hallmarks of several neurological conditions. Naringenin is a citrus flavanone with anti-inflammatory, neuroprotective, and antioxidant potential. In this study, the protective effect of naringenin against lipopolysaccharide (LPS)-induced cognitive decline was evaluated in the rat. LPS was daily injected at a dose of 167 µg/kg for 1 week and naringenin was administered p.o. at doses of 25, 50, or 100 mg/kg/day. Treatment of LPS-injected rats with naringenin dose-dependently improved spatial recognition memory in Y maze, discrimination ratio in novel object discrimination task, and retention and recall capability in passive avoidance test. Furthermore, naringenin lowered hippocampal malondialdehyde (MDA) as an index of lipid peroxidation and improved antioxidant defensive system comprising superoxide dismutase (SOD), catalase, and glutathione (GSH) in addition to decreasing acetylcholinesterase (AChE) activity. Additionally, naringenin was able to lower hippocampal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), tumor necrosis factor α (TNFα), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP) level and its immunoreactivity, and to elevate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Taken together, naringenin could alleviate LPS-induced cognitive deficits and neuroinflammation, as was evident from attenuation of oxidative stress and AChE and modulation of Nrf2/NF-κB/TNFα/COX2/iNOS/TLR4/GFAP.

Phos-tau peptide immunization of amyloid-tg-mice reduced non-mutant phos-tau pathology, improved cognition and reduced amyloid plaques.

Tau-immumotherapy has shown promising results in tangle/tauopathy-tg animal models. Here we immunized amyloid-mice (APPSwe/PSEN1dE9-tg, presenting amyloid-plaques, not neurofibrillary-tangles) with phos-tau peptides, previously shown by us to have high efficacy in mutant-tau tauopathy-mice. These amyloid-mice allowed us to test the effect of the vaccine in a model of familial AD patients with mutant amyloid plaque pathology, where tau pathology - once develops - is of non-mutant tau. Fourteen-month-old amyloid-mice were immunized with phos-tau peptides or vehicle. Eight weeks later, amelioration of cognitive impairment was noticed. Histological analysis revealed that the phos (non-mutant)-tau pathology (detected by us in these aged amyloid-mice while not in non-tg-mice), was lower in the phos-tau immunized amyloid-mice than in the non-immunized mice. Interestingly, we detected a decrease in amyloid plaque pathology, probably associated with the increased microglial burden, which surrounded both tau and amyloid pathology. These results point to the added value of immunizing AD-mice with the phos-tau-vaccine, targeting both tau and amyloid pathology, which may have clinical relevance. It also points to the multifaceted interplay between tau/amyloid pathologies.

Sustained high-fat diet modulates inflammation, insulin signalling and cognition in mice and a modified xenin peptide ameliorates neuropathology in a chronic high-fat model.

AIMS: To demarcate pathological events in the brain as a result of short-term to chronic high-fat-diet (HFD) feeding, which leads to cognitive impairment and neuroinflammation, and to assess the efficacy of Xenin-25[Lys(13)PAL] in chronic HFD-fed mice. METHODS: C57BL/6 mice were fed an HFD or a normal diet for 18 days, 34 days, 10 and 21 weeks. Cognition was assessed using novel object recognition and the Morris water maze. Markers of insulin signalling and inflammation were measured in brain and plasma using immunohistochemistry, quantitative PCR and multi-array technology. Xenin-25[Lys(13)PAL] was also administered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathological stage. RESULTS: Recognition memory was consistently impaired in HFD-fed mice and spatial learning was impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer616 were increased in the brain on day 18 in HFD-fed mice and were reduced by Xenin-25[Lys(13)PAL] in 21-week HFD-fed mice. In plasma, HFD feeding elevated interleukin (IL)-6 and chemokine (C-X-C motif) ligand 1 at day 34 and IL-5 at week 10. In the brain, HFD feeding reduced extracellular signal-regulated kinase 2 (ERK2), mechanistic target of rapamycin (mTOR), NF-κB1, protein kinase C (PKC)θ and Toll-like receptor 4 (TLR4) mRNA at week 10 and increased expression of glucacon-like peptide-1 receptor, inhibitor of NF-κB kinase ß, ERK2, mTOR, NF-κB1, PKCθ and TLR4 at week 21, elevations that were abrogated by Xenin-25[Lys(13)PAL]. CONCLUSIONS: HFD feeding modulates cognitive function, synapse density, inflammation and insulin resistance in the brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation and insulin signalling dysregulation and may have therapeutic potential in the treatment of diseases associated with neuroinflammation or perturbed insulin signalling in the brain.

[Update on anti-N-methyl-D-aspartate receptor encephalitis]. / Update Anti-N-Methyl-D-Aspartat-Rezeptor-Enzephalitis.

Autoimmune encephalitis is a group of autoimmune inflammatory disorders affecting both grey and white matter of the central nervous system. Encephalitis with autoantibodies against the N­methyl-D-aspartate receptor (NMDA-R) is the most frequent autoimmune encephalitis syndrome presenting with a characteristic sequence of psychiatric and neurological symptoms. Treatment necessitates a close interdisciplinary cooperation. This article provides an update on the current knowledge on diagnostic standards, pathogenesis, and treatment strategies for anti-NMDA-R encephalitis from psychiatric and neurological perspectives.

Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation.

BACKGROUND: Sleep deprivation (SD) leads to cognitive impairment. Neuroinflammation could be a significant contributing factor in the same. An increase in regional brain pro-inflammatory cytokines induces cognitive deficits, however, the magnitude of the effect under SD is not apparent. It is plausible that microglia activation could be involved in the SD-induced cognitive impairment by modulation of neuronal cell proliferation, differentiation, and brain-derived neuronal factor (BDNF) level. The present study aimed to evaluate the possible beneficial effect of minocycline in amelioration of spatial memory decline during SD by its anti-inflammatory and neuroprotective actions. We scrutinized the effect of minocycline on the inflammatory cytokine levels associated with glial cells (microglia and astrocytes) activity and neurogenesis markers crucial for behavioral functions during SD. METHODS: Male Sprague-Dawley rats weighing 230-250 g were sleep deprived for 48 h using automated cage shaking apparatus. The spatial memory was tested using MWM apparatus immediately after completion of SD with and without minocycline. The animals were euthanized, blood was collected, and brain was extracted for neuroinflammation and neurogenesis studies. The set of experiments were also conducted with use of temozolomide, a neurogenesis blocker. RESULTS: Minocycline treatment increased the body weight, food intake, and spatial memory performance which declined during SD. It reduced the pro-inflammatory and increased the anti-inflammatory cytokine levels in hippocampus and plasma and inhibited the reactive gliosis in the hippocampus evidenced by improved cell count, morphology, and immunoreactivity. Additionally, minocycline administration promoted neurogenesis at different stages: proliferation (BrdU, Ki-67), differentiation (DCX) cells and growth factor (BDNF). However, no significant change was observed in maturation (NeuN) during SD. In addition, molecules related to behavior, inflammation, and neurogenesis were shown to be more affected after temozolomide administration during SD, and changes were restored with minocycline treatment. We observed a significant correlation of neurogenesis with microglial activation, cytokine levels, and spatial memory during SD. CONCLUSION: The present study demonstrated that the SD-induced decline in spatial memory, neuronal cells proliferation, differentiation, and BDNF level could be attributed to upregulation of neuroinflammatory molecules, and minocycline may be an effective intervention to counteract these changes. Microglial activation is involved in SD-induced changes in inflammatory molecules, neurogenesis, and spatial memory.