Interleukin-33 ameliorates perioperative neurocognitive disorders by modulating microglial state.

Perioperative neurocognitive disorders (PND) are cognitive dysfunctions that usually occur in elderly patients after anesthesia and surgery. Microglial overactivation is a key underlying mechanism. Interleukin-33 (IL-33) is a member of the IL-1 family that orchestrates microglial function. In the present study, we explored how IL-33, which regulates microglia, contributes to cognitive improvement in a male mouse model of PND. An exploratory laparotomy was performed to establish a PND model. The expression levels of IL-33 and its receptor ST2 were evaluated using Western blot. IL-33/ST2 secretion, microglial density, morphology, phagocytosis of synapse, and proliferation, and dystrophic microglia were assessed using immunofluorescence. Synaptic plasticity was measured using Golgi staining and long-term potentiation. The Morris water maze and open field test were used to evaluate cognitive function and anxiety. Hippocampal expression of IL-33 and ST2 were elevated on postoperative day 3. We confirmed that IL-33 was secreted by astrocytes and neurons, whereas ST2 mainly colocalized with microglia. IL-33 treatment induced microgliosis after anesthesia and surgery. These microglia had larger soma sizes and shorter and fragmented branches. Compared to the Surgery group, IL-33 treatment reduced the synaptic phagocytosis of microglia and increased microglial proliferation and dystrophic microglia. IL-33 treatment also reversed the impaired synaptic plasticity and cognitive function caused by anesthesia and surgery. In conclusion, these results indicate that IL-33 plays a key role in regulating microglial state and synaptic phagocytosis in a PND mouse model. IL-33 treatment has a therapeutic potential for improving cognitive dysfunction in PND.

HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology.

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood-brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.

HIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes.

Human immunodeficiency virus type-1 (HIV-1) is responsible for significant mortality and morbidity worldwide. Despite complete control of viral replication with antiretrovirals, cells with integrated HIV-1 provirus can produce viral transcripts. In a cross-sectional study of 84 HIV+ individuals of whom 43 were followed longitudinally, we found that HIV-1 RNAs are present in extracellular vesicles (EVs) derived from cerebrospinal fluid and serum of all individuals. We used seven digital droplet polymerase chain reaction assays to evaluate the transcriptional status of the latent reservoir. EV-associated viral RNA was more abundant in the CSF and correlated with neurocognitive dysfunction in both, the cross-sectional and longitudinal studies. Sequencing studies suggested compartmentalization of defective viral transcripts in the serum and CSF. These findings suggest previous studies have underestimated the viral burden and there is a significant relationship between latent viral transcription and CNS complications of long-term disease despite the adequate use of antiretrovirals.

Neuropathogenic role of astrocyte-derived extracellular vesicles in HIV-associated neurocognitive disorders.

Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer's-like pathology-a comorbidity of HIV-Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV-1 Tat stimulated astrocyte-derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF-1α could likely mitigate HIV-1 Tat-ADEV-mediated neuronal injury. Rat hippocampal neurons when exposed to HIV-1 Tat-ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF-1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV-1 Tat-ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV-1 Tat-ADEVs, exhibited behavioural changes, and Alzheimer's 's-like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF-1α silenced ADEVs. This is the first report demonstrating the role of amyloid-carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF-1α.

Research Progress of Hippocampal Dopamine System Changes in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND.

Crosstalk between gut microbiome and neuroinflammation in pathogenesis of HIV-associated neurocognitive disorder.

HIV-associated neurocognitive disorder (HAND) has become a chronic neurodegenerative disease affecting the quality of life in people living with HIV (PLWH). Despite an established association between HAND and neuroinflammation induced by HIV proteins (gp120, Tat, Rev., Nef, and Vpr), the pathogenesis of HAND remains to be fully elucidated. Accumulating evidence demonstrated that the gut microbiome is emerging as a critical regulator of various neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), suggesting that the crosstalk between the gut microbiome and neuroinflammation may contribute to the development of these diseases, for example, gut dysbiosis and microbiota-derived metabolites can trigger inflammation in the brain. However, the potential role of the gut microbiome in the pathogenesis of HAND remains largely unexplored. In this review, we aim to discuss and elucidate the HAND pathogenesis correlated with gut microbiome and neuroinflammation, and intend to explore the probable intervention strategies for HAND.

Oral administration of ellagic acid mitigates perioperative neurocognitive disorders, hippocampal oxidative stress, and neuroinflammation in aged mice by restoring IGF-1 signaling.

This study investigates the potential of ellagic acid (EA), a phytochemical with antioxidant and anti-inflammatory properties, in managing perioperative neurocognitive disorders (PND). PND, which represents a spectrum of cognitive impairments often faced by elderly patients, is principally linked to surgical and anesthesia procedures, and heavily impacted by oxidative stress in the hippocampus and microglia-induced neuroinflammation. Employing an aged mice model subjected to abdominal surgery, we delve into EA's ability to counteract postoperative oxidative stress and cerebral inflammation by engaging the Insulin-like growth factor-1 (IGF-1) pathway. Our findings revealed that administering EA orally notably alleviated post-surgical cognitive decline in older mice, a fact that was manifested in improved performance during maze tests. This enhancement in the behavioral performance of the EA-treated mice corresponded with the rejuvenation of IGF-1 signaling, a decrease in oxidative stress markers in the hippocampus (like MDA and carbonylated protein), and an increase in the activity of antioxidant enzymes such as SOD and CAT. Alongside these, we observed a decrease in microglia-driven neuroinflammation in the hippocampus, thus underscoring the antioxidant and anti-inflammatory roles of EA. Interestingly, when EA was given in conjunction with an IGF1R inhibitor, these benefits were annulled, accentuating the pivotal role that the IGF-1 pathway plays in the neuroprotective potential of EA. Hence, EA could serve as a potent candidate for safeguarding against PND in older patients by curbing oxidative stress and neuroinflammation through the activation of the IGF-1 pathway.

The P38MAPK/ATF2 signaling pathway is involved in PND in mice.

Accumulating evidence indicates that microglia-mediated neuroinflammation in the hippocampus contributes to the development of perioperative neurocognitive disorder (PND). P38MAPK, a point of convergence for different signaling processes involved in inflammation, can be activated by various stresses. This study aims to investigate the role of the P38MAPK/ATF2 signaling pathway in the development of PND in mice. Aged C57BL/6 mice were subjected to tibial fracture surgery under isoflurane anesthesia to establish a PND animal model. The open field test was used to evaluate the locomotor activity of the mice. Neurocognitive function was assessed with the Morris water maze (MWM) and fear conditioning test (FCT) on postoperative days 1, 3 and 7. The mice exhibited cognitive impairment accompanied by increased expression of proinflammatory factors (IL-1ß, TNF-α), proapoptotic molecules (caspase-3, bax) and microglial activation in the hippocampus 1, 3 and 7 days after surgery. Treatment with SB239063 (a P38MAPK inhibitor) decreased the expression of proinflammatory factors, proapoptotic molecules and Iba-1 in the CA1 region of the hippocampus. The number of surviving neurons was significantly increased. Inhibition of the P38MAPK/ATF2 signaling pathway attenuates hippocampal neuroinflammation and neuronal apoptosis in aged mice with PND, thus improving the perioperative cognitive function of the mice.

HIV-1 Tat Induces Dysregulation of PGC1-Alpha and Sirtuin 3 Expression in Neurons: The Role of Mitochondrial Biogenesis in HIV-Associated Neurocognitive Disorder (HAND).

During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in the observed alterations within the central nervous system (CNS), with mitochondrial dysfunction emerging as a prominent hallmark. As a result, our objective was to examine the expression of genes associated with mitophagy and mitochondrial biogenesis in the brain exposed to the HIV-1 Tat protein. We achieved this by performing bilateral stereotaxic injections of 100 ng of HIV-1 Tat into the hippocampus of Sprague-Dawley rats, followed by immunoneuromagnetic cell isolation. Subsequently, we assessed the gene expression of Ppargc1a, Pink1, and Sirt1-3 in neurons using RT-qPCR. Additionally, to understand the role of Tert in telomeric dysfunction, we quantified the activity and expression of Tert. Our results revealed that only Ppargc1a, Pink1, and mitochondrial Sirt3 were downregulated in response to the presence of HIV-1 Tat in hippocampal neurons. Interestingly, we observed a reduction in the activity of Tert in the experimental group, while mRNA levels remained relatively stable. These findings support the compelling evidence of dysregulation in both mitophagy and mitochondrial biogenesis in neurons exposed to HIV-1 Tat, which in turn induces telomeric dysfunction.

Transforming Growth Factor ß1 Ameliorates Microglial Activation in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorder (PND) is a common complication of surgery and anesthesia, especially among older patients. Microglial activation plays a crucial role in the occurrence and development of PND and transforming growth factor beta 1 (TGF-ß1) can regulate microglial homeostasis. In the present study, abdominal surgery was performed on 12-14 months-old C57BL/6 mice to establish a PND model. The expression of TGF-ß1, TGF-ß receptor 1, TGF-ß receptor 2, and phosphor-smad2/smad3 (psmad2/smad3) was assessed after anesthesia and surgery. Additionally, we examined changes in microglial activation, morphology, and polarization, as well as neuroinflammation and dendritic spine density in the hippocampus. Behavioral tests, including the Morris water maze and open field tests, were used to examine cognitive function, exploratory locomotion, and emotions. We observed decreased TGF-ß1 expression after surgery and anesthesia. Intranasally administered exogenous TGF-ß1 increased psmad2/smad3 colocalization with microglia positive for ionized calcium-binding adaptor molecule 1. TGF-ß1 treatment attenuated microglial activation, reduced microglial phagocytosis, and reduced surgery- and anesthesia-induced changes in microglial morphology. Compared with the surgery group, TGF-ß1 treatment decreased M1 microglial polarization and increased M2 microglial polarization. Additionally, surgery- and anesthesia-induced increase in interleukin 1 beta and tumor necrosis factor-alpha levels was ameliorated by TGF-ß1 treatment at postoperative day 3. TGF-ß1 also ameliorated cognitive function after surgery and anesthesia as well as rescue dendritic spine loss. In conclusion, surgery and anesthesia induced decrease in TGF-ß1 levels in older mice, which may contribute to PND development; however, TGF-ß1 ameliorated microglial activation and cognitive dysfunction in PND mice.

Research Advances of Mitochondrial Dysfunction in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) increases postoperative dementia and mortality in patients and has no effective treatment. Although the detailed pathogenesis of PND is still elusive, a large amount of evidence suggests that damaged mitochondria may play an important role in the pathogenesis of PND. A healthy mitochondrial pool not only provides energy for neuronal metabolism but also maintains neuronal activity through other mitochondrial functions. Therefore, exploring the abnormal mitochondrial function in PND is beneficial for finding promising therapeutic targets for this disease. This article summarizes the research advances of mitochondrial energy metabolism disorder, inflammatory response and oxidative stress, mitochondrial quality control, mitochondria-associated endoplasmic reticulum membranes, and cell death in the pathogenesis of PND, and briefly describes the application of mitochondria-targeted therapies in PND.

The role of TREM1 in regulating microglial polarization in sevoflurane-induced perioperative neurocognitive disorders.

Microglia-mediated neuroinflammatory responses play a key role in perioperative neurocognitive disorders (PND). Triggering receptor expressed on myeloid cells-1 (TREM1) has been shown to be a key regulator of inflammation. However, its role in PND remains largely unknown. This study aimed to evaluate the role of TREM1 in sevoflurane-induced PND. We applied AAV knockdown TREM1 in hippocampal microglia in aging mice. The mice were then subjected to neurobehavioral and biochemical testing after the intervention of sevoflurane. We found that sevoflurane inhalation can cause PND in mice, increase hippocampal TREM1 expression, polarize microglia to M1 type, upregulate TNF-α and IL-1ß expression (pro-inflammatory), and inhibit TGF-ß and IL-10 expression (anti-inflammatory). Knocking down TREM1 can improve sevoflurane-induced cognitive dysfunction, reduce M1 type marker iNOS, and increase M2 type marker ARG, improving the neuroinflammation. TREM1 is a target for sevoflurane-induced PND prevention.

Effects of oral ß-caryophyllene (BCP) treatment on perioperative neurocognitive disorders: Attenuation of neuroinflammation associated with microglial activation and reinforcement of autophagy activity in aged mice.

Perioperative neurocognitive disorders (PND) are a constellation of cognitive impairments that arise following surgical procedures and anesthesia, with a higher incidence in elderly patients. PND is deeply entwined with microglia-mediated neuroinflammation and disrupted autophagy. ß-caryophyllene (BCP) is a natural terpene that occurs widely in dietary plants, and possesses robust anti-inflammatory properties by selectively activating CB2 receptors (CB2R). Accordingly, the present study endeavors to investigate the potential of BCP in ameliorating PND in aged mice, by mitigating hippocampal neuroinflammation and improving autophagy. In this study, an abdominal surgery was utilized to induce perioperative neurocognitive disorders (PND) in aged mice. BCP was administered orally at a dosage of 200 mg/kg for seven consecutive days prior to the scheduled surgery. In order to explore the relationship between BCP and CB2 receptors (CB2R), a co-administration of intraperitoneal injections of the CB2R antagonist AM630 was implemented, 30 min preceding the oral gavage of BCP. Postoperative cognitive functions were assessed using Morris water maze (MWM) tests. The extent of hippocampal inflammation was examined by measuring the microglial marker Iba-1 protein levels, Iba-1 and GFAP immunoactivity, as well as IL-1ß and IL-6 concentrations. Evaluation of autophagy activity was conducted based on the ratio of LC3B2/LC3B1 and protein levels of Beclin-1, p62, and phospho-mTOR (p-mTOR). After being orally administered BCP, the compromised behavioral performance of abdominal surgical interventions on aged mice was alleviated. This was evident by the extended escape latency, reduced time spent in the target quadrant, and fewer platform crossings observed through MWM testing. While hippocampal CB2R mRNA or protein expression remained unaffected by the abdominal surgical procedure, their levels were significantly upregulated in mice that were administered BCP. Moreover, the oral administration of BCP was able to reduce neuroinflammation in response to microglia activation, as evidenced by the decreased levels of Iba-1 protein and immunoactivity, as well as the reduction of IL-1ß and IL-6 concentrations. Additionally, BCP intensified autophagic activity, as detected by increased LC3B2/LC3B1 ratio and Beclin-1 protein levels, coupled with decreased levels of p62 and p-mTOR in the hippocampus of aged mice. Conversely, the treatment of AM630 ameliorated the suppressive effect of BCP triggered by the neuroinflammation caused by microglial activation post-surgery in aged mice (increased Iba-1 protein levels and immunoactivity, accompanied by higher IL-1ß and IL-6 concentrations). Furthermore, the pro-autophagy effect of BCP on aged mice following surgery was partially blocked by AM630, culminating in decreased LC3B2/LC3B1 ratio and Beclin-1 protein levels. However, the levels of p62 and p-mTOR remained unchanged by AM630. Our investigation unveils the remarkable therapeutic benefits of oral BCP administration for managing PND in aged mice through the attenuation of neuroinflammation associated with microglial activation and the fortification of autophagy activity. Hence, BCP holds great promise as a formidable candidate englobing various potential physiological mechanisms that would mitigate cognitive decline associated with aging.

Tibial fracture surgery in elderly mice caused postoperative neurocognitive disorder via SOX2OT lncRNA in the hippocampus.

Increasing evidence indicates the major role of mitochondrial function in neurodegenerative disease. However, it is unclear whether mitochondrial dynamics directly affect postoperative neurocognitive disorder (PND). This study aimed to analyze the underlying mechanisms of mitochondrial dynamics in the pathogenesis of PND. Tibial fracture surgery was performed in elderly mice to generate a PND model in vivo. Cognitive behavior was evaluated 3 days post-surgery using novel object recognition and fear conditioning. A gradual increase in the SOX2OT mRNA level and decrease in the SOX2 mRNA level were noted, with impaired cognitive function, in the mice 3 days after tibial surgery compared with mice in the sham group. To evaluate the role of SOX2OT in PND, SOX2OT knockdown was performed in vitro and in vivo using lentivirus transfection in HT22 cells and via brain stereotactic injection of lentivirus, respectively. SOX2OT knockdown reduced apoptosis, inhibited oxidative stress, suppressed mitochondrial hyperdivision, attenuated surgery-induced cognitive dysfunction, and promoted downstream SOX2 expression in elderly mice. Furthermore, Sox2 alleviated mitochondrial functional damage by inhibiting the transcription of mitochondrial division protein Drp1. Our study findings indicate that SOX2OT knockout alleviates surgery-induced mitochondrial fission and cognitive function defects by upregulating the expression of Sox2 in mice, resulting in the inhibition of drp1 transcription. Therefore, regulation of the SOX2/Drp1 pathway may be a potential mechanism for the treatment of patients with PND.

Kynurenic acid blunts A1 astrocyte activation against neurodegeneration in HIV-associated neurocognitive disorders.

Despite extensive astrocyte activation in patients suffering from HIV-associated neurocognitive disorders (HAND), little is known about the contribution of astrocytes to HAND neuropathology. Here, we report that the robust activation of neurotoxic astrocytes (A1 astrocytes) in the CNS promotes neuron damage and cognitive deficits in HIV-1 gp120 transgenic mice. Notably, knockout of α7 nicotinic acetylcholine receptors (α7nAChR) blunted A1 astrocyte responses, ultimately facilitating neuronal and cognitive improvement in the gp120tg mice. Furthermore, we provide evidence that Kynurenic acid (KYNA), a tryptophan metabolite with α7nAChR inhibitory properties, attenuates gp120-induced A1 astrocyte formation through the blockade of α7nAChR/JAK2/STAT3 signaling activation. Meanwhile, compared with gp120tg mice, mice fed with tryptophan showed dramatic improvement in cognitive performance, which was related to the inhibition of A1 astrocyte responses. These initial and determinant findings mark a turning point in our understanding of the role of α7nAChR in gp120-mediated A1 astrocyte activation, opening up new opportunities to control neurotoxic astrocyte generation through KYNA and tryptophan administration.

M1/M4-Preferring Muscarinic Cholinergic Receptor Agonist Xanomeline Reverses Wake and Arousal Deficits in Nonpathologically Aged Mice.

Degeneration of the cholinergic basal forebrain is implicated in the development of cognitive deficits and sleep/wake architecture disturbances in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Indirect-acting muscarinic cholinergic receptor agonists, such as acetylcholinesterase inhibitors (AChEIs), remain the only FDA-approved treatments for the cognitive impairments observed in AD that target the cholinergic system. Novel direct-acting muscarinic cholinergic receptor agonists also improve cognitive performance in young and aged preclinical species and are currently under clinical development for AD. However, little is known about the effects of direct-acting muscarinic cholinergic receptor agonists on disruptions of sleep/wake architecture and arousal observed in nonpathologically aged rodents, nonhuman primates, and clinical populations. The purpose of the present study was to provide the first assessment of the effects of the direct-acting M1/M4-preferring muscarinic cholinergic receptor agonist xanomeline on sleep/wake architecture and arousal in young and nonpathologically aged mice, in comparison with the AChEI donepezil, when dosed in either the active or inactive phase of the circadian cycle. Xanomeline produced a robust reversal of both wake fragmentation and disruptions in arousal when dosed in the active phase of nonpathologically aged mice. In contrast, donepezil had no effect on either age-related wake fragmentation or arousal deficits when dosed during the active phase. When dosed in the inactive phase, both xanomeline and donepezil produced increases in wake and arousal and decreases in nonrapid eye movement sleep quality and quantity in nonpathologically aged mice. Collectively, these novel findings suggest that direct-acting muscarinic cholinergic agonists such as xanomeline may provide enhanced wakefulness and arousal in nonpathological aging, MCI, and AD patient populations.

Neuro-immune deconvolution analysis of OAS3 as a transcriptomic central node in HIV-associated neurocognitive disorders.

Neurological complications of AIDS (NeuroAIDS) include primary HIV-associated neurocognitive disorder (HAND). OAS3 is an enzyme belonging to the 2', 5' oligoadenylate synthase family induced by type I interferons and involved in the degradation of both viral and endogenous RNA. Here, we used microarray datasets from NCBI of brain samples of non-demented HIV-negative controls (NDC), HIV, deceased patients with HAND and encephalitis (HIVE) (treated and untreated with antiretroviral therapy, ART), and with HAND without HIVE. The HAND/HIVE patients were stratified according to the OAS3 gene expression. The genes positively and negatively correlated to the OAS3 gene expression were used to perform a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to sixteen signatures. Expression analysis revealed significantly higher OAS3 expression in HAND/HIVE and HAND/HIVE/ART compared with NDC. OAS3 expressed an excellent diagnostic ability to discriminate NDC from HAND/HIVE, HAND from HAND/HIVE, HAND from HAND/HIVE/ART, and HIV from HAND/HIVE. Noteworthy, OAS3 expression levels in the brains of HAND/HIVE patients were positively correlated with viral load in both peripheral blood and cerebrospinal fluid (CSF). Furthermore, deconvolution analysis revealed that the genes positively correlated to OAS3 expression were associated with inflammatory signatures. Neuronal activation profiles were significantly activated by the genes negatively correlated to OAS3 expression levels. Moreover, gene ontology analysis performed on genes characterizing the microglia signature highlighted an immune response as a main biological process. According to our results, genes positively correlated to OAS3 gene expression in the brains of HAND/HIVE patients are associated with inflammatory transcriptomic signatures and likely worse cognitive impairment.

IL-33/ST2 axis promotes remodeling of the extracellular matrix and drives protective microglial responses in the mouse model of perioperative neurocognitive disorders.

Anesthesia and surgery induce cognitive impairment via uncertain mechanisms. Increasing evidence has suggested that microglial activity mediated by IL-33 /ST2 plays a critical role in immune regulation and inflammatory responses. Yet, the implications for microglia activity mediated by IL-33 in perioperative neurocognitive disorders (PND) are not well established. We showed that IL-33 and ST2 were downregulated in the hippocampus after anesthesia and surgery, and the expression of aggrecan, remodeling by microglia, was upregulated. Meanwhile, the expression of pro-inflammatory cytokines (IL-6 and IL-1ß) and M1-like microglia marker (iNOS) increased, and the expression of M2-like microglia marker (CD206) decreased. Notably, the administration of IL-33 attenuated neuroinflammation and shifted the polarization of microglia in the hippocampus after anesthesia and surgery. Furthermore, IL-33 treatment rescued the increase of aggrecan, loss of dendritic spines, and impairment of LTP, improving cognitive performance. In conclusion, our study suggests that microglia activity mediated by IL-33/ST2 plays a vital role in cognitive impairments after anesthesia and surgery, which may serve as a therapeutic target for PND.

Research Progress on Exosomes and MicroRNAs in the Microenvironment of Postoperative Neurocognitive Disorders.

Postoperative neurocognitive disorder (PND) is a disease that frequently develops in older patients during the perioperative period. It seriously affects the quality of life of the affected patients. Despite advancements in understanding PND, this disorder's mechanisms remain unclear, including pathophysiological processes such as central synaptic plasticity and function, neuroinflammation, excitotoxicity, and neurotrophic support. Growing evidence suggests that microenvironmental changes are major factors for PND induction in older individuals. Exosomes are carriers for transporting different bioactive molecules between nerve cells in the microenvironment and maintaining intercellular communication and tissue homeostasis. Studies have shown that exosomes and microRNAs (miRNAs) are involved in various physiological and pathological processes, including neural processes related to PND, such as neurogenesis and cell death, neuroprotection, and neurotrophy. This article reviews the effects of exosomes and miRNAs on the brain microenvironment in PND and has important implications to improve PND diagnosis, as well as to develop targeted therapy of this disorder.

Vitamin C deficiency induces hypoglycemia and cognitive disorder through S-nitrosylation-mediated activation of glycogen synthase kinase 3ß.

Vitamin C (VC, l-ascorbic acid) is an essential nutrient that plays a key role in metabolism and functions as a potent antioxidant in regulating the S-nitrosylation and denitrosylation of target proteins. The precise function of VC deprivation in glucose homeostasis is still unknown. In the absence of L-gulono-1,4-lactone oxidoreductase, an essential enzyme for the last step of VC synthesis, VC deprivation resulted in persistent hypoglycemia and subsequent impairment of cognitive functions in female but not male mouse pups. The cognitive disorders caused by VC deprivation were largely reversed when these female pups were given glucose. VC deprivation-induced S-nitrosylation of glycogen synthase kinase 3ß (GSK3ß) at Cys14, which activated GSK3ß and inactivated glycogen synthase to decrease glycogen synthesis and storage under the feeding condition, while VC deprivation inactivated glycogen phosphorylase to decrease glycogenolysis under the fasting condition, ultimately leading to hypoglycemia and cognitive disorders. Treatment with Nω-Nitro-l-arginine methyl ester (l-NAME), a specific inhibitor of nitric oxide synthase, on the other hand, effectively prevented S-nitrosylation and activation of GSK3ß in female pups in response to the VC deprivation and reversed hypoglycemia and cognitive disorders. Overall, this research identifies S-nitrosylation of GSK3ß and subsequent GSK3ß activation as a previously unknown mechanism controlling glucose homeostasis in female pups in response to VC deprivation, implying that VC supplementation in the prevention of hypoglycemia and cognitive disorders should be considered in the certain groups of people, particularly young females.