Neuroinflammatory Processes Research Articles

Microglia targeting by adeno-associated viral vectors.

Microglia play a crucial role in maintaining homeostasis of the central nervous system and they are actively involved in shaping the brain's inflammatory response to stress. Among the multitude of involved molecules, purinergic receptors and enzymes are of special importance due to their ability to regulate microglia activation. By investigating the mechanisms underlying microglial responses and dysregulation, researchers can develop more precise interventions to modulate microglial behavior and alleviate neuroinflammatory processes. Studying gene function selectively in microglia, however, remains technically challenging. This review article provides an overview of adeno-associated virus (AAV)-based microglia targeting approaches, discussing potential prospects for refining these approaches to improve both specificity and effectiveness and encouraging future investigations aimed at connecting the potential of AAV-mediated microglial targeting for therapeutic benefit in neurological disorders.

Neurodegenerative diseases and catechins: (-)-epigallocatechin-3-gallate is a modulator of chronic neuroinflammation and oxidative stress.

Catechins, a class of phytochemicals found in various fruits and tea leaves, have garnered attention for their diverse health-promoting properties, including their potential in combating neurodegenerative diseases. Among these catechins, (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, has emerged as a promising therapeutic agent due to its potent antioxidant and anti-inflammatory effects. Chronic neuroinflammation and oxidative stress are key pathological mechanisms in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). EGCG has neuroprotective efficacy due to scavenging free radicals, reducing oxidative stress and attenuating neuroinflammatory processes. This review discusses the molecular mechanisms of EGCG's anti-oxidative stress and chronic neuroinflammation, emphasizing its effects on autoimmune responses, neuroimmune system interactions, and focusing on the related effects on AD and PD. By elucidating EGCG's mechanisms of action and its impact on neurodegenerative processes, this review underscores the potential of EGCG as a therapeutic intervention for AD, PD, and possibly other neurodegenerative diseases. Overall, EGCG emerges as a promising natural compound for combating chronic neuroinflammation and oxidative stress, offering novel avenues for neuroprotective strategies in the treatment of neurodegenerative disorders.

Matrix stiffness-dependent microglia activation in response to inflammatory cues: in situ investigation by scanning electrochemical microscopy.

Microglia play a crucial role in maintaining the homeostasis of the central nervous system (CNS) by sensing and responding to mechanical and inflammatory cues in their microenvironment. However, the interplay between mechanical and inflammatory cues in regulating microglia activation remains elusive. In this work, we constructed in vitro mechanical-inflammatory coupled microenvironment models of microglia by culturing BV2 cells (a murine microglial cell line) on polyacrylamide gels with tunable stiffness and incorporating a lipopolysaccharide (LPS) to mimic the physiological and pathological microenvironment of microglia in the hippocampus. Through characterization of activation-related proteins, cytokines, and reactive oxygen species (ROS) levels, we observed that the LPS treatment induced microglia on a stiff matrix to exhibit overexpression of NOX2, higher levels of ROS and inflammatory factors compared to those on a soft matrix. Additionally, using scanning electrochemical microscopy (SECM), we performed in situ characterization and discovered that microglia on a stiff matrix promoted extracellular ROS production, leading to a disruption in their redox balance and increased susceptibility to LPS-induced ROS production. Furthermore, the respiratory activity and migration behavior of microglia were closely associated with their activation process, with the stiff matrix-LPS-induced microglia demonstrating the most pronounced changes in respiratory activity and migration ability. This work represents the first in situ and dynamic monitoring of microglia activation state alterations under a mechanical-inflammatory coupled microenvironment using SECM. Our findings shed light on matrix stiffness-dependent activation of microglia in response to an inflammatory microenvironment, providing valuable insights into the mechanisms underlying neuroinflammatory processes in the CNS.

Neuroinflammation: The missing link between pain and immunity

The density of corneal nerves in the cornea is the highest of the entire body. Most ocular surface diseases/injuries affect corneal neurons and are followed by a process named neurogenic inflammation, which eventually leads to pain, activation and recruitment of leukocytes and neoangiogenesis. On the other hand, leukocytes affect nerve physiology by secreting pro‐inflammatory cytokines and neuropeptides. The clinical outcome of the neuroinflammatory process is two‐faced. While immune activation is beneficial to prevent/control infections and ensure prompt wound healing, a prolonged and/or excessive neuroinflammatory response can have catastrophic consequences on corneal integrity and vision, or induce chronic pain. Clearly, a better understanding of these complex processes can have a deep impact on the treatment of highly prevalent ocular disorders, such as dry eye or infectious keratitis.

Association of multiple sclerosis with stroke: A comprehensive review.

Multiple sclerosis (MS) is a chronic immune-mediated disorder characterized by the degradation of the myelin sheath in the central nervous system. Research indicates that individuals with MS exhibit a higher susceptibility to stroke compared to the general population. This association is rooted in shared underlying mechanisms, specifically involving neuroinflammatory processes. We performed an extensive search on PubMed, MEDLINE, Embase, Scopus, and Google Scholar using specific terms. The search terms included variations of "multiple sclerosis," "stroke," "cerebrovascular disease," "vascular risk factors," "disease-modifying therapies," and "neuroinflammation." The search was limited to articles published from January 1, 2000, up to 31 May, 2023. Stroke, a global health burden characterized by significant mortality and adult disability, underscores the critical importance of understanding the link between MS and stroke. Despite a growing body of research establishing an elevated risk of stroke in MS patients, notable information gaps persist. Limited prospective multicenter studies on stroke incidence in MS patients contribute to an incomplete understanding of the precise relationship between these two conditions. In conclusion, this review underscores the critical need for a thorough understanding of the complex relationship between MS and stroke. The identified risk factors and the influence of MS DMTs on stroke risk necessitate further investigation to inform evidence-based preventive and therapeutic strategies. Bridging the existing information gaps through prospective multicenter studies is imperative for a comprehensive understanding of this association. The development of targeted diagnostic and therapeutic approaches for acute stroke risk in MS patients is paramount to mitigate the impact of these debilitating conditions. Ultimately, this review serves as a foundation for future efforts to enhance preventative measures and therapeutic interventions, thereby improving the overall quality of life for individuals with MS susceptible to strokes.

Increased Resting-State BOLD Turnover (TBOLD) is Associated With Decreased Cognitive Performance During Aging

Increasing evidence documents turnover of the resting-state blood-oxygen-level dependent signal (TBOLD) as a key measure of local cortical brain status. Here we evaluated contemporaneous and lagged associations between TBOLD and cognitive function in 711 participants in the Human Connectome Project on Aging (HCP-A; 316 males and 395 females, age range 36-90 years). We found that TBOLD was negatively associated with Montreal Cognitive Assessment (MoCA) Total scores and with performance on 2 subscales, Delayed Recall and Visuospatial/Executive Function, controlling for sex, age, and handedness. This negative association was largely documented across brain areas and was significantly stronger in the left hemisphere compared to the right. In addition, analyses evaluating forward lagged crosscorrelations between TBOLD and cognitive performance demonstrated that TBOLD predicted decrements in future performance on MoCA Total score, Delayed Recall, and Visuospatial/Executive Function subscales, controlling for sex and handedness. Taken together, we found that increased TBOLD is associated with decreased cognitive performance contemporaneously and in the future. On the hypothesis that increased TBOLD is the outcome of neuroinflammatory processes, these findings provide a mechanism linking neuroinflammation with decreased cognitive performance.

Limited contribution of the of P2X4 receptor to LPS-induced microglial reaction in mice.

Sepsis is life-threatening condition that can trigger long-term neurological sequelae, including cognitive impairment in survivors. The pathogenesis of the so-called sickness behavior is poorly understood, but sepsis-driven neuroinflammation is thought to play a key role. Microglia are the central nervous system resident immune cells and play major roles in the induction and the control of neuroinflammatory processes. Accordingly, we recently demonstrated important microglia reaction, characterized by dramatic microglia transcriptome remodeling, in an experimental model of sepsis. Interfering with microglia pathways thus represents an interesting opportunity to tune microglia reaction towards beneficial outcomes. Purinergic signaling is central to microglia biology and controls key microglia functions. In particular, P2X4 receptors, which are highly permeable to calcium and de novo expressed in reactive microglia, seem to be an interesting target to modulate microglia reaction. Here, we investigated the impact of P2X4 receptors on the LPS-driven microglia transcriptome remodeling. Although we used complementary and sensitive biostatistical approaches, we did not measure significant impact of P2X4 deficiency onto microglia transcriptome either in homeostatic nor reactive condition. Overall, our results revealed that microglia reaction elicited by LPS-mediated sepsis is P2X4 independent and highlights the functional diversity of microglia reaction. These results also promote for the search of disease-specific targets to tune microglia reaction towards beneficial outcomes.

How Early Is Early Multiple Sclerosis?

The development and further optimization of the diagnostic criteria for multiple sclerosis (MS) emphasize the establishment of an early and accurate diagnosis. So far, numerous studies have revealed the significance of early treatment administration for MS and its association with slower disease progression and better late outcomes of the disease with regards to disability accumulation. However, according to current research results, both neuroinflammatory and neurodegenerative processes may exist prior to symptom initiation. Despite the fact that a significant proportion of individuals with radiologically isolated syndrome (RIS) progress to MS, currently, there is no available treatment approved for RIS. Therefore, our idea of "early treatment administration" might be already late in some cases. In order to detect the individuals who will progress to MS, we need accurate biomarkers. In this review, we present notable research results regarding the underlying pathology of MS, as well as several potentially useful laboratory and neuroimaging biomarkers for the identification of high-risk individuals with RIS for developing MS. This review aims to raise clinicians' awareness regarding "subclinical" MS, enrich their understanding of MS pathology, and familiarize them with several potential biomarkers that are currently under investigation and might be used in clinical practice in the future for the identification of individuals with RIS at high risk for conversion to definite MS.

Plasma interleukin 6 as an outcome predictor of traumatic brain injury patients.

Traumatic brain injury is one of the leading causes of death and disability in young adults. Previous studies have suggested that neuroinflammatory process involves the overexpression of interleukin 6 (IL-6); however, data on the predictive ability of IL-6 is limited and conflicting in traumatic head injury patients. The aim of this study was to assess the ability of plasma IL-6 as a predictor of outcome in head injury patients. A cross-sectional study was conducted between June and December 2020 among traumatic head injury patients admitted to Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia. Demographic, clinical data, and IL-6 level were collected and measured on admission. The outcome was assessed by the Glasgow outcome scale extended (GOSE) in the first- and third-month of post-injury. A total of 50 traumatic brain injury patients were recruited of which 54% were male, 64% had mild head injury, 82% had leukocytosis, and 60% had non-bleeding head CT scan. The mean of IL-6 level was 79.32 pg/mL while the GOSE scores ranged from 1 (death) to 8 (upper good recovery). Early IL-6 level (<24 hours post-injury) was significantly correlated with worse outcome in traumatic head injury, though the correlation strength was moderate (p<0.001; r=-0.42). As a predictor, IL-6 yielded the area under curve (AUC) value of 93.5% (p<0.001) and a cut-off point of 46.33 pg/mL. The sensitivity and specificity of this predictor were 87.5% and 95.24%, respectively. In conclusion, early IL-6 level can be used as a predictor for traumatic head injury. Nevertheless, further multi-center study with a bigger sample size is needed to confirm this finding.

Inhibition of voltage-gated Hv1 alleviates LPS-induced neuroinflammation via regulation of microglial metabolic reprogramming

A growing body of evidence highlights the crucial role of metabolic reprogramming in activated immune cells, significantly contributing to both the initiation and progression of neuroinflammation and neurodegenerative diseases. The voltage-gated H channel (Hv1) has been reported to be involved in microglial activation and acts as a key driver of neuroinflammation. This study aimed to explore how Hv1-mediated metabolic reprogramming contributes to neuroinflammation and to assess the therapeutic potential of the Hv1 inhibitor 2-GBI in a model of lipopolysaccharide (LPS)-induced neuroinflammation. We investigated the influence of 2-GBI on the generation of ROS, metabolic reprogramming, and pro-inflammatory mediator production in vitro and examined the therapeutic effect of 2-GBI on microglial activation and hippocampal neuroinflammation in vivo. The results indicated that 2-GBI attenuated the LPS-induced pro-inflammatory response and aerobic glycolysis in microglia, specifically mitigating HIF1α-mediated upregulation of glycolysis. 2-GBI exerted a protective effect against LPS-induced neuroinflammation through HIF1α pathway-regulated aerobic glycolysis. Using a transwell coculture system, we demonstrated that 2-GBI reversed PC12 cell death caused by BV2-mediated neuroinflammation. In vivo experiments further suggested that 2-GBI mitigated neuroinflammatory processes and cognitive dysfunction via microglial metabolic reprogramming. Collectively, our results highlight the potential of Hv1 inhibition as a therapeutic strategy for alleviating LPS-induced neuroinflammation by modulating microglial metabolic reprogramming.

Segmentation and quantification of venous structures and perivascular spaces in the thalamus in epilepsy using 7 Tesla MRI

Background and purposeEpilepsy is a complex neurological disorder affecting 50 million people worldwide. Persistent seizures may correlate with neural network, microstructural, and vascular changes within the thalamus. These thalamic changes may result from seizure activity or broader alterations involving neuronal vasculature and neuroinflammatory processes linked to glymphatic drainage. Improved resolution with Ultra-high field (UHF) magnetic resonance imaging (MRI) may be useful in identifying possible thalamic vascular abnormalities not otherwise detectable at lower field strengths. Materials and methodsWe outline a novel method which leverages UHF neuroimaging for detection and quantification of vessels and perivascular spaces (PVS) within the thalamus in 25 epilepsy patients and 16 controls, to uncover possible underlying imaging biomarkers of epilepsy. In our analysis, we optimize a MATLAB-based Frangi-based detection tool called Perivascular Space Semi-Automated Segmentation (PVSSAS) to detect thalamic PVSs, and additionally use a second Frangi-based segmentation tool method to automate detection of vascular structures in the thalamus. The resulting PVS and vessel masks were used to quantify differences in the number of vessels, PVS, overlaps, and number of PVS overlaps per vessel detected between groups, using a Hessian detection filter linked on an 18-connected network. ResultsWe found significantly more thalamic PVS (p = 0.0307) and a significant increase in the number of thalamic vessels (p = 0.038) in patients compared to controls. ConclusionHere we have developed a novel process which leverages UHF MRI to quantify and detect thalamic vessels and PVS that may provide a potential neuroimaging biomarker of epilepsy. Statement of SignificanceWe use 7T, ultra-high field MRI and employed an innovative combination of semi-automated perivascular space segmentation and automated vessel segmentation to visualize and quantify vessels and perivascular spaces (PVS) within the thalamus, a highly cited region of interest in epilepsy. To our knowledge, this is the first study to semi-automatically visualize and segment PVS in the thalamus and automatically detect thalamic vessels. We uncovered detectable differences in thalamic vasculature and PVS. These findings suggests that increases in the number of thalamic PVS and vessels may be a potential neuroimaging biomarker in epilepsy. This tool may be useful in the detection of subtle vascular changes in other regions of the brain related to epilepsy or can be employed in other neurological conditions.

Traumatic brain injury derived pathological tau polymorphs induce the distinct propagation pattern and neuroinflammatory response in wild type mice

The misfolding and aggregation of the tau protein into neurofibrillary tangles constitutes a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs. However, the mechanisms orchestrating the dissemination of TBI brain-derived tau polymorphs (TBI-BDTPs) remain elusive. In this study, we explored whether TBI-BDTPs could initiate pathological tau formation, leading to distinct pathogenic trajectories. Wild-type mice were exposed to TBI-BDTPs from sham, single-blast (SB), or repeated-blast (RB) conditions, and their memory function was assessed through behavioral assays at 2- and 8-month post-injection. Our findings revealed that RB-BDTPs induced cognitive and motor deficits, concurrently fostering the emergence of toxic tau aggregates within the injected hippocampus. Strikingly, this tau pathology propagated to cortical layers, intensifying over time. Importantly, RB-BDTP-exposed animals displayed heightened glial cell activation, NLRP3 inflammasome formation, and increased TBI biomarkers, particularly triggering the aggregation of S100B, which is indicative of a neuroinflammatory response. Collectively, our results shed light on the intricate mechanisms underlying TBI-BDTP-induced tau pathology and its association with neuroinflammatory processes. This investigation enhances our understanding of tauopathies and their interplay with neurodegenerative and inflammatory pathways following traumatic brain injury.

Novel hippocampal genes involved in enhanced susceptibility to chronic pain-induced behavioral emotionality

Altered mood and psychiatric disorders are commonly associated with chronic pain conditions; however, brain mechanisms linking pain and comorbid clinical depression are still largely unknown. In this study, we aimed to identify whether key genes/cellular mechanisms underlie susceptibility/resiliency to development of depressive-like behaviors during chronic pain state. Genome-wide RNA-seq analysis was used to examine the transcriptomic profile of the hippocampus, a limbic brain region that regulates mood and stress responses, from male rats exposed to chronic inflammatory pain. Pain-exposed animals were separated into either ‘resilient’ or ‘susceptible’ to development of enhanced behavioral emotionality based on behavioral testing. RNA-seq bioinformatic analysis, followed by validation using qPCR, revealed dysregulation of hippocampal genes involved in neuroinflammation, cell cycle/neurogenesis and blood-brain barrier integrity. Specifically, ADAM Metallopeptidase Domain 8 (Adam8) and Aurora Kinase B (Aurkb), genes with functional roles in activation of the NLRP3 inflammasome and microgliosis, respectively, were significantly upregulated in the hippocampus of ‘susceptible’ animals expressing increased behavioral emotionality. In addition, genes associated with blood-brain barrier integrity, such as the Claudin 4 (Cldn4), a tight junction protein and a known marker of astrocyte activation, were also significantly dysregulated between ‘resilient’ or ‘susceptible’ pain groups. Furthermore, differentially expressed genes (DEGs) were further characterized in rodents stress models to determine whether their hippocampal dysregulation is driven by common stress responses vs. affective pain processing. Altogether these results continue to strengthen the connection between dysregulation of hippocampal genes involved in neuroinflammatory and neurodegenerative processes with increased behavioral emotionality often expressed in chronic pain state

Epilepsy is more than a simple seizure disorder: Causal relationships between epilepsy and its comorbidities

This review draws connections between the pathogenesis of canine epilepsy and its most commonly recognised comorbidities: cognitive impairment (CI), attention deficit hyperactivity disorder (ADHD)-like behaviour, fear and anxiety. Uni/bidirectional causalities and the possibility of a common aetiology triggering both epilepsy and the associated diseases are considered. Research on this topic is sparse in dogs, so information has been gathered and assessed from human and laboratory animal studies. Anatomical structures, functional connections, disrupted neurotransmission and neuroinflammatory processes collectively serve as a common foundation for epilepsy and its comorbidities. Specific anatomical structures, especially parts of the limbic system, such as the amygdala and the hippocampus, are involved in generating seizures, as well as cognitive- and behavioural disorders. Furthermore, disturbances in inhibitory and excitatory neurotransmission influence neuronal excitability and networks, leading to underlying brain dysfunction. Functional magnetic resonance imaging (fMRI), interictal epileptiform discharges (IEDs), and electroencephalography (EEG) have demonstrated functional brain connections that are related to the emergence of both epilepsy and its various comorbidities. Neuroinflammatory processes can either cause or be a consequence of seizures, and inflammatory mediators, oxidative stress and mitochondrial dysfunction, can equally evoke mood disorders. The extensive relationships contributing to the development and progression of seizures and comorbid cognitive and behavioural conditions illustrate the complexity of the disease that is epilepsy.

Comparative Insight into Microglia/Macrophages-Associated Pathways in Glioblastoma and Alzheimer's Disease.

Microglia and macrophages are pivotal to the brain's innate immune response and have garnered considerable attention in the context of glioblastoma (GBM) and Alzheimer's disease (AD) research. This review delineates the complex roles of these cells within the neuropathological landscape, focusing on a range of signaling pathways-namely, NF-κB, microRNAs (miRNAs), and TREM2-that regulate the behavior of tumor-associated macrophages (TAMs) in GBM and disease-associated microglia (DAMs) in AD. These pathways are critical to the processes of neuroinflammation, angiogenesis, and apoptosis, which are hallmarks of GBM and AD. We concentrate on the multifaceted regulation of TAMs by NF-κB signaling in GBM, the influence of TREM2 on DAMs' responses to amyloid-beta deposition, and the modulation of both TAMs and DAMs by GBM- and AD-related miRNAs. Incorporating recent advancements in molecular biology, immunology, and AI techniques, through a detailed exploration of these molecular mechanisms, we aim to shed light on their distinct and overlapping regulatory functions in GBM and AD. The review culminates with a discussion on how insights into NF-κB, miRNAs, and TREM2 signaling may inform novel therapeutic approaches targeting microglia and macrophages in these neurodegenerative and neoplastic conditions. This comparative analysis underscores the potential for new, targeted treatments, offering a roadmap for future research aimed at mitigating the progression of these complex diseases.

Targeting Dysregulated Neuroinflammation in CNS Disorders

A critical mechanism driving neurodegenerative disease progression is dysregulated brain inflammation. Neuroinflammatory repair processes are fundamental to CNS homeostasis, but inflammation that is inefficient, excessive, or prolonged can contribute to neurodegeneration. A specific aspect of neuroinflammation, stressor-induced proinflammatory cytokine overproduction from abnormally activated glia, has been linked to subsequent neurological damage and cognitive deficits in both acute and chronic CNS disorders. This cytokine/synaptic dysfunction axis (Fig. 1) has emerged as an attractive druggable target for neurodegenerative diseases. However, despite advances in our understanding of these molecular neuroinflammatory mechanisms, approved therapeutics that target this pathological process are lacking. To address this need, we used an integrated, recursive drug discovery platform (Fig. 2) to develop brain-penetrant, small molecule drug candidates that normalize cytokine levels and exhibit efficacy at low doses in multiple animal models of CNS disorders. The molecule design stage began with a pyridazine chemotype that was diversified using established chemistries to create a library of compounds. Compounds were screened for concentration dependence and selectivity using either a single molecular target approach or the historically successful functional/pathway-based approach. A pharmacology assessment stage was incorporated to assess compounds for drug-like properties, such as chemical and metabolic stability, CNS penetrance, and potential for safety. Prioritized compounds were then tested in relevant animal models, and the most promising drug candidates taken into formal IND-enabling preclinical testing. The platform yielded three clinical drug candidates, MW150, MW151, and MW189, that are all in human phase 1b/2a clinical trials.

Effect of long-term social isolation on behavior and brain plasticity in mice with tumor necrosis factor gene knockout

Prolonged social isolation can disrupt the functional activity of the serotonin (5-HT) neurotransmitter system and neurotrophic support of the brain, activate neuroinflammatory processes, and cause various behavioral disorders [1]. On the contrary, the pro-inflammatory cytokine, specifically tumor necrosis factor (TNF), affects the synthesis of serotonin and the expression of neurotrophins in the brain [2]. Additionally, TNF gene knockout alters the severity of depression-like behavior and cognitive functions in rodents [3]. The objective of this study was to examine the impact of prolonged social isolation on the 5-HT system in the brain as well as the expression of the neurotrophic factors BDNF and NGF in Tnf gene knockout (TNF KO) mice and wild-type C57BL/6 mice. Mice from each strain were divided into two groups: “control”, which were kept in groups, and “experimental”, which were isolated in cages for six weeks. The mice were subjected to a battery of tests including the “open field”, “three-chamber”, and “forced swimming” tests. The expression of genes was gauged in the brain structure of mice through real-time RT-PCR and protein content was analyzed through Western blotting. Serotonin and its metabolite 5-HIAA were quantified using HPLC. The results were analyzed using a two-way analysis of variance followed by Fisher’s multiple comparisons. The animals’ locomotor activity did not differ between groups. Social isolation in TNF KO mice led to reduced exploratory activity and increased anxiety (p 0.05) in the open field test. In isolated wild-type mice, social object preference in the three-chamber test decreased (p 0.01). Isolation had no effect on depression-like freezing in the “forced swimming” test and cognitive functions in the “new object” test in animals of both strains. Social isolation resulted in decreased expression of the tryptophan hydroxylase 2 gene (synthesizes 5-HT) in the midbrain of wild-type mice (p 0.05) and increased expression of the 5-HT1A receptor gene in this structure in knockout animals (p 0.05). Only the knockout mice exhibited a reduction in 5-HT levels in the hippocampus due to isolation (p 0.05). However, there were no differences observed in the levels of the neurotransmitter and its metabolite 5-HIAA in the frontal cortex and midbrain between groups of both strains of mice. In TNF KO mice exposed to isolation, the mRNA level of the nerve growth factor gene NGF increased in the frontal cortex (p 0.01); additionally, the content of proBDNF protein (a precursor of the BDNF factor) increased in both the hippocampus and frontal cortex (p 0.05). Our findings indicate that Tnf gene knockout modifies the influence of long-term social isolation on behavior, the 5-HT system, and the expression of neurotrophic factors in the brain.

Disease- and stage-specific alterations of the oral and fecal microbiota in Alzheimer's disease.

Microbial communities in the intestinal tract are suggested to impact the ethiopathogenesis of Alzheimer's disease (AD). The human microbiome might modulate neuroinflammatory processes and contribute to neurodegeneration in AD. However, the microbial compositions in patients with AD at different stages of the disease are still not fully characterized. We used 16S rRNA analyses to investigate the oral and fecal microbiota in patients with AD and mild cognitive impairment (MCI; n = 84), at-risk individuals (APOE4 carriers; n = 17), and healthy controls (n = 50) and investigated the relationship of microbial communities and disease-specific markers via multivariate- and network-based approaches. We found a slightly decreased diversity in the fecal microbiota of patients with AD (average Chao1 diversity for AD = 212 [SD = 66]; for controls = 215 [SD = 55]) and identified differences in bacterial abundances including Bacteroidetes, Ruminococcus, Sutterella, and Porphyromonadaceae. The diversity in the oral microbiota was increased in patients with AD and at-risk individuals (average Chao1 diversity for AD = 174 [SD = 60], for at-risk group = 195 [SD = 49]). Gram-negative proinflammatory bacteria including Haemophilus, Neisseria, Actinobacillus, and Porphyromonas were dominant oral bacteria in patients with AD and MCI and the abundance correlated with the cerebrospinal fluid biomarker. Taken together, we observed a strong shift in the fecal and the oral communities of patients with AD already prominent in prodromal and, in case of the oral microbiota, in at-risk stages. This indicates stage-dependent alterations in oral and fecal microbiota in AD which may contribute to the pathogenesis via a facilitated intestinal and systemic inflammation leading to neuroinflammation and neurodegeneration.

Interaction of somatic findings and psychiatric symptoms in COVID-19. Ascoping review

An infection with SARS-CoV‑2 can affect the central nervous system, leading to neurological as well as psychiatric symptoms. In this respect, mechanisms of inflammation seem to be of much greater importance than the virus itself. This paper deals with the possible contributions of organic changes to psychiatric symptomatology and deals especially with delirium, cognitive symptoms, depression, anxiety, posttraumatic stress disorder and psychosis. Processes of neuroinflammation with infection of capillary endothelial cells and activation of microglia and astrocytes releasing high amounts of cytokines seem to be of key importance in all kinds of disturbances. They can lead to damage in grey and white matter, impairment of cerebral metabolism and loss of connectivity. Such neuroimmunological processes have been described as aorganic basis for many psychiatric disorders, as affective disorders, psychoses and dementia. As the activation of the glia cells can persist for along time after the offending agent has been cleared, this can contribute to long term sequalae of the infection.

Insights into Neurocognitive Sequelae of COVID‐19 Infection from Studies of Brain Organoids

AbstractBackgroundCOVID‐19 has been associated with chronic neurocognitive changes which persist after resolution of the acute infection. Brain organoids composed of different neuronal cell types serve as a useful model to evaluate the underlying effects of SARS‐CoV‐2 infection to the brain and facilitate insights into the neurocognitive sequelae of COVID‐19.MethodA review of studies which used brain organoids to evaluate the effects of COVID‐19 was conducted. The studies were identified from the PubMed/MEDLINE database using the search terms “SARS‐CoV‐2” or “COVID‐19” in combination with “organoid” or “brain” or “3D” or “iPSC”. Articles published in English between 1 Jan 2020 and 31 Mar 2023 were included.ResultWe identified a total of 16 studies which used brain organoids to study SARS‐CoV‐2 neurotropism and downstream effects. Although SARS‐CoV‐2 was able to infect neurons, the extent of neurotropism was limited. Instead, choroidal epithelial cells and glial cells including, astrocytes and microglial, demonstrated significant susceptibility to SARS‐CoV‐2 infection. Furthermore it was observed that certain downstream effects of SARS‐CoV‐2 infection were associated with pathways seen in neurodegenerative diseases like Alzheimer’s Disease (AD). These included findings of reactive astrogliosis, impairment of glutamate and choline transporters, microglial‐mediated synapse loss, increased pTau expression and beta amyloid protein accumulation. Overall, the studies suggested that the neurocognitive manifestations of COVID‐19 may be contributed by neuroinflammatory processes and pathways that are found in chronic neurodegenerative conditions like AD.ConclusionAlthough brain organoid technology remains a relatively new tool, it has provided important insights into the pathophysiology of COVID‐19. The use of “assembloids” to recapitulate interactions between different brain regions and development of high throughput evaluation to analyse transcriptome and epigenome changes of infected brain organoids may be further expanded to allow a better understanding of potential neurodegenerative pathways that may result in neurocognitive changes after a viral infection.