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Despite advancements, the prevalence of HIV-associated neurocognitive impairment remains at approximately 40%, attributed to factors like pre-cART (combination antiretroviral therapy) irreversible brain injury. People with HIV (PWH) treated with cART do not show significant neurocognitive changes over relatively short follow-up periods. However, quantitative neuroimaging may be able to detect ongoing subtle microstructural changes. In this study, we hypothesized that tensor-valued diffusion encoding metrics would provide greater sensitivity than conventional diffusion tensor imaging (DTI) metrics in detecting HIV-associated brain microstructural injury. We further hypothesized that tensor-valued metrics would exhibit stronger associations with blood markers of neuronal and glial injury, such as neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP), as well as with cognitive performance. Using MRI at 3T, 24 PWH and 31 healthy controls underwent cross-sectional examination. The results revealed significant variations in tensor-valued diffusion encoding metrics across white matter regions, with associations observed between these metrics, cognitive performance, NFL and GFAP. Moreover, a significant interaction between HIV status and imaging metrics in gray and white matter was observed, particularly impacting total cognitive scores. Of interest, DTI metrics were less likely to be associated with HIV status than tensor-valued diffusion metrics. These findings suggest that tensor-valued diffusion encoding metrics offer heightened sensitivity in detecting subtle changes associated with axonal injury in HIV infection. Longitudinal studies are needed to further evaluate responsiveness of tensor-valued diffusion b-tensor encoding metrics in the contest HIV-associate mild chronic neuroinflammation., Competing Interests: Competing interests: FS and MN are inventors on patents related to b-tensor encoding and declares financial conflicts of interest. None of the other authors have any competing financial or non-financial interests in relation to the work described in this manuscript. Approval for human experiments: All protocols were reviewed and approved by the Research Subjects Review Board (RSRB) at the University of Rochester Medical Center. All participants signed a written consent form. Consent to participate: All participants signed a written consent form., (© 2024. The Author(s).)

Dementia, especially Alzheimer's disease, presents a major clinical challenge, and researchers are still searching for an optimal animal model. To address this gap, we compared male and ovariectomized female C57BL/6 mice treated with 30 mg/kg aftin-4, which induces neurodegeneration, with naturally aged (15-16 months old) mice not treated with aftin-4. We performed a series of behavioral tests; measured postmortem plasma β-amyloid levels (Aβ1-40 and Aβ1-42) and the levels of the oxidative stress indicators glutathione peroxidase (GPx), superoxide dismutase (SOD) and malondialdehyde (MDA); and evaluated astrocytic reactivity in the brain using glial fibrillary acid protein (GFAP) levels. Our results revealed no behavioral changes in the aged or aftin-4-treated mice compared with the control mice. Aftin-4 mice presented lower brain MDA levels and no detectable changes in plasma Aβ levels. In general, female mice had higher GPx and SOD levels and lower Aβ1-42 levels than male mice did. In contrast, aged and aftin-4-treated male mice presented elevated levels of GFAP, indicating astrocyte damage. Our results could not confirm that either aftin-4-treated or aged mice are reliable models for dementia. However, the observed molecular changes suggest that male animals may be more susceptible to oxidative stress and brain damage than females are. This study demonstrates the complexity of modeling dementia in animals and the importance of future studies in this area., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Cancer pain has a significant impact on patient's quality of life. Astrocytes play an important role in cancer pain signaling. The direct targeting of astrocytes can effectively suppress cancer pain, however, they can cause many side effects. Therefore, there is an urgent need to identify the specific signaling pathways or proteins involved within astrocytes in cancer pain as targets for treating pain., Methods: A neuropathic cancer pain (NCP) model was established by inoculating mouse S-180 sarcoma cells around the right sciatic nerve in C57BL/6 mice. Spontaneous persistent pain and paw withdrawal thresholds were measured using von Frey filaments. The NCP spinal cord dorsal horn (L4-L6) and mouse astrocyte cell line MA-C were used to study protein palmitoylation using acyl-biotin exchange, real-time polymerase chain reaction, ELISA, western blotting, and immunofluorescent staining., Results: In a cancer pain model, along with tumor growth, peripheral nerve tissue invasion, and cancer pain onset, astrocytes in the dorsal horn of the spinal cord were activated and palmitoyltransferase ZDHHC23 expression was upregulated, leading to increased palmitoylation levels of GFAP and increased secretion of inflammatory factors, such as (C-X-C motif) ligand (CXCL)10 (CXCL-10), interleukin 6, and granulocyte-macrophage colony-stimulating factor. These factors in turn activate astrocytes by activating the signal transducer and activator of transcription 3 (STAT3) signaling pathway. A competitive peptide targeting GFAP palmitoylations was designed to effectively alleviate morphine tolerance in cancer pain treatment as well as cancer pain signaling and inflammatory factor secretion., Conclusions: In a rodent model, targeting GFAP palmitoylation appears to be an effective strategy in relieving cancer pain and morphine tolerance. Human translational research is warranted., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background Synaptic loss is an important factor in Alzheimer disease (AD); however, blood assays that conveniently and rapidly reflect changes in synaptic density are lacking. Purpose To correlate multiple potential synaptic blood markers with synaptic density measured using 18 F-SynVesT-1, a fluorine 18 ( 18 F)-labeled radiotracer, brain PET and to explore the independent associations between these markers and synaptic density. Materials and Methods This prospective study included 50 cognitively unimpaired (mean age, 65.0 years ± 8.3 [SD]; 37 female) participants and 70 participants with cognitive impairment (mean age, 69.5 years ± 7.9; 43 female) from the Memory Clinic of Shanghai Jiao Tong University Affiliated Ruijin Hospital and communities in Shanghai. Amyloid-β (Aβ) and tau were assessed using 18 F-florbetapir and 18 F-MK6240 PET/CT. Synaptic density was evaluated with 18 F-SynVesT-1 PET/MRI. Pearson correlation analysis was used to investigate relationships of plasma (Aβ42/40 ratio, phosphorylated tau 181 [p-tau-181], glial fibrillary acid protein [GFAP], neurofilament light) and serum (C-reactive protein, tumor necrosis factor-α, α-synuclein, neurogranin, active plasminogen activator inhibitor-1, tissue plasminogen activator) biomarkers with synaptic density. Linear regression models and mediation analysis were used to explore effects of other AD-related pathologies on these relationships. Results Correlations were observed between increased p-tau-181 and GFAP and decreased synaptic density in global cortex ( r p-tau-181 = -0.352, r GFAP = -0.386; both P < .001) and hippocampus ( r p-tau-181 = -0.361, r GFAP = -0.369; both P < .001) at 18 F-SynVesT-1 PET/MRI. The relationships between p-tau-181 and GFAP with 18 F-SynVesT-1 PET/MRI persisted after controlling for plasma Aβ42/40 ratio, Aβ PET, or cortical thickness ( P value range, <.001-.01). This association disappeared after controlling for tau PET ( P value range, .08-.83). Conclusion Plasma p-tau-181 and GFAP are closely associated with synaptic density measured using 18 F-SynVesT-1 PET/MRI, with the relationship primarily influenced by tau accumulation rather than Aβ deposition or cortical thickness. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Giannakopoulos in this issue.

Porcine hemagglutinating encephalomyelitis (PHE), caused by a betacoronavirus named porcine hemagglutinating encephalomyelitis virus (PHEV), is a highly fatal disease of pigs characterized by nonsuppurative encephalitis. Activation of astrocytes is a hallmark of viral encephalomyelitis; however, the mechanism of PHEV-induced astrocyte activation is currently unknown. Based on mouse model, we show that PHEV infection led to astrogliosis in mouse brain and brain slice cultures (BSCs), as indicated by increased expression of glial fibrillary acidic protein (GFAP). PHEV can neither infect nor activate primary astrocytes in vitro, indicating that activation of astrocytes maybe mediated by factors secreted from viral infected neurons but not by direct viral infection of astrocytes. PHEV infection results in increased interferon (IFN) response in later stage, we thereafter focused on whether IFN-β can activate astrocytes after PHEV infection similar to other neurotropic viruses. IFN-β treatment resulted in both the upregulation of GFAP and activation-associated cytokines/chemokines in mouse primary astrocytes. Furthermore, the addition of IFN-β neutralization antibody prevented PHEV-infected mouse brain tissue homogenate from activating astrocytes. Taken together, IFN-β triggers the activation of astrocytes in the central nervous system (CNS) following PHEV infection. Further understanding of the role of activated astrocytes during PHEV infection may provide new insights for treatment this disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

N-methyl-D-aspartate receptors (NMDARs) play a crucial role in mediating Amyloid-β (Aβ) synaptotoxicity. Our previous studies have demonstrated an opposite (neuroprotection and neurotoxicity) effect of activating astrocytic and neuronal NMDARs with higher dose (10 μM) of NMDA, an agonist of NMDARs. By contrast, activating neuronal or astrocyitc NMDARs with lower dose (1 μM) of NMDA both exerts neuroprotective effect in Aβ-induced neurotoxicity. However, the underlying mechanism of activating astrocytic NMDARs with lower dose of NMDA to protect against Aβ neurotoxicity remains unclear. Based on our previous related work, in this study, using a co-cultured cell model of primary hippocampal neurons and astrocytes, we further investigated the possible factors involved in 1 μM of NMDA activating astrocytic NMDARs to oppose Aβ-induced synaptotoxicity. Our results showed that activation of astrocytic NMDARs by 1 μM NMDA rescued Aβ-induced reduction of brain-derived neurotrophic factor (BDNF), and inhibited Aβ-induced increase of GFAP, complement 3 (C3) and activation of NF-κB. Furthermore, blockade of astrocytic GluN2A with TCN201 abrogated the ability of 1 μM NMDA to counteract the effects of Aβ decreasing BDNF, and increasing GFAP, C3 and activation of NF-κB. These findings suggest that activation of astrocytic NMDARs protect against Aβ-induced synaptotoxicity probably through elevating BDNF and suppressing GFAP and C3. Our present research provides valuable insights for elucidating the underlying mechanism of astrocytic NMDARs activation resisting the toxic effects of Aβ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

The relation of astrocytic endfeet to the vasculature plays a key functional role in the neuro-glia-vasculature unit. We characterize the spatial organization of astrocytes and the structural aspects that facilitate their involvement in molecular exchanges. Using double transgenic mice, we performed co-immunostaining, confocal microscopy, and three-dimensional digital segmentation to investigate the biophysical and molecular organization of astrocytes and their intricate endfoot network at the micrometer level in the isocortex and hippocampus. The results showed that hippocampal astrocytes had smaller territories, reduced endfoot dimensions, and fewer contacts with blood vessels compared with those in the isocortex. Additionally, we found that both connexins 43 and 30 have a higher density in the endfoot and the former is overexpressed relative to the latter. However, due to the limitations of the method, further studies are needed to determine the exact localization on the endfoot. The quantitative information obtained in this study will be useful for modeling the interactions of astrocytes with the vasculature., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Estrone and estradiol differentially modulate neuroplasticity and cognition. How they influence the maturation of new neurons in the adult hippocampus, however, is not known. The present study assessed the effects of estrone and estradiol on the maturation timeline of neurogenesis in the dentate gyrus (DG) of ovariectomized (a model of surgical menopause) young adult Sprague-Dawley rats using daily subcutaneous injections of 17β-estradiol, estrone or vehicle. Rats were injected with a DNA synthesis marker, 5-bromo-2-deoxyuridine (BrdU), and were perfused 1, 2, or 3 weeks after BrdU injection and daily hormone treatment. Brains were sectioned and processed for various markers including: sex-determining region Y-box 2 (Sox2), glial fibrillary acidic protein (GFAP), antigen kiel 67 (Ki67), doublecortin (DCX), and neuronal nuclei (NeuN). Immunofluorescent labeling or co-labelling of BrdU with Sox2 (progenitor cells), Sox2/GFAP (neural progenitor cells), Ki67 (cell proliferation), DCX (immature neurons), NeuN (mature neurons) was used to examine the trajectory and maturation of adult-born neurons over time. Estrogens had early (1 week of exposure) effects on different stages of neurogenesis (neural progenitor cells, cell proliferation and early maturation of new cells into neurons) but these effects were less pronounced after prolonged treatment. Estradiol enhanced, whereas estrone reduced cell proliferation after 1 week but not after longer exposure to either estrogen. Both estrogens increased the density of immature neurons (BrdU/DCX-ir) after 1 week of exposure compared to vehicle treatment but this increased density was not sustained over longer durations of treatments to estrogens, suggesting that the enhancing effects of estrogens on neurogenesis were short-lived. Longer duration post-ovariectomy, without treatments with either of the estrogens, was associated with reduced neural progenitor cells in the DG. These results demonstrate that estrogens modulate several aspects of adult hippocampal neurogenesis differently in the short term, but may lose their ability to influence neurogenesis after long-term exposure. These findings have potential implications for treatments involving estrogens after surgical menopause., (© 2024 The Author(s). Hippocampus published by Wiley Periodicals LLC.)

Subtle craniofacial dysmorphology has been reported in schizophrenia patients. This dysmorphology includes midline facial elongation, frontonasal anomalies and a sexually dimorphic deviation from normal directional asymmetry of the face, with male patients showing reduced and female patients showing enhanced facial asymmetry relative to healthy control subjects. GFAP.HMOX1 0-12m transgenic mice (Mus musculus) that overexpress heme oxygenase-1 in astrocytes recapitulate many schizophrenia-relevant neurochemical, neuropathological and behavioral features. As morphogenesis of the brain, skull and face are highly interrelated, we hypothesized that GFAP.HMOX1 0-12m mice may exhibit craniofacial anomalies similar to those reported in persons with schizophrenia. We examined craniofacial anatomy in male GFAP.HMOX1 0-12m mice and wild-type control mice at the early adulthood age of 6-8 months. We used computer vision techniques for the extraction and analysis of mouse head shape parameters from systematically acquired 2D digital images, and confirmed our results with landmark-based geometric morphometrics. We performed skull bone morphometry using digital calipers to take linear distance measurements between known landmarks. Relative to controls, adult male GFAP.HMOX1 0-12m mice manifested craniofacial dysmorphology including elongation of the nasal bones, alteration of head shape anisotropy and reduction of directional asymmetry in facial shape features. These findings demonstrate that GFAP.HMOX1 0-12m mice exhibit craniofacial anomalies resembling those described in schizophrenia patients, implicating heme oxygenase-1 in their development. As a preclinical mouse model, GFAP.HMOX1 0-12m mice provide a novel opportunity for the study of the etiopathogenesis of craniofacial and other anomalies in schizophrenia and related disorders., (© 2024 The Authors. The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases hair cell regeneration, however, these cells fail to fully mature. Here, we profiled mouse utricles at 14 time points, and defined transcriptomes of developing and mature vestibular hair cells. To mimic native hair cells which downregulate endogenous ATOH1 as they mature, we engineered viral vectors carrying the supporting cell promoters GFAP and RLBP1. In utricles damaged ex vivo, both CMV-ATOH1 and GFAP-ATOH1 increased regeneration more effectively than RLBP1-ATOH1, while GFAP-ATOH1 and RLBP1-ATOH1 induced hair cells with more mature transcriptomes. In utricles damaged in vivo, GFAP-ATOH1 induced regeneration of hair cells expressing genes indicative of maturing type II hair cells, and more hair cells with bundles and synapses than untreated organs. Together our results demonstrate the efficacy of spatiotemporal control of ATOH1 overexpression in inner ear hair cell regeneration., (© 2024. The Author(s).)

Treatment strategies that are efficient against established Alzheimer's disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid β (Aβ) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized the expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood-brain barrier (BBB) in age-matched wild-type mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes that affect cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology., (© 2024. The Author(s).)

Purpose: Cumulating evidence supports the close association between periodontal diseases, neuroinflammation and neurodegenerative pathologies, except for peri-implantitis (PI). Thus, this study explored the association between experimental PI and neuropathological changes in the rat brain., Materials and Methods: After bilateral first molars extraction, experimental PI was induced at titanium implants placed in the maxillae by lipopolysaccharide injections and ligature placement. Following 28-weeks of disease progression, the maxillae and brains were retrieved from 6 rats. Healthy brains from 3 rats were used as control. Brains were analyzed by immunohistochemistry to detect signs of neuroinflammation (interleukin (IL)-6 and tumor necrosis factor (TNF)-α)), microglial activation (IBA-1) and astrogliosis (GFAP). To explore signs of neurodegeneration, hematoxylin/eosin and Nissl stainings were used. Also, four different antibodies against amyloid beta (Aβ 1-42) were tested., Results: Chronic PI lesions showed peri-implant bone resorption accompanied by large inflammatory infiltrates. IL-6 + and TNF-α + cells were found within the CA1 and Dentate Gyrus regions of the hippocampus of the PI-affected group, while almost no immune-positivity was detected in the control (p < 0.05). Detection of activated GFAP + microglia and IBA-1 + astrocytes surface were significantly higher at the CA areas, and cerebral cortex of the PI-affected group, in comparison with control (p < 0.05). Shrunk neurons with pyknotic nuclei were inconsistently found among the PI-affected group, and these were almost not detected in control. No positive Aβ reactivity was detected in any of the samples., Conclusion: Chronic experimental PI lesions led to an increased detection of IL-6 and TNF-α, GFAP + microgliosis and IBA-1 + astrocytosis, and in some cases, neurodegeneration, in the rat brain., (© 2024. The Author(s).)

Aim: The aim of this study was to evaluate the potential protective effect of Qiju Granule in a rat model of age-related macular degeneration (AMD) and investigate the underlying mechanisms involved., Methods: Rats were injected intravenously with 40 mg/kg of sodium iodate (SI) to induce a dry AMD model. The rats in the treatment group received three different doses of Qiju Granule once a day via gavage, while the rats in the control group were given an equal volume of physiological saline. On day 14 and day 28 following the intervention, various methods were employed to evaluate retinal function and structure, including electroretinography (ERG), optical coherence tomography (OCT), and histological examination. The expression of glial fibrillary acidic protein (GFAP), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) was assessed via immunofluorescence. Beyond immunofluorescence, the mRNA levels of bFGF, BDNF, and CNTF were quantitatively determined using real-time polymerase chain reaction (qRT-PCR)., Results: Rats treated with Qiju Granule exhibited significant improvements in both retinal function and structure compared to the model group. The most noteworthy effects were observed at a high dose of Qiju Granule. Furthermore, the expression levels of bFGF, BDNF, and CNTF were significantly unregulated in the treated groups compared to the model group., Conclusions: Qiju Granule demonstrated a protective effect on the retina in the SI-induced rat model of AMD. The protective mechanism may be attributed to the upregulation of retinal neurotrophic factors expression., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests related to this study. There are no financial or personal relationships with other people or organizations that could influence the conduct or interpretation of the research., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

High-intensity physical activity is a non-pharmacological intervention that has been tested as a treatment for Parkinson's disease (PD). The objective of the study was to investigate the benefits of high-intensity physical exercise on the number of neurons and astrocytes in a a rat model of Parkinson's disease submitted to training before and after the inducing injury. Seventy Wistar rats were used, distributed as follows: nine rats trained before PD induction (DP-Exa), nine trained after PD induction (DP-Exd), 10 trained before and after PD induction (DP-Exad), and nine sedentary rats (DP-Sed). There were also the same groups but with the rats exposed to the sham surgery (control). High-intensity physical exercise on a vertical ladder was performed before and/or after PD induction for 5 days/week, 30-45 min a day, for 4 weeks. PD was induced with an electrolytic lesion (AP -4.9, ML 1.7, and DV 8.1). At the end of the experiment, the brain was removed for Nissl staining and immunohistochemistry of glial fibrillary acidid protein (GFAP) in the substantia nigra and striatum. The DP-Exa, Sham-Exa, DP-Exad, and Sham-Exad groups showed a greater number of neurons and higher expression of GFAP in the substantia nigra and stiatum compared with the the DP-Exd, Sham-Exd, DP-Sed, and Sham-Sed groups. Thus, rats that performed high-intensity training before or before and after PD induction had higher densities of neurons and astrocytes.

Environmental noise is associated with various health outcomes. However, the mechanisms through which these outcomes influence behavior and metabolism remain unclear. This study investigated how environmental noise affects the liver, adipose tissue, and brain metabolic functions, leading to behavioral and body weight changes. Mice were divided into a noise group exposed to construction noise and an unexposed (control) group. Behavior and body weight changes were monitored over 50 days. Early changes in response to noise exposure were assessed by measuring plasma cortisol and glial fibrillary acidic protein expression in brain tissues on days 1, 15, and 30. Chronic responses, including changes in lipoprotein and fat metabolism and neurotransmitters, were investigated by analyzing serum lipoprotein levels and body fat mass and evaluating liver, fat, and brain tissue after 50 days. The noise group showed higher locomotor activity and reduced anxiety in the open-field and Y-maze tests. Noise exposure caused an initial weight loss; however, chronic noise increased fat mass and induced adipocyte hypertrophy. Our findings underscore the role of environmental noise-induced stress in augmenting locomotor activity and reducing anxiety in mice through neurotransmitter modulation while increasing the risk of obesity by decreasing HDL cholesterol levels and promoting adipocyte hypertrophy.

Neuroinflammation is a symptom of different neurodegenerative diseases, and growing interest is directed towards active drug development for the reduction of its negative effects. The anti-inflammatory activity of polyunsaturated fatty acids, eicosapentaenoic (EPA), docosahexaenoic (DHA), and their amide derivatives was largely investigated on some neural cells. Herein, we aimed to elucidate the protective role of both EPA and DHA and the corresponding N -ethanolamides EPA-EA and DHA-EA on neonatal mouse Olfactory Ensheathing Cells (OECs) after exposition to lipopolysaccharide (LPS)-induced neuroinflammation. To verify their anti-inflammatory effect and cell morphological features on OECs, the expression of IL-10 cytokine, and cytoskeletal proteins (vimentin and GFAP) was evaluated by immunocytochemical procedures. In addition, MTT assays, TUNEL, and mitochondrial health tests were carried out to assess their protective effects on OEC viability. Our results highlight a reduction in GFAP and vimentin expression in OECs exposed to LPS and treated with EPA or DHA or EPA-EA or DHA-EA in comparison with OECs exposed to LPS alone. We observed a protective role of EPA and DHA on cell morphology, while the amides EPA-EA and DHA-EA mainly exerted a superior anti-inflammatory effect compared to free acids.

The 5-lipoxygenase/leukotriene system has been implicated in both physiological and pathological states within the central nervous system. Understanding how this system interacts with the dopaminergic system could provide valuable insights into dopamine-related pathologies. This study focused on examining both motor and non-motor dopamine-related responses in 5-lipoxygenase/leukotriene-deficient mice. We used pharmacological agents such as amphetamine, apomorphine, and reserpine to challenge the dopaminergic system, evaluating their effects on prepulse inhibition reaction (PPI), general motor activity, and oral involuntary movements. Additionally, we analyzed striatal glial marker expression (GFAP and Iba-1) in reserpine-treated mice. The 5-lipoxygenase/leukotriene-deficient mice exhibited increased spontaneous locomotor activity, including both horizontal and vertical exploration, along with stereotyped behavior compared to wild-type mice. This hyperactivity was reduced by acute apomorphine treatment. Although basal PPI responses were unchanged, 5-lipoxygenase/leukotriene-deficient mice displayed a significant reduction in susceptibility to amphetamine-induced PPI disruption. Conversely, these mice were more vulnerable to reserpine-induced involuntary movements. There were no significant differences in the basal expression of striatal GFAP and Iba-1 positive cells between 5-lipoxygenase/leukotriene-deficient and wild-type mice. However, reserpine treatment significantly increased GFAP immunoreactivity in wild-type mice, an effect not observed in 5-lipoxygenase-deficient mice. Additionally, the percentage of activated microglia was significantly higher in reserpine-treated wild-type mice, an effect absents in 5-lipoxygenase/leukotriene-deficient mice. Our findings suggest that 5-lipoxygenase/leukotriene deficiency leads to a distinctive dopaminergic phenotype, indicating that leukotrienes may influence the modulation of dopamine-mediated responses., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glial fibrillary acidic protein (GFAP) astrocytopathy is a recently described autoimmune inflammatory disorder of the CNS characterized by the presence of specific antibodies targeting the intracellular filament protein in mature astrocytes. The pathogenesis is heterogeneous and poorly understood, with around 20%-34% of cases occurring as a paraneoplastic syndrome, most frequently associated with ovarian teratomas. It presents clinically as acute or subacute encephalomyelitis, and the diagnosis relies on imaging and detection of GFAP-Immunoglobulin (GFAP-IgG) in the CSF. Characteristic imaging findings include linear perivascular enhancement in the white matter extending in a radial pattern. Other imaging findings include periependymal enhancement, longitudinally extensive cord signal changes, intramedullary enhancement, optic neuritis, and papillitis. There is significant imaging overlap with other neuroinflammatory diseases like neuromyelitis optica spectrum disorder and lymphoproliferative conditions. GFAP astrocytopathy is characteristically responsive to steroids with, however, a significant rate of relapse. Currently, literature on this novel entity is limited with no established diagnostic criteria or standard treatment regimen. This comprehensive review explores the clinical, radiographic, and histopathologic aspects of GFAP astrocytopathy, shedding light on its complex nature and potential diagnostic challenges. The paper highlights the neuroimaging findings with a focus on differentiating GFAP astrocytopathy from other neuroinflammatory disorders., (© 2024 by American Journal of Neuroradiology.)

The present study aimed to assess the potential effect of vitamin B 12 (Vit B 12 ) on cognition impairment caused by nicotine (Nic) cessation in adolescent male rats. Adolescent male rats were categorized into two main groups as vehicle (normal saline, intraperitoneally), and Nic group in which received Nic (2 mg/kg) from 21 to 42 days of ages and then the Nic group were divided into three groups as withdrawal (the animals returned to regular diet without treatment), second and third groups received bupropion (20 mg/kg), and Vit B 12 at three different doses including 0.5,1, and 1.5 mg/kg by oral gavage as treatments to attenuate Nic withdrawal symptoms. The last group including normal animals received the highest doses of Vit B 12 just in the Nic abstinence period to compare the effect of that with vehicle. In MWM, Vit B 12 and bupropion increased the time spent in the target quadrant that is strongly associated with spatial memory as well as the more time spent with the NORT. Vit B 12 and bupropion modulated both oxidant/antioxidant and inflammatory/anti-inflammatory balance, alongside inhibitory effect on AChE, and GFAP. However, BDNF and amyloid-B showed insignificant difference as compared to Vit B 12 and bupropion. Considering the present results and similar related studies, Vit B 12 can be introduced as a strong anti-oxidant, and anti-inflammatory agent by which probably improved memory impairment caused by Nic addiction accompanied by withdrawal. Further, other mechanisms including activity reduction of AChE, and GFAP should be considered; however, it needs further investigation and larger-scale evidences., Competing Interests: Declaration of Competing Interest There was no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

We studied morphological features of the cerebellum in 14-day-old Wistar rats from reduced litters (the number of pups was reduced from 10-12 to 6 on the next day after birth). The control group comprised 14-day-old animals from litters of medium size (10-12 rat pups). Rats from reduced litters had greater body weight and brain weight. The weight of the cerebellum, together with the weight of the adjacent part of the brain stem and the thickness of cerebellar cortex also significantly exceeded the corresponding parameters in control animals. The thickness of the molecular layer of the cerebellar cortex and the numerical density of Purkinje cells in these rats did not differ significantly from the control. The thickness of the external granular (neurogenic) layer of the cerebellar cortex in rats from reduced litters was smaller. This can indicate accelerated reduction of this layer that persists in rats until days 20-22 of age. Numerical density of cells in the external granular layer of control and experimental animals was similar. Numerical density Ki-67 + cells in this layer, as well as GFAP + glial cells in the granular layer of the cerebellar cortex in rats from reduced litters significantly exceeded the corresponding parameters in control animals. The cerebellum of rats from litters reduced 1 day after birth had a number of differences in important indicators reflecting the rate of its development during the neonatal and suckling periods of ontogeny., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Aquaporin-4 (AQP4), predominantly expressed in astrocytes, has been implicated in the development of brain edema following ischemic events. However, its role in post-stroke neuroinflammation is not fully understood., Methods: Using a middle cerebral artery occlusion (MCAO) mouse model, we assessed AQP4's role in post-stroke inflammation. Brain tissue slices from male C57BL/6 mice were subjected to immunohistochemistry and western blot post-MCAO. Additionally, primary astrocytes were isolated for quantitative real-time PCR and immunofluorescence assays to evaluate the expression of inflammatory markers glial fibrillary acidic protein (GFAP) and AQP4. AQP4 modulation was achieved using viral knockdown and overexpression methods. Neuronal damage was assessed using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) tests in co-culture studies., Results: MCAO mice exhibited a significant upregulation in GFAP. This reactive astrogliosis corresponded with an elevation in inflammatory markers. AQP4 expression responded to this inflammatory trend, peaking at 6 h after OGD and returning to baseline levels at 24 and 48 h. Co-culture experiments revealed that AQP4(+) astrocytes exacerbated injury in OGD-treated neurons, as evidenced by increased TUNEL positivity and apoptotic events. Conversely, AQP4(-) astrocytes appeared to have a protective effect. Knockdown of AQP4 resulted in reduced post-OGD inflammatory response, whereas AQP4 overexpression intensified the injury to neurons post-OGD. In vivo experiments also confirmed that AQP4 inhibitor TGN-020 reduced and overexpression of AQP4 increased behavioral abnormalities and brain infarcts., Conclusion: Our findings underscore AQP4's pivotal role in modulating post-stroke neuroinflammation. Targeting AQP4 may present a novel therapeutic avenue for mitigating ischemia-induced neuronal damage., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Purpose: To examine the effects of hydrogen water on retinal blood flow (RBF) dysregulation in diabetes, we evaluated changes in RBF in response to flicker stimulation and systemic hyperoxia in diabetic mice., Methods: Twelve type 2 diabetic mice were divided into a group that received non-hydrogen water (n = 6, control group) and the other that received hydrogen-rich water (0.6-0.8 mM) (n = 6, HRW group) from six weeks of age. Body weight, blood glucose, intraocular pressure, and blood pressure were evaluated from eight to 14 weeks of age. RBF was measured in the vascular area of the optic disc as mean blur rate using laser speckle flowgraphy in the resting state and response to flicker stimulation and hyperoxia. We evaluated glial activation and oxidative stress based on immunofluorescence expression., Results: At 14 weeks, blood glucose level was significantly lower in the HRW group, though still elevated. RBF changes improved significantly in the HRW group compared with the control group from eight weeks of age and persisted throughout the study. Immunofluorescent expression of glial fibrillary acidic protein, particularly in the outer plexiform layer, was significantly decreased in the HRW group. Among oxidative stress markers, 3-nitrotyrosine was significantly suppressed in the HRW group., Conclusions: Hydrogen-rich water intake significantly improved RBF dysregulation in diabetic mice. Hydrogen may improve impaired neurovascular coupling function in diabetic mice by suppressing gliosis and oxidative stress in the retina., Translational Relevance: This study highlights the potential of oral intake of hydrogen-rich water to mitigate retinal dysfunction in diabetic mice.

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, neuro-acquired HIV (neuroHIV) remains a significant problem and approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND). Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, neuronal injury and synaptodendritic culling, viral replication, and potentially altering antiretroviral concentrations within the brain. The present study examined the effects of HIV and morphine co-exposure on the accumulation and spatial distribution of antiretroviral drugs across multiple regions within the brain in an HIV-1 Tat transgenic mouse model by using infrared-matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI MSI). Morphine exposure uniquely decreased antiretroviral concentrations in anterior cerebral (primary motor and somatosensory) cortices, corpus collosum (anterior forceps), caudoputamen, nucleus accumbens, and posterior regions including the hippocampus, corpus callosum (main body), cerebral cortex (somatosensory and auditory cortices), thalamus, and hypothalamus. Interestingly, male mice experienced greater morphine-associated decreases in antiretroviral concentrations than females. The study also assessed whether changes in antiretroviral concentrations were linked with inflammation in astroglia, assessed through the measurement of astroglial activation using glial fibrillary acidic protein (GFAP) as a marker. Alterations in antiretroviral concentrations co-registering with areas of astroglial activation exhibited sex-specific treatment differences. This study highlights the intricate interplay between HIV, opioids, and antiretroviral drugs within the CNS, elucidating distinct regional and sex variations in responsiveness. Our findings emphasize the identification of vulnerabilities within the neural landscape and underscore the necessity of carefully monitoring opioid use to maintain the efficacy of antiretroviral therapies., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: To investigate the role of satellite glial cells in irritable bowel syndrome (IBS) and the effect of electroacupuncture (EA) at the Tianshu (ST25) and Shangjuxu (ST37) combination., Methods: A model for visceral hypersensitivity in IBS was induced through colorectal distension (CRD) stimulation. Clean-grade male Sprague-Dawley (SD) rats were randomly divided into four groups: a normal group (NG), a model group (MG), an electroacupuncture group (EA), and a glial cell inhibitor group (FCA). Bilateral EA (2/100 Hz, 1 mA, 30 min) was administered at the Tianshu (ST25) and Shangjuxu (ST37) in week 6. Abdominal withdrawal reflex (AWR) scores were used to assess the behavioral response associated with visceral hyperalgesia, while hematoxylin-eosin staining was employed to evaluate pathological changes in the colon. The protein and mRNA levels of glial fibrillary acidic protein (GFAP) in the colon and colon-related dorsal root ganglion (DRG) were analyzed using immun-ofluorescence, immun-ohistochemistry, Western blotting, real-time polymerase chain reaction. The impact of EA on electrophysiological properties of colon-related DRG neurons was observed through whole-cell patch clamp analysis., Results: EA significantly reduced the visceral pain behavior scores in rats with IBS in response to graded (20, 40, 60, 80 mm Hg) CRD stimulation. Additionally, EA downregulated the protein and mRNA expression levels of GFAP in the colon and colon-related DRG of rats with IBS. EA also regulated the resting membrane potential, rheobase and action potential of colon-related DRG neurons in rats with IBS., Conclusions: EA can regulate the excitatory properties of colon-related DRG neurons by downregulating the protein and mRNA expression of GFAP in the colon and colon-related DRG, indicating a potential neurobiological mechanism by which EA relieves visceral hypersensitivity in rats with IBS.

Scope: Maternal high fructose diet (HFD) during pregnancy and lactation can initiate retinal dysfunction. However, the underlying mechanism remains largely unknown., Methods and Results: By using the rodent model of maternal HFD in this study, the results from electroretinography (ERG) indicate that b-wave amplitude, an index of inner retinal function, is significantly reduced as early as 3 months old and the deteriorated effect can be detected at 15 months old. Further, the protein expressions of CD11b (a marker of active microglia), p40 phox subunit of NADPH oxidase, GFAP (a marker of active astrocytes), and NLPR3 examined by western blot and immunofluorescence are significantly increased in the retina of the male HFD offspring at 3 months old. Treatment with omega-3 polyunsaturated fatty acids (ω-3 PUFAs) for 2 weeks (from 2.5 to 3 months old) effectively reverses the aforementioned changes., Conclusion: Together, these results indicate that the early onset and extensive retinal dysfunction may be a result of glial activation which is induced by maternal HFD to initiate an inflammatory microenvironment leading to a long-term progression of retinopathy. Short-term administration of ω-3 PUFA at a young age may be a feasible strategy to intervene in the maternal HFD-programmed retinal impairment in male offspring., (© 2024 Wiley‐VCH GmbH.)

Glial fibrillary acidic protein (GFAP) immunohistochemistry was investigated in the developing human brain using two measures; the number of GFAP-positive cells (density, GFAP+/mm 2 ), and a reactivity score (R-score), which we recently introduced to indicate astrogliosis, with scores ≥120 indicative of pathological processes. The primary aim was to report on GFAP expression and cell soma size in 26 microscopically defined regions of the amygdala, basal ganglia, cerebellum, hippocampus and medulla, and to determine whether they are affected by postconceptional age (PCA) from 40 to 83 weeks. The secondary aim was to determine if GFAP expression differs according to the classification of sudden infant death syndrome (SIDS) as opposed to infant deaths of known causes, or for the presence of major SIDS risk factors of male sex, cigarette smoke exposure, upper respiratory tract infection (URTI), bed-sharing and prone sleeping. The cerebellar molecular layer was void of GFAP+ cells, while the internal granular layer (IGL) had the highest density, with >60% of infants having an R-Score >120. GFAP expression decreased with increasing PCA in the entorhinal and temporal cortex, subiculum and regions of the cerebellum and medulla. GFAP cell soma size corresponded with astrogliosis score and no effect of PCA was evident. Various region-dependent GFAP expressional differences were seen according to SIDS classification and the risk factors studied. The findings indicate that the density of GFAP decreases in specific regions of the brain within the first year of postnatal development, and that reactive astrocytes are common, particularly within the early postnatal months., (© 2024 The Author(s). Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Alzheimer's disease, a prevalent neurodegenerative condition primarily affecting older adults, remains incurable. Its principle pathological hallmark is the accelerated accumulation of amyloid β (Aβ) protein. This study investigates the potential of photobiomodulation using near infrared light to counteract Aβ 1-42 -induced synaptic degeneration and neurotoxicity. We focused on the effect of 808 nm near-infrared laser diode (LD) on Aβ 1-42 cytotoxicity in primary cultured cortical neurons. We assessed cell survival using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, observing substantial benefits from LD irradiation with a power of 10 mW and a dose of 30 J. Cells exposed to Aβ 1-42 exhibited morphological changes indicative of synaptic damage and a significant decrease in the number of postsynaptic density protein-95 (PSD-95) contacts, which were significantly improved with near-infrared LD therapy. Furthermore, this therapy reduced Aβ and phosphorylated tau (P-tau) protein accumulation. Additionally, near-infrared LD irradiation substantially lessened the Aβ 1-42 -induced rise in glial fibrillary acid protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA1) in astrocytes and microglia. Remarkably, near-infrared LD irradiation effectively inhibited phosphorylation of key proteins involved in Aβ 1-42 -induced necroptosis, namely Receptor-interacting protein kinase-3 (RIP3) and Mixed Lineage Kinase domain-Like protein (MLKL). Our findings suggest that near-infrared LD treatment significantly reduces neurodegeneration by reducing glial overactivation and neuronal necroptosis triggered by Aβ 1-42 . Thus, near-infrared LD treatment emerges as a promising approach for slowing or treating Alzheimer's disease, offering new avenues in its management., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Early life seizures (ELS) are commonly associated with autism spectrum disorder (ASD); however, the exact role of ELS in the pathology is unknown. Prior studies have demonstrated social deficits, a core feature of ASD, following ELS; consequently, alterations in sensory modalities may contribute to the overall social deficits. Considering the speculated contribution of sensory deficit to social communication, we examined the developmental consequences of early postnatal kainic acid (KA)-induced seizures on olfactory preference and neural markers in the olfactory bulb in both male and female Sprague Dawley rats., Methods: KA-induced seizures or saline was administered. Rats were then exposed to a series of biologically relevant scents including male scent, female scent, nest scent, and phenylethylamine during the juvenile period and again during adulthood. Alterations in sensory modalities were expected to be expressed via abnormal preference for certain scents and/or production of abnormal ultrasonic vocalizations in response to scents. The olfactory bulbs were also assessed for the biologically relevant markers glial fibrillary acidic protein (GFAP) and calcium/calmodulin-dependent protein kinase II (CAMKII)., Results: Our findings resulted in no significant differences in olfactory preference following ELS for juveniles or adults compared to controls. Similarly, there were no differences in GFAP expression or the ratio of phosphorylated CAMKII to CAMKII in either olfactory bulb. Interestingly, despite a lack of treatment differences, different scents were shown to elicit different responses in juvenile rats, yet these differences subsided in adulthood., Significance: Overall, the results of this study suggest that olfaction does not contribute to socialization deficit following ELS within the KA model., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The damage of the diabetic visual pathway is one of the main causes of blindness in diabetic patients. Visual pathways include anatomic parts from the retina to the occipital lobe. This study investigated the involvement of ferroptosis, a planned cell death brought on by the buildup of free iron in cells, in the impairment of visual pathways in diabetes mellitus. Streptozotocin (STZ) was used to construct a diabetic rat model. Pathological and ultrastructural changes of the occipital lobe, retina, and optic nerve were observed by Hematoxylin-Eosin (HE) staining and transmission electron microscopy (TEM). The expressions of Neuronal nuclei (NeuN), Glial fibrillary acidic protein (GFAP), and Glutathione Peroxidase 4 (GPX4) in the occipital lobe and retina were detected by immunofluorescence, and Western Blotting was used to identify the NeuN GFAP and GPX4 expressions in the occipital lobe. Iron content in the occipital lobe and retina was detected by Iron Assay Kit. The success rate of the diabetic rat model was 93.3%. In the diabetic group, the cells of the occipital lobe and retina were arranged disorderly, and the boundaries were unclear. The membrane of the occipital lobe, retina, and optic nerve was broken, some vacuoles were observed, mitochondrial morphology was changed, swelling was observed, and the mitochondrial ridge disappeared. There was a large increase in GFAP expression and iron concentration and a significant decrease in the expression of NeuN, and GPX4 in the retina and occipital lobe. Ferroptosis plays an important role in visual pathway damage in diabetes, and GPX4 regulates this process., (© 2024. The Author(s).)

Astrocytes play key roles in the brain. When astrocyte support fails, neurological disorders follow, resulting in disrupted synaptic communication, neuronal degeneration, and cell death. We posit that astrocytes overexpressing neurotrophic factors, such as Insulin Like Growth Factor 1 (IGF1), prevent the onset of neurodegeneration. We overexpressed IGF1 and the reporter TdTomato (TOM) in hippocampal astrocytes with bicistronic Adeno-Associated Virus (AAV) harboring the Glial Fibrillary Acidic Protein (GFAP) promoter and afterwards induced neurodegeneration by the intracerebroventricular (ICV) injection of streptozotocin (STZ), a rat model of behavioral impairment, neuroinflammation and shortening of hippocampal astrocytes. We achieved a thorough transgene expression along the hippocampus with a single viral injection. Although species typical behavior was impaired, memory deficit was prevented by IGF1. STZ prompted astrocyte shortening, albeit the length of these cells in animals injected with GFP and IGF1 vectors did not statistically differ from the other groups. In STZ control animals, hippocampal microglial reactive cells increased dramatically, but this was alleviated in IGF1 rats. We conclude that overexpression of IGF1 in astrocytes prevents neurodegeneration onset. Hence, individuals with early neurotrophic exhaustion would be vulnerable to age-related neurodegeneration., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is an established risk factor for developing neurodegenerative disease. However, how TBI leads from acute injury to chronic neurodegeneration is limited to postmortem models. There is a lack of connections between in vitro and in vivo TBI models that can relate injury forces to both macroscale tissue damage and brain function at the cellular level. Needle-induced cavitation (NIC) is a technique that can produce small cavitation bubbles in soft tissues, which allows us to relate small strains and strain rates in living tissue to ensuing acute cell death, tissue damage, and tissue remodeling. Here, we applied NIC to mouse brain slices to create a new model of TBI with high spatial and temporal resolution. We specifically targeted the hippocampus, which is a brain region critical for learning and memory and an area in which injury causes cognitive pathologies in humans and rodent models. By combining NIC with patch-clamp electrophysiology, we demonstrate that NIC in the cornu ammonis 3 region of the hippocampus dynamically alters synaptic release onto cornu ammonis 1 pyramidal neurons in a cannabinoid 1 receptor-dependent manner. Further, we show that NIC induces an increase in extracellular matrix protein GFAP associated with neural repair that is mitigated by cannabinoid 1 receptor antagonism. Together, these data lay the groundwork for advanced approaches in understanding how TBI impacts neural function at the cellular level and the development of treatments that promote neural repair in response to brain injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

This initial methods study presents the initial immunohistochemical and transcriptomic changes in the optic nerve head and retina from three research-consented brain-dead organ donors following prolonged and transient intraocular pressure (IOP) elevation. In this initial study, research-consented brain-dead organ donors were exposed to unilateral elevation of IOP for 7.5 h (Donor 1), 30 h (Donor 2), and 1 h (Donor 3) prior to organ procurement. Optic nerve tissue and retinal tissue was obtained following organ procurement for immunohistological and transcriptomic analysis. Optic nerve sections in Donor 1 exposed to 7.5-hours of unilateral sub-ischemic IOP elevation demonstrated higher levels of protein expression of the astrocytic marker, glial fibrillary acidic protein (GFAP), within the lamina cribrosa with greatest expression inferior temporally in the treated eye compared to control. Spatial transcriptomic analysis performed on optic nerve head tissues from Donor 2 exposed to 30 h of unilateral IOP elevation demonstrated differential transcription of mRNA across laminar and scleral regions. Immunohistochemistry of retinal sections from Donor 2 exhibited higher GFAP and IBA1 expression in the treated eye compared with control, but this was not observed in Donor 3, which was exposed to only 1-hour of IOP elevation. While there were no differences in GFAP protein expression in the retina following the 1-hour IOP elevation in Donor 3, there were higher levels of transcription of GFAP in the inner nuclear layer, and CD44 in the retinal ganglion cell layer, indicative of astrocytic and Müller glial reactivity as well as an early inflammatory response, respectively. We found that transcriptomic differences can be observed across treated and control eyes following unilateral elevation of IOP in brain dead organ donors. The continued development of this model affords the unique opportunity to define the acute mechanotranscriptomic response of the optic nerve head, evaluate the injury and repair mechanisms in the retina in response to IOP elevation, and enable correlation of in vivo imaging and functional testing with ex vivo cellular responses for the first time in the living human eye., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Postnatal hippocampal neurogenesis is essential for learning and memory. Hippocampal neural precursor cells (NPCs) can be induced to proliferate and differentiate into either glial cells or dentate granule cells. Notably, hippocampal neurogenesis decreases dramatically with age, partly due to a reduction in the NPC pool and a decrease in their proliferative activity. Alpha-melanocyte-stimulating hormone (α-MSH) improves learning, memory, neuronal survival and plasticity. Here, we used postnatally-isolated hippocampal NPCs from Wistar rat pups (male and female combined) to determine the role of the melanocortin analog [Nle 4 , D-Phe 7 ]-α-MSH (NDP-MSH) in proliferation and fate acquisition of NPCs. Incubation of growth-factor deprived NPCs with 10 nM NDP-MSH for 6 days increased the proportion of Ki-67- and 5-bromo-2'-deoxyuridine (BrdU)-positive cells, compared to the control group, and these effects were blocked by the MC4R antagonist JKC-363. NDP-MSH also increased the proportion of glial fibrillar acidic protein (GFAP)/Ki-67, GFAP/sex-determining region Y-box2 (SOX2) and neuroepithelial stem cell protein (NESTIN)/Ki-67-double positive cells (type-1 and type-2 precursors). Finally, NDP-MSH induced peroxisome proliferator-activated receptor (PPAR)-γ protein expression, and co-incubation with the PPAR-γ inhibitor GW9662 prevented the effect of NDP-MSH on NPC proliferation and differentiation. Our results indicate that in vitro activation of MC4R in growth-factor-deprived postnatal hippocampal NPCs induces proliferation and promotes the relative expansion of the type-1 and type-2 NPC pool through a PPAR-γ-dependent mechanism. These results shed new light on the mechanisms underlying the beneficial effects of melanocortins in hippocampal plasticity and provide evidence linking the MC4R and PPAR-γ pathways in modulation of hippocampal NPC proliferation and differentiation., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Astrocytic reactivity in substance use disorders (SUDs) has been extensively studied, yet the molecular effect of delta-9-tetrahydrocannabinol (∆9-THC, the main psychoactive compound in cannabis) on glial cells, especially astrocytes, remains poorly understood. Exploring ∆9-THC's impact on astrocytic markers can provide insight into its effects on brain functions such as homeostasis, synaptic transmission, and response to neuronal injury. This systematic review synthesizes findings from studies investigating ∆9-THC's impact on astrocytic markers., Methods: A systematic review was conducted using EMBASE, Medline, and PsychoInfo via the OvidSP platform. Studies reporting astrocytic markers following ∆9-THC exposure in animals and humans were included. Data were extracted from twelve eligible full-text articles, and the risk of bias was assessed using the Systematic Review Center for Laboratory Animal Experimentation., Results: This research identified several astrocytic markers, including glial fibrillary acidic protein (GFAP), nestin, and glutamate-aspartate transporter (GLAST). Both GFAP and nestin expressions increased in adulthood following adolescence and adult ∆9-THC exposure. An increase in GLAST expression was also noted during early development after ∆9-THC exposure., Conclusions: This review indicates varying levels of astrocytic reactivity to ∆9-THC across different developmental stages, including adolescence and adulthood. ∆9-THC appears to impact maturation, particularly during early developmental stages, and exhibits sex-dependent effects.

Background: Previous studies have found that Alzheimer's disease (AD)-related plasma markers are associated with amyloid beta (Aβ) deposition, but the change of this association in different Aβ pathological stages remains unclear., Methods: Data were obtained from the SILCODE. According to the standardized uptake value ratio (SUVR) and Aβ stage classification, correlation analysis was performed among plasma biomarkers, and voxel/SUVR values in the regions of interest (ROI) and clinical scale information, respectively. Mediation analysis was used to study the possible pathways., Results: The proportion of cognitively normal (CN) and subjective cognitive decline (SCD) was the highest in stages A0 to 1, while in stages A2 to 4, the proportion of mild cognitive impairment (MCI) and AD increased. Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) levels were significantly lower in stage A0 compared to the later phases. Two pathways demonstrated fully mediated effects: positron emission tomography (PET) SUVR-plasma p-tau181-Mini-Mental State Examination (MMSE) and PET SUVR-plasma GFAP-MMSE., Discussion: This study demonstrated the role of plasma biomarkers in the early stage of AD, especially in SCD, from both the clinical diagnosis and Aβ stage dimensions., Highlights: Plasma ptau181 and GFAP level serve as indicators of early Alzheimer's disease and the pathologic Aβ staging classification. A possible ceiling effect of GFAP was observed in the mid-to-late stages of the AD course. This study confirms the role of AD plasma markers in promoting Aβ deposition at an early stage, particularly in females with subjective cognitive decline(SCD). The overlapping brain regions of plasma p-tau181, GFAP, and neurofilament light for Aβ deposition in the brain in early AD were distributed across various regions, including the posterior cingulate gyrus, rectus gyrus, and inferior temporal gyrus., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28 days. From 15 th to the 22 nd day, the animals received RIP I or RIP II (50 mg/kg) or fluoxetine (FLU, 10 mg/kg) or vehicle, by gavage. On the 29 th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 - Iba-1) and astrocyte (glial fibrillary acidic protein - GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1β) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1β levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Emerging evidence suggests an important role of astrocytes in mediating behavioral and molecular effects of commonly misused drugs. Passive exposure to nicotine alters molecular, morphological, and functional properties of astrocytes. However, a potential involvement of astrocytes in nicotine reinforcement remains largely unexplored. The overall hypothesis tested in the current study is that astrocytes play a critical role in nicotine reinforcement. Protein levels of the astrocyte marker glial fibrillary acidic protein (GFAP) were examined in key mesocorticolimbic regions following chronic nicotine intravenous self-administration. Fluorocitrate, a metabolic inhibitor of astrocytes, was tested for its effects on behaviors related to nicotine reinforcement and relapse. Effects of fluorocitrate on extracellular neurotransmitter levels, including glutamate, GABA, and dopamine, were determined with microdialysis. Chronic nicotine intravenous self-administration increased GFAP expression in the nucleus accumbens core (NACcr), but not other key mesocorticolimbic regions, compared to saline intravenous self-administration. Both intra-ventricular and intra-NACcr microinjection of fluorocitrate decreased nicotine self-administration. Intra-NACcr fluorocitrate microinjection also inhibited cue-induced reinstatement of nicotine seeking. Local perfusion of fluorocitrate decreased extracellular glutamate levels, elevated extracellular dopamine levels, but did not alter extracellular GABA levels in the NACcr. Fluorocitrate did not alter basal locomotor activity. These results indicate that nicotine reinforcement upregulates the astrocyte marker GFAP expression in the NACcr, metabolic inhibition of astrocytes attenuates nicotine reinforcement and relapse, and metabolic inhibition of astrocytes disrupts extracellular dopamine and glutamate transmission. Overall, these findings suggest that astrocytes play an important role in nicotine reinforcement and relapse, potentially through regulation of extracellular glutamate and dopamine neurotransmission., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The subventricular zone (SVZ) is one of the neurogenic regions of the adult mammalian brain. Neural stem cells (NSCs) in the SVZ have certain key features: they express glial fibrillary acidic protein (GFAP), proliferate slowly, have a radial glia-like (RG-L) morphology, and are in contact with the cerebrospinal fluid (CSF). NSCs have been isolated by FACS to analyse them, but their morphology has not been systematically examined. To address this knowledge gap, we sparsely labelled RG-L cells in the SVZ of neonatal mice by introducing via electroporation a plasmid expressing fluorescent protein under the control of the GFAP promoter. We then classified RG-L cells into three types (RG-L1, 2, and 3) based on their morphologies. RG-L1 cells had a basal process with some branches and numerous fine processes. RG-L2 cells had a basal process, but fewer branches and fine processes than RG-L1 cells. RG-L3 cells had one basal process that was almost free of branches and fine processes. Importantly, regardless of the cell type, about half of their somata resided on the basal side of the SVZ. Based on changes in their proportions during postnatal development and their expression of GFAP and cell proliferation markers at the adult stage, we speculated that NSCs change their morphologies during development/maturation and not all NSCs must always be in the apical SVZ or in contact with the CSF. Our results indicate that in addition to expression of markers for NSCs, the morphology is a critical feature to identify NSCs., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Tirzepatide (LY3298176), a GLP-1 and GIP receptor agonist, is fatty-acid-modified and 39-amino acid linear peptide, which ameliorates learning and memory impairment in diabetic rats. However, the specific molecular mechanism remains unknown. In the present study, we investigated the role of tirzepatide in the neuroprotective effects in Alzheimer's disease (AD) model mice. Tirzepatide was administrated intraperitoneal (i.p.) APP/PS1 mice for 8 weeks with at 10 nmol/kg once-weekly, it significantly decreased the levels of GLP-1R, and GFAP protein expression and amyloid plaques in the cortex, it also lowered neuronal apoptosis induced by amyloid-β (Aβ), but did not affect the anxiety and cognitive function in APP/PS1 mice. Moreover, tirzepatide reduced the blood glucose levels and increased the mRNA expression of GLP-1R, SACF1, ATF4, Glu2A, and Glu2B in the hypothalamus of APP/PS1 mice. Tirzepatide increased the mRNA expression of glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase in the cortex. Lastly, tirzepatide improved the energetic metabolism by regulated reactive oxygen species production and mitochondrial membrane potential caused by Aβ, thereby decreasing mitochondrial function and ATP levels in astrocytes through GLP-1R. These results provide valuable insights into the mechanism of brain glucose metabolism and mitochondrial function of tirzepatide, presenting potential strategies for AD treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing or conflicting interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: To comprehensively assess the neurologic recovery potential of chondroitinase ABC (ChABC) in rats after spinal cord injury (SCI)., Methods: The PubMed, Embase, ScienceDirect, Web of Science, and China National Knowledge Infrastructure databases were searched for animal experiments that evaluated the use of ChABC in the treatment of SCI up to November 2022. Studies reporting neurological function using the Basso, Beattie, and Bresnahan (BBB) scale, as well as assessments of cavity area, lesion area, and glial fibrillary acidic protein (GFAP) levels, were included in the analysis., Results: A total of 46 studies were ultimately selected for inclusion. The results of the study showed that rats with SCI that received ChABC therapy exhibited a significant improvement in locomotor function after 7 days compared with controls (32 studies, weighted mean difference (WMD) = 0.58, [0.33, 0.83], p  < 0.00001). Furthermore, the benefits of ChABC therapy were maintained for up to 28 days according to BBB scale. The lesion area was reduced by ChABC (5 studies, WMD = -20.94, [-28.42, -13.46], p  < 0.00001). Meanwhile, GFAP levels were reduced in the ChABC treatment group (8 studies, WMD = -29.15, [-41.57, -16.72], p <  0.00001). Cavity area is not statistically significant. The subgroup analysis recommended that a single injection of 10 μL (8 studies, WMD = 2.82, [1.99, 3.65], p <  0.00001) or 20 U/mL (4 studies, WMD = 2.21, [0.73, 3.70], p =  0.003) had a better effect on improving the function. The funnel plot of the BBB scale was found to be essentially symmetrical, indicating a low risk of publication bias., Conclusions: This systematic review and meta-analysis has indicated that ChABC could improve functional recovery in rats after SCI.

Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) patients points to activation of neurobiological mechanisms that may be targetable by therapeutic approaches. However, evidence for AE-related recovery of striatal dopamine (DA) signaling or tyrosine hydroxylase (TH) loss has been inconsistent in rodent studies. This ambiguity may be related to the timing of AE intervention in relation to the status of nigrostriatal neuron loss. Here, we replicated human PD at diagnosis by establishing motor impairment with >80% striatal DA and TH loss prior to initiating AE, and assessed its potential to alleviate motor decline and restore DA and TH loss. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), biomarkers of human PD severity, changed in response to AE. 6-hydroxydopamine (6-OHDA) was infused unilaterally into rat medial forebrain bundle to induce progressive nigrostriatal neuron loss over 28 days. Moderate intensity AE (3× per week, 40 min/session), began 8-10 days post-lesion following establishment of impaired forelimb use. Striatal tissue DA, TH protein and mRNA, and serum levels of NfL/GFAP were determined 3-wks after AE began. Despite severe striatal DA depletion at AE initiation, forelimb use deficits and hypokinesia onset were alleviated by AE, without recovery of striatal DA or TH protein loss, but reduced NfL and GFAP serum levels. This proof-of-concept study shows AE alleviates motor impairment when initiated with >80% striatal DA loss without obligate recovery of striatal DA or TH protein. Moreover, the AE-related reduction of NfL and GFAP serum levels may serve as objective blood-based biomarkers of AE efficacy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Central poststroke pain (CPSP) is a type of central neuropathic pain whose mechanisms remain unknown. Recently, we showed that activated astrocytes and microglial cells are present in the spinal cord of CPSP model mice. Activated glial cells exacerbate cerebral ischemic pathology by increasing the expression of inflammatory factors. However, the involvement of spinal glial cells in CPSP remains unknown. We hypothesized that spinal glial cell-derived molecules cause hyperexcitability or promoted the development of CPSP. In this study, we identified glial cell-derived factors involved in the development of CPSP using a bilateral common carotid occlusion (BCAO)-induced CPSP mouse model. Male ddY mice were subjected to BCAO for 30 min. The von Frey test assessed mechanical hypersensitivity in the right hind paw of mice. BCAO mice showed hypersensitivity to mechanical stimuli and astrocyte activation in the spinal cord 3 days after treatment. DNA microarray analysis revealed a significant increase in lipocalin 2 (LCN2), is known as neutrophil gelatinase-associated lipocalin, in the superficial dorsal horns of BCAO-induced CPSP model mice. LCN2 colocalized with GFAP, an astrocyte marker. Spinal GFAP-positive cells in BCAO mice co-expressed signal transducer and activator of transcription 3 (STAT3). The increase in the fluorescence intensity of LCN2 and GFAP in BCAO mice was suppressed by intrathecal injection of AG490, an inhibitor of JAK2 and downstream STAT3 activation, or anti-LCN2 antibody. Our findings indicated that LCN2 in spinal astrocytes may be a key molecule and may be partly involved in the development of CPSP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine., Background: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain., Methods: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed., Results: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification., Conclusions: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed., (© 2024 American Headache Society.)

Ischemic stroke is characterized by high morbidity and mortality and a lack of effective therapeutic interventions. Leptin plays an important role in regulating oxidative stress, angiogenesis, hematopoiesis, etc. Although recent studies have found a neuroprotective effect of leptin, little is known about its role in cerebral ischemia. This study explores the possible roles and potential preventative mechanisms of leptin in cerebral ischemia-reperfusion injury (CIRI). An in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was used to replicate the CIRI model, low (0.5 mg/kg), medium (1 mg/kg) and high (2 mg/kg) concentrations of leptin were injected intraperitoneally immediately after inserting the embolic line. After 1.5 h of ischemia and 24 h of reperfusion, we examined the neural function of the mice, collected brain tissue for histological examination, and screened for the optimal concentrations of leptin intervention. On this basis, we observed the changes of cortical apoptosis injury, intracellular calcium fluorescence intensity and astrocyte glial fibrillary acidic protein (GFAP) expression and morphological changes. In addition, we also tested the expression of transporters and metabolism-related enzymes (VGLUT-1, VGLUT-2, GLAST, GLT-1, GS, ATP1α1), the expression of inflammatory factors and the content of glutamate (Glu). Compared with the I/R group, we found that leptin improved neurological deficits, reduced the area of infarcts, maintained the normal morphology of astrocytes (AST), downregulated the expression of VGLUT-1, and upregulates the expression of GLT-1 and GLAST, thereby reducing the content of Glu in the synaptic cleft. Our studies suggest that leptin may have a neuroprotective effect by decreasing the excitotoxicity of glutamate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aimed to compare clinical and pathological features of retroperitoneal classical schwannomas and cellular schwannomas. A total of 64 cases of retroperitoneal classical schwannoma and 48 cases of cellular schwannoma were studied. Histopathological analysis was performed using hematoxylin and eosin staining and immunohistochemistry. Retroperitoneal cellular schwannomas exhibited 100% (48/48) and 75% (36/48) positive expression for glial fibrillary acidic protein (GFAP) and cytokeratins (CK), respectively. Classical schwannomas showed rates of 6.25% (4/64) and 15.63% (10/64), respectively (P < .05). In classic schwannomas, 85.9% (55/64) showed a reticular pattern of positive anti-CD34 staining around tumor margins and subcapsular areas vs 52.1% (25/48) in cellular schwannomas (P < .05). Cellular schwannomas exhibited more mitotic figures than classical schwannoma (P < .05). The recurrence rate of cellular schwannomas was 10.42% (5/48), while that of classical schwannomas was 1.56% (1/64) (P < .05). Retroperitoneal cellular schwannomas commonly express GFAP and CK compared to classical schwannomas, suggesting that cellular schwannoma may originate from unmyelinated Schwann cells, while classical schwannoma may originate from myelinated Schwann cells. Anti-CD34 staining patterns may be used to distinguish between the 2 types. Retroperitoneal cellular schwannomas also show higher mitotic activity and are more prone to recurrence., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

ABSTRACT Borna disease virus 1 (BoDV-1) was just recently shown to cause predominantly fatal encephalitis in humans. Despite its rarity, bornavirus encephalitis (BVE) can be considered a model disease for encephalitic infections caused by neurotropic viruses and understanding its pathomechanism is of utmost relevance. Aim of this study was to compare the extent and distribution pattern of cerebral inflammation with the clinical course of disease, and individual therapeutic procedures. For this, autoptic brain material from seven patients with fatal BVE was included in this study. Tissue was stained immunohistochemically for pan-lymphocytic marker CD45, the nucleoprotein of BoDV-1, as well as glial marker GFAP and microglial marker Iba1. Sections were digitalized and counted for CD45-positive and BoDV-1-positive cells. For GFAP and Iba1, a semiquantitative score was determined. Furthermore, detailed information about the individual clinical course and therapy were retrieved and summarized in a standardized way. Analysis of the distribution of lymphocytes shows interindividual patterns. In contrast, when looking at the BoDV-1-positive glial cells and neurons, a massive viral involvement in the brain stem was noticeable. Three of the seven patients received early high-dose steroids, which led to a significantly lower lymphocytic infiltration of the central nervous tissue and a longer survival compared to the patients who were treated with steroids later in the course of disease. This study highlights the potential importance of early high-dose immunosuppressive therapy in BVE. Our findings hint at a promising treatment option which should be corroborated in future observational or prospective therapy studies. ABBREVIATIONS: BoDV-1: Borna disease virus 1; BVE: bornavirus encephalitis; Cb: cerebellum; CNS: central nervous system; FL: frontal lobe; GFAP: glial fibrillary acid protein; Hc: hippocampus; Iba1: ionized calcium-binding adapter molecule 1; Iba1 act : general activation of microglial cells; Iba1 nod : formation of microglial nodules; IL: insula; Me: mesencephalon; Mo: medulla oblongata; OL: occipital lobe; pASS: per average of 10 screenshots; pat early : patients treated with early high dose steroid shot; pat late : patients treated with late or none high dose steroid shot; Po: pons; So: stria olfactoria; Str: striatum.

Alzheimer's disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein ( Gfap ), triggering receptor expressed on myeloid cells ( Trem2 ) and cystatin F ( Cst7 ), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha ( Cebpa ) and myelin proteolipid protein ( Plp ) in the PFC, as well as for BCL2 apoptosis regulator ( Bcl2 ) and purinergic receptor P2Y12 ( P2yr12 ) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells.

Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown. In this study, PACAP/VIP levels were assessed in the brain of GFAP-IL6 mice. In addition, we utilised bi-genic GFAP-IL6 mice carrying the human sgp130-Fc transgene (termed GFAP-IL6/sgp130Fc mice) to determine whether trans-signalling inhibition rescued PACAP/VIP changes in the CNS. Transcripts and protein levels of PACAP and VIP, as well as their receptors PAC1, VPAC1 and VPAC2, were significantly increased in the cerebrum and cerebellum of GFAP-IL6 mice vs. wild type (WT) littermates. These results were paralleled by a robust activation of the JAK/STAT3, NF-κB and ERK1/2MAPK pathways in GFAP-IL6 mice. In contrast, co-expression of sgp130Fc in GFAP-IL6/sgp130Fc mice reduced VIP expression and activation of STAT3 and NF-κB pathways, but it failed to rescue PACAP, PACAP/VIP receptors and Erk1/2MAPK phosphorylation. We conclude that forced expression of IL-6 in astrocytes induces the activation of the PACAP/VIP neuropeptide system in the brain, which is only partly modulated upon IL-6 trans-signalling inhibition. Increased expression of PACAP/VIP neuropeptides and receptors may represent a homeostatic response of the CNS to an uncontrolled IL-6 synthesis and its neuroinflammatory consequences.