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AimAstrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis.MethodsWe investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors.ResultsOverexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI.ConclusionsThe APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.

Cancer-related cognitive impairment (CRCI) is a consequence of chemotherapy and extracranial radiation therapy (ECRT). Our prior work demonstrated gliosis in the brain following ECRT in SKH1 mice. The signals that induce gliosis were unclear. Right hindlimb skin from SKH1 mice was treated with 20 Gy or 30 Gy to induce subclinical or clinical dermatitis, respectively. Mice were euthanized at 6 h, 24 h, 5 days, 12 days, and 25 days post irradiation, and the brain, thoracic spinal cord, and skin were collected. The brains were harvested for spatial proteomics, immunohistochemistry, Nanostring nCounter® glial profiling, and neuroinflammation gene panels. The thoracic spinal cords were evaluated by immunohistochemistry. Radiation injury to the skin was evaluated by histology. The genes associated with neurotransmission, glial cell activation, innate immune signaling, cell signal transduction, and cancer were differentially expressed in the brains from mice treated with ECRT compared to the controls. Dose-dependent increases in neuroinflammatory-associated and neurodegenerative-disease-associated proteins were measured in the brains from ECRT-treated mice. Histologic changes in the ECRT-treated mice included acute dermatitis within the irradiated skin of the hindlimb and astrocyte activation within the thoracic spinal cord. Collectively, these findings highlight indirect neuronal transmission and glial cell activation in the pathogenesis of ECRT-related CRCI, providing possible signaling pathways for mitigation strategies.

Subretinal injections provide direct access to photoreceptors and RPE, which is crucial for the delivery of gene therapy and neuroprotective approaches. To access the subretinal space, transvitreal (TV) and transscleral (TS) subretinal injections have been widely used in humans and animal models. In this work, we investigated recent trends and outcomes of utilizing TV and TS subretinal models of retinal detachment (RD). A literature review revealed an increasing utilization of both models over the past two decades, with TS emerging as the predominant model since 2012. Subretinal injection in CX3CR1 + /GFP CCR2 + /RFP mice revealed early inflammatory responses, with TS injections inducing higher infiltration of CD11b + CCR2 + cells compared to TV. Further leukocyte immunophenotyping indicated divergent infiltration patterns, with the TS approach exhibiting higher proportions of neutrophils and macrophages/microglia-like cells, while the TV injections had higher CD45hi CD11b + Ly6G- Ly6C + infiltration. Notably, late-stage analysis demonstrates higher photoreceptor cell death in the TS approach, paralleled by increased subretinal infiltration of CD11b + cells. Both models showed significant reactive gliosis, suggesting comparable late-stage wound healing responses. These findings underscore the utility of these approaches for subretinal delivery, offering insights into their distinctive leukocyte infiltration and late-stage tissue responses. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a complex debilitating condition leading to permanent life-long neurological deficits. Estrogen (E2) treatment is known to be neuroprotectant in SCI. This hormone is highly pleiotropic and has been shown to decrease apoptosis, modulate calcium signaling, regulate growth factor expression, act as an anti-inflammatory, and drive angiogenesis. These beneficial effects were found in our earlier study at the low dose of 10 µg/kg E2 in rats. However, the dose remains non-physiologic, which poses a safety hurdle for clinical use. Thus, we recently devised/constructed a fast release nanoparticle (NP) estrogen embedded (FNP-E2) construct and tested a focal delivery system in a contused SCI rat model which showed protection in the short run. In the current study, we have developed a novel slow-release NP estrogen (SNP-E2) delivery system that shows sustained release of E2 in the injured spinal cord and no systemic exposure in the host. The study of E2 release and kinetics of this SNP-E2 construct in vitro and in vivo supported this claim. Delivery of E2 to the injured spinal cord via this approach reduced inflammation and gliosis, and induced microglial differentiation of M1 to M2 in rats after SCI. Analysis of spinal cord samples showed improved myelination and survival signals (AKT) as demonstrated by western blot analysis. SNP-E2 treatment also induced astrocytic differentiation into neuron-like (MAP2/NeuN) cells, supported the survival of oligodendrocyte precursor cells (OPC), and improved bladder and locomotor function in rats following SCI. These data suggest that this novel delivery strategy of SNP-E2 to the injured spinal cord may provide a safe and effective therapeutic approach to treat individuals suffering from SCI. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is one of the major causes of severe neurological disorders and long-term dysfunction in the nervous system. Besides inducing neurodegeneration, TBI alters stem cell activity and neurogenesis within primary neurogenic niches. However, the fate of dividing cells in other brain regions remains unclear despite offering potential targets for therapeutic intervention. Here, we investigated cell division and differentiation in non-neurogenic brain regions during the acute and delayed phases of TBI-induced neurodegeneration. We subjected mice to lateral fluid percussion injury (LFPI) to model TBI and analyzed them 1 or 7 weeks later. To assess cellular proliferation and differentiation, we administered 5-ethinyl-2′-deoxyuridine (EdU) and determined the number and identity of dividing cells 2 h later using markers of neuronal precursors and astro-, micro-, and oligodendroglia. Our results demonstrated a significant proliferative response in several brain regions at one week post-injury that notably diminished by seven weeks, except in the optic tract. In addition to active astro- and microgliosis, we detected oligodendrogenesis in the striatum and optic tract. Furthermore, we observed trauma-induced neurogenesis in the striatum. These findings suggest that subcortical structures, particularly the striatum and optic tract, may possess a potential for self-repair through neuronal regeneration and axon remyelination. [ABSTRACT FROM AUTHOR]

Abstract Subretinal injections provide direct access to photoreceptors and RPE, which is crucial for the delivery of gene therapy and neuroprotective approaches. To access the subretinal space, transvitreal (TV) and transscleral (TS) subretinal injections have been widely used in humans and animal models. In this work, we investigated recent trends and outcomes of utilizing TV and TS subretinal models of retinal detachment (RD). A literature review revealed an increasing utilization of both models over the past two decades, with TS emerging as the predominant model since 2012. Subretinal injection in CX3CR1 + /GFP CCR2 + /RFP mice revealed early inflammatory responses, with TS injections inducing higher infiltration of CD11b + CCR2 + cells compared to TV. Further leukocyte immunophenotyping indicated divergent infiltration patterns, with the TS approach exhibiting higher proportions of neutrophils and macrophages/microglia-like cells, while the TV injections had higher CD45hi CD11b + Ly6G- Ly6C + infiltration. Notably, late-stage analysis demonstrates higher photoreceptor cell death in the TS approach, paralleled by increased subretinal infiltration of CD11b + cells. Both models showed significant reactive gliosis, suggesting comparable late-stage wound healing responses. These findings underscore the utility of these approaches for subretinal delivery, offering insights into their distinctive leukocyte infiltration and late-stage tissue responses.

Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of diseases. We previously reported that Lipoxins A4 and B4 (LXA4 and LXB4) have protective activities against neurodegenerative injury. Yet, lipoxin activities and downstream signaling in neuroinflammatory processes are not well understood. Here, we utilized a model of posterior uveitis induced by lipopolysaccharide endotoxin (LPS), which results in rapid retinal neuroinflammation primarily characterized by activation of resident macroglia (astrocytes and Müller glia), and microglia. Using this model, we observed that each lipoxin reduces acute inner retinal inflammation by affecting endogenous glial responses in a cascading sequence beginning with astrocytes and then microglia, depending on the timing of exposure; prophylactic or therapeutic. Subsequent analyses of retinal cytokines and chemokines revealed inhibition of both CXCL9 (MIG) and CXCL10 (IP10) by each lipoxin, compared to controls, following LPS injection. CXCL9 and CXCL10 are common ligands for the CXCR3 chemokine receptor, which is prominently expressed in inner retinal astrocytes and ganglion cells. We found that CXCR3 inhibition reduces LPS-induced neuroinflammation, while CXCR3 agonism alone induces astrocyte reactivity. Together, these data uncover a novel lipoxin-CXCR3 pathway to promote distinct anti-inflammatory and proresolution cascades in endogenous retinal glia.

The positive effect of cellular protein kinases blockade in diabetes and diabetic retinopathy (DR) justifies the need to clarify molecular mechanisms, among which the trigger regulatory role belongs to calcium-binding proteins S100. Aim: to establish the expression of S100 protein in retinal tissues and the effect of cellular protein kinases blockade with Sorafenib on it in experimental DR. Materials and methods. Diabetic retinopathy was modeled in male Wistar rats. For this purpose, they were administered a single injection of streptozotocin at a dose of 50 mg/kg (Sigma-Aldrich, Co, China). Experimental rats were divided into three groups: control; with the administration of insulin 30 U (NovoNordiskA/S, Bagsvaerd, Germany); with the administration of insulin and sorafenib at a dose of 50 mg/kg (Cipla, India). Monoclonal antibodies against S100 (ThermoFisher Scietific, USA) were used during immunohistochemical studies. Results. With the development of experimental DR, the expression of S100 protein significantly increased in the bodies and processes of astrocytes and Müller cells. The latter were mainly located in the inner nuclear layer, significantly increased in size and had a process-like shape (reactive gliosis). Intensely stained S100-positive astrocyte fibers were in close contact with microaneurysms that formed on the retina inner surface. The appearance of individual S100-positive cells in the outer layers of the retina was noted. Treatment of animals with insulin led to a decrease in the expression of the S100 protein, and the use of Sorafenib prevented the activation of the expression of the S100 protein, preventing the development of DR, reactive gliosis, and the formation of microaneurysms on the inner surface of the retina. Conclusions. One of the mechanisms of the positive effect of Sorafenib in DR was discovered – the prevention of reactive gliosis, which prevented early manifestations of DR.

Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients. Methods We analyzed expression levels of 770 neuroinflammation‐related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the “recurrence group (RG)” or “non‐recurrence group (NRG)” were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort (n = 30). Results Forty‐five of 770 NFR genes were highly expressed in the RG (3‐year overall survival (OS, 22.2%), compared with the NRG group (3‐year OS 66.7%). Signatures related to glial cells were enriched in the RG‐associated gene set. Multivariate analysis revealed that high expressions of TUBB4A (p = 0.028, HR: 3.88), S100B (p = 0.046, HR: 3.093), and SLC6A1 (p = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells. Conclusion These data suggest that TME‐related genes play a crucial role in the pathogenesis of PCNSL, complementing the well‐known involvement of the NF‐kB signaling pathway. TME targeting, especially glial cell‐specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL.

This study investigates the effect of Licochalcone A (Lico-A), a flavonoid from licorice roots known for its anti-inflammatory, anti-cancer, and antioxidant properties, on NMDA-induced neurotoxicity in primary cultured rat hippocampal neurons. The study measured cell survival following NMDA and Lico-A exposure, revealing that Lico-A at a 2.5 μg/ml significantly improved cell viability, countering the detrimental effects of NMDA. The study also analyzed synaptic changes by examining both postsynaptic density 95 (PSD95) and synaptophysin-targeted imaging, showing that Lico-A treatment resulted in a significant increase in synaptic puncta, contrasting with the reduction observed under NMDA exposure. Furthermore, levels of phosphorylated mixed lineage kinase domain-like pseudokinase (P-MLKL) and phosphorylated receptor-interacting serine/threonine-protein kinase 3 (P-RIP3), key necroptosis regulators, were measured using Western blotting. The results showed an increase in P-MLKL and P-RIP3 in neurons exposed to NMDA, which was reduced following Lico-A treatment. The response of astrocyte and microglia was also evaluated by immunostaining for glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (IBA-1) and tumor necrosis factor alpha (TNF-α). These markers exhibited heightened expression in the NMDA group, which was substantially reduced by Lico-A treatment. These findings suggest that Lico-A has neuroprotective effects against NMDA-induced neurotoxicity, potentially contributing to synaptic preservation, inhibition of neuronal necroptosis, and modulation of glial activation. Therefore, Lico-A shows promise as a neuroprotective agent for conditions associated with NMDA-related neurotoxicity.

Lipocalin-2 (LCN2) is an acute-phase secretory molecule significantly upregulated in various neuroinflammatory and demyelinating conditions. Krabbe disease (KD) is a neurodegenerative lysosomal disorder caused by a galactosylceramidase (GALC) deficiency, accumulating cytotoxic psychosine in nervous systems, and subsequent neuroinflammation. Here, we show that LCN2 is highly overexpressed in GALC-deficient astrocytes. To further understand if the elevated LCN2 is critical for KD progression, we globally deleted Lcn2 in the Galc-knockout (KO) mouse model. Interestingly, the Galc and Lcn2 double KO mice showed dramatically reduced neuroinflammation including gliosis. Pro-inflammatory cytokines such as TNF-α, MMP3, and MCP-1 were significantly downregulated in the brain of the double KO mice compared to Galc-KO. In addition, the ablation of Lcn2 marginally increased the survival and attenuated disease progression in Galc-KO mice. However, the accumulation of psychosine was not altered in the brain by LCN2 deficiency. Our findings suggest that the upregulation of LCN2 is crucial for the aggravation of neuroinflammation in a mouse model of Krabbe disease. [ABSTRACT FROM AUTHOR]

In this neuropathological study, we investigated neuroinflammation surrounding recent and old cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs) in 18 cases of cerebral amyloid angiopathy (CAA). We used several serial stainings and immunolabellings to identify microvascular lesions, define their recent or old stage, and characterize neuroinflammatory response (scavenging activity and astrogliosis). We found that both CMBs and CMIs induce a neuroinflammatory response, which was more pronounced in old lesion than recent. Astrogliosis and scavenging activity were differentially prominent according to the ischemic/hemorrhagic nature of the lesion. Our findings provide insights into the pathophysiology of microvascular injuries in CAA. [ABSTRACT FROM AUTHOR]

Hypothalamic inflammation underlies diet-induced obesity and diabetes in rodent models. While diet normalization largely allows for recovery from metabolic impairment, it remains unknown whether long-term hypothalamic inflammation induced by obesogenic diets is a reversible process. In this study, we aimed at determining sex specificity of hypothalamic neuroinflammation and gliosis in mice fed a fat- and sugar-rich diet, and their reversibility upon diet normalization. Mice were fed a 60%-fat diet complemented by a 20% sucrose drink (HFHSD) for 3 days or 24 weeks, followed by a third group that had their diet normalized for the last 8 weeks of the study (reverse diet group, RevD). We determined the expression of pro- and anti-inflammatory cytokines, and of the inflammatory cell markers IBA1, CD68, GFAP and EMR1 in the hypothalamus, and analyzed morphology of microglia (IBA-1+ cells) and astrocytes (GFAP+ cells) in the arcuate nucleus. After 3 days of HFHSD feeding, male mice showed over-expression of IL-13, IL-18, IFN-γ, CD68 and EMR1 and reduced expression of IL-10, while females showed increased IL-6 and IBA1 and reduced IL-13, compared to controls. After 24 weeks of HFHSD exposure, male mice showed a general depression in the expression of cytokines, with prominent reduction of TNF-α, IL-6 and IL-13, but increased TGF-β, while female mice showed over-expression of IFN-γ and IL-18. Furthermore, both female and male mice showed some degree of gliosis after HFHSD feeding for 24 weeks. In mice of both sexes, diet normalization after prolonged HFHSD feeding resulted in partial neuroinflammation recovery in the hypothalamus, but gliosis was only recovered in females. In sum, HFHSD-fed mice display sex-specific inflammatory processes in the hypothalamus that are not fully reversible after diet normalization. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a prevalent complication of type 2 diabetes mellitus, characterized by progressive damage to the retinal structure and function. Photobiomodulation therapy, using red or near-infrared light, has been proposed as a non-invasive intervention to mitigate retinal damage, but has been tested generally with short-term stimuli. This study aimed to evaluate the effects of prolonged photobiomodulation with deep red light on retinal structure and function in a type 2 diabetes mouse model. Transgenic LepRdb/J (db/db) mice were exposed to photobiomodulation therapy via LED devices emitting 654 nm light for 12 h daily over ten weeks and compared to untreated mice. Retinal function was evaluated by flash electroretinography, while structural changes were assessed through histology and immunohistochemistry to detect astro- and microgliosis. At 33 weeks of age, db/db mice were obese and severely diabetic, but exhibited only incipient indicators of retinal deterioration. Electroretinogram b-wave peak latencies were prolonged at intermediate flash intensities, while the outer plexiform layer displayed significantly elevated IBA1 expression. Photobiomodulation therapy prevented these two markers of early retinal deterioration but had no effect on other morphological and functional parameters. Photobiomodulation is well-tolerated and maintains potential as a complementary treatment option for diabetic retinopathy but requires further optimization of therapeutic settings and combinatory treatment approaches. [ABSTRACT FROM AUTHOR]

Piezoelectric bone cutting has gained popularity in neurosurgical osteotomies due to perceived lower trauma compared to rotary instruments. However, histological confirmation of its decreased aggressiveness is lacking, hindering conclusive proof. This study compares the bony and neuro-meningeal invasiveness of piezoelectric craniotomy with high-speed drill techniques. Histological data from 21 sheep undergoing piezoelectric craniotomy and 19 sheep subjected to high-speed electric drill craniotomy were compared. Piezoelectric craniotomy utilized a 0.35 mm micro saw titanium nitride coated. Outcome parameters included the detection of the "smear layer," average osteoblast count per high-power field, and residual bone matrix for bony invasiveness assessment. Parameters for meningeal and brain parenchymal invasiveness included pachymeningeal and leptomeningeal injury, gliosis, and histiocytic infiltration. Statistical significance was determined at P < 0.05. Results showed the Piezo group had fewer frequent smear layers (P <0.001), higher residual bone matrix (P < 0.05), and greater osteoblast counts per high-power field (P < 0.05). Additionally, the Piezo group exhibited lower rates of leptomeningeal injury, cerebral gliosis, and histiocytic infiltration (P < 0.05). Piezoelectric craniotomy preserves residual osteoblast viability and leptomeningeal integrity while demonstrating lower rates of thermally induced gliosis and histiocytic infiltration compared to high-speed drills. This suggests the piezoelectric osteotome's minimal invasiveness in bone, meningeal, and brain tissue. [ABSTRACT FROM AUTHOR]

Simple Summary: Spinal cord injury affects millions of individuals worldwide, underscoring the urgent need for more effective treatments that can facilitate the recovery of motor and sensory functions. The use of neuroprotective molecules in conjunction with stem cell therapy may facilitate the restoration of function, thereby enabling patients to resume a productive lifestyle. The present study demonstrates that the combination of dimethyl fumarate, an immunomodulatory drug, with adult mesenchymal stem cells derived from adipose tissue exhibits neuroprotective and immunomodulatory properties. Furthermore, we observed a notable rescue of spinal motoneurons following the avulsion and reimplantation of ventral roots. Additionally, glial reactions were reduced, which may contribute to enhanced long-term outcomes. The collective findings support the potential of integrated regenerative strategies following spinal cord root injury. Spinal cord injury results in significant motor and sensory loss. In the experimental ventral root avulsion (VRA) model, the ventral (motor) roots are disconnected from the spinal cord surface, disrupting contact between spinal motoneurons and muscle fibers. Axotomized motoneurons typically degenerate within two to three weeks after avulsion, the situation being exacerbated by an increased glial response and chronic inflammation. Nevertheless, root reimplantation has been observed to stimulate regenerative potential in some motoneurons, serving as a model for CNS/PNS regeneration. We hypothesized that a combination of neuroprotective and immunomodulatory therapies is capable of enhancing regenerative responses following nerve root injury and repair. A heterologous fibrin biopolymer (HFB) was used for surgical repair; dimethyl fumarate (DMF) was used for neuroprotection and immunomodulation; and adipose tissue-derived mesenchymal stem cells (AT-MSCs) were used as a source of trophic factors and cytokines that may further enhance neuronal survival. Thus, adult female Lewis rats underwent unilateral VRA of the L4–L6 roots, followed by reimplantation with HFB, AT-MSCs transplantation, and daily DMF treatment for four weeks, with a 12-week postoperative survival period. An evaluation of the results focused on light microscopy, qRT-PCR, and the Catwalk motor function recovery system. Data were analyzed using one-way or two-way ANOVA (p < 0.05). The results indicate that the combined therapy resulted in a reduced glial response and a 70% improvement in behavioral motor recovery. Overall, the data support the potential of combined regenerative approaches after spinal cord root injury. [ABSTRACT FROM AUTHOR]

Purpose: Accurate detection and resection of the epileptogenic zone (EZ) in patients with long-term epilepsy-associated tumors (LEATs) are significantly correlated with favorable seizure prognosis. However, the relationship between tumors and the EZ remains unknown. This study aimed to evaluate the spatial relationship between LEATs and the EZ, as well as the electrophysiological features of LEATs. Methods: We retrospectively studied five patients with LEATs who underwent deep electrode implantation and EZ resection in the hospital. The clinical characteristics, surgical outcomes, localizing features and intracranial SEEG results were reviewed. Results: One female and four males (mean age: 25.2 years; median age: 24 years; range: 13–45 years) were included in the study. Five-to-eleven electrodes (mean: 8.4) were implanted per patient. The EZ was located in the tumor and nearby cortex in three cases and in the tumor and distant areas in two cases. Pathological examination revealed ganglioglioma in four cases, two of which were associated with hippocampal sclerosis, and the other case showed a multinodular and vacuolating neuronal tumor with gliosis. All patients were seizure-free for at least 24 months postoperatively. Conclusions: SEEG provides valuable insights into the electrophysiological mechanisms of LEATs. The EZ often contains brain tissue around the tumor. However, only a few cases, particularly those with temporoparietal occipital (TPO) area involvement, a long history of epilepsy and other abnormalities on MRI, such as hippocampal sclerosis and focal cortical dysplasia, may include distant areas. [ABSTRACT FROM AUTHOR]

Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is a common complication of diabetes characterized by vascular pathology and neuroinflammation. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule that functions at the crossroads between innate immunity, inflammation, and tissue remodeling. DR is known to involve inflammatory pathways, although the potential relevance of PTX3 has not been explored. We found that PTX3 protein levels increased in the retina of diabetic mice. Similarly, evaluation of a publicly available transcriptomic human dataset revealed increased PTX3 expression in DR with diabetic macular edema and proliferative retinopathy, when compared to nondiabetic retinas or diabetic retinas without complications. To further understand the role of PTX3 within DR, we employed the streptozotocin-induced diabetes model in PTX3 knockout mice (PTX3KO), which were followed up for 9 mo to evaluate hallmarks of disease progression. In diabetic PTX3KO mice, we observed decreased reactive gliosis, diminished microglia activation, and reduced vasodegeneration, when compared to diabetic PTX3 wild-type littermates. The decrease in DR-associated pathological features in PTX3KO retinas translated into preserved visual function, as evidenced by improved optokinetic response, restored b-wave amplitude in electroretinograms, and attenuated neurodegeneration. We showed that PTX3 induced an inflammatory phenotype in human retinal macroglia, characterized by GFAP upregulation and increased secretion of IL6 and PAI-1. We confirmed that PTX3 was required for TNF-α-induced reactive gliosis, as PTX3KO retinal explants did not up-regulate GFAP in response to TNF-α. This study reveals a unique role for PTX3 as an enhancer of sterile inflammation in DR, which drives pathogenesis and ultimately visual impairment. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively affects motoneurons, causing muscle atrophy and evolving to death. Astrocytes inhibit the expression of MHC-I by neurons, contributing to a degenerative outcome. The present study verified the influence of interferon β (IFN α) treatment, a proinflammatory cytokine that upregulates MHC-I expression, in SOD1G93A transgenic mice. For that, 17 days old presymptomatic female mice were subjected to subcutaneous application of IFN β (250, 1,000, and 10,000 IU) every other day for 20 days. Rotarod motor test, clinical score, and body weight assessment were conducted every third day throughout the treatment period. No significant intergroup variations were observed in such parameters during the pre-symptomatic phase. All mice were then euthanized, and the spinal cords collected for comparative analysis of motoneuron survival, reactive gliosis, synapse coverage, microglia morphology classification, cytokine analysis by flow cytometry, and RT-qPCR quantification of gene transcripts. Additionally, mice underwent Rotarod motor assessment, weight monitoring, and neurological scoring. The results show that IFN β treatment led to an increase in the expression of MHC-I, which, even at the lowest dose (250 IU), resulted in a significant increase in neuronal survival in the ALS presymptomatic period which lasted until the onset of the disease. The treatment also influenced synaptic preservation by decreasing excitatory inputs and upregulating the expression of AMPA receptors by astrocytes. Microglial reactivity quantified by the integrated density of pixels did not decrease with treatment but showed a less activated morphology, coupled with polarization to an M1 profile. Disease progression upregulated gene transcripts for pro- and anti-inflammatory cytokines, and IFN β treatment significantly decreased mRNA expression for IL4. Overall, the present results demonstrate that a low dosage of IFN β shows therapeutic potential by increasing MHC-I expression, resulting in neuroprotection and immunomodulation. [ABSTRACT FROM AUTHOR]

Background: Some lower‐grade gliomas (LGG) are difficult to distinguish morphologically from glial cell proliferation or inflammatory changes during surgery, leading to a high risk of incorrect diagnosis. It is crucial to differentiate between the two for making surgical decisions. We define these critical cases as "ultra early stage lower‐grade gliomas (UES‐LGG)". Methods: We analyzed 11 out of 13 cases diagnosed with "gliosis" or "inflammatory changes" during surgery who tested positive for isocitrate dehydrogenase (IDH). Additionally, we conducted qRT‐PCR detection on 35 samples diagnosed with LGG during surgery and analyzed their DNA content within an effective circulating threshold range to infer the critical value between UES‐LGG and LGG. We conducted experiments using five standardized samples to infer the limited range of accurate detection of UES‐LGG during surgery. Results: In the comparative analysis of 11 samples and 35 samples, it was found that while there was no significant difference in the average DNA detection concentration between the two groups (159.36 ± 83.3 ng/μL and 146.83 ± 122.43 ng/μL), there was a notable statistical variance in the detection threshold for positive mutations (31.78 ± 1.14 and 26.14 ± 2.69, respectively). This suggests that the IDH mutation rate may serve as an indicator for differentiation between the two groups. Subsequently, DNA was extracted from standardized IDH mutant samples and subjected to gradient dilution for detection purposes. The results indicated a consistent increase in detection threshold as detection concentration decreased. When the detection concentration fell below <0.1 ng/μL, it became impossible to carry out effective threshold range detections. To further identify the precise detection interval, we conducted gradient division once again and sought to simulate the functional relationship between DNA copy number and cycle threshold within this interval. The research revealed that when the minimum detection concentration exceeded 250 copies/μL, a 100% detection rate could be achieved. Conclusions: This article defines UES‐LGG as a tumor type easily misdiagnosed in clinical practice due to its extremely low positivity rate during surgery. The popularization of qRT‐PCR based intraoperative molecular diagnosis greatly reduces errors caused by manual detection and improves disease detection rates during surgery. It provides a theoretical basis for more accurate surgical plans for surgeons. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms that underpin the transition from acute to chronic pain is critical for the development of more effective and targeted treatments. There is growing interest in the contribution of glial cells to this process, with cross-sectional preclinical studies demonstrating specific changes in these cell types capturing targeted timepoints from the acute phase and the chronic phase. In vivo longitudinal assessment of the development and evolution of these changes in experimental animals and humans has presented a significant challenge. Recent technological advances in preclinical and clinical positron emission tomography, including the development of specific radiotracers for gliosis, offer great promise for the field. These advances now permit tracking of glial changes over time and provide the ability to relate these changes to pain-relevant symptomology, comorbid psychiatric conditions, and treatment outcomes at both a group and an individual level. In this article, we summarize evidence for gliosis in the transition from acute to chronic pain and provide an overview of the specific radiotracers available to measure this process, highlighting their potential, particularly when combined with ex vivo/in vitro techniques, to understand the pathophysiology of chronic neuropathic pain. These complementary investigations can be used to bridge the existing gap in the field concerning the contribution of gliosis to neuropathic pain and identify potential targets for interventions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by complex interactions between neuropathological markers, metabolic dysregulation, and structural brain changes. In this study, we utilized a multimodal approach, combining immunohistochemistry, functional metabolic mapping, and microstructure sensitive diffusion MRI (dMRI) to progressively investigate these interactions in the 5xFAD mouse model of AD. Our analysis revealed age-dependent and region-specific accumulation of key AD markers, including amyloid-beta (Aβ), GFAP, and IBA1, with significant differences observed between the hippocampal formation and upper and lower regions of the cortex by 6 months of age. Functional metabolic mapping validated localized disruptions in energy metabolism, with glucose hypometabolism in the hippocampus and impaired astrocytic metabolism in the cortex. Notably, increased cortical glutaminolysis suggested a shift in microglial metabolism, reflecting an adaptive response to neuroinflammatory processes. While dMRI showed no significant microstructural differences between 5xFAD and wild-type controls, the study highlights the importance of metabolic alterations as critical events in AD pathology. These findings emphasize the need for targeted therapeutic strategies addressing specific metabolic disturbances and underscore the potential of integrating advanced imaging with metabolic and molecular analyses to advance our understanding of AD progression. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer's disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine β-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H2S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H2S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H2S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model. [ABSTRACT FROM AUTHOR]

Abstract Background Amyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer’s disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD. Results Immunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid β (Aβ) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aβ load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model. Conclusion Aged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender.

Abstract Retinitis pigmentosa (RP), an inherited retinal disease, affects 1,5 million people worldwide. The initial mutation-driven photoreceptor degeneration leads to chronic inflammation, characterized by Müller cell activation and upregulation of CD44. CD44 is a cell surface transmembrane glycoprotein and the primary receptor for hyaluronic acid. It is involved in many pathological processes, but little is known about CD44’s retinal functions. CD44 expression is also increased in Müller cells from our Pde6b STOP/STOP RP mouse model. To gain a more detailed understanding of CD44’s role in healthy and diseased retinas, we analyzed Cd44 −/− and Cd44 −/− Pde6b STOP/STOP mice, respectively. The loss of CD44 led to enhanced photoreceptor degeneration, reduced retinal function, and increased inflammatory response. To understand the underlying mechanism, we performed proteomic analysis on isolated Müller cells from Cd44 −/− and Cd44 −/− Pde6b STOP/STOP retinas and identified a significant downregulation of glutamate transporter 1 (SLC1A2). This downregulation was accompanied by higher glutamate levels, suggesting impaired glutamate homeostasis. These novel findings indicate that CD44 stimulates glutamate uptake via SLC1A2 in Müller cells, which in turn, supports photoreceptor survival and function.

Abstract Subretinal fibrosis is a major untreatable cause of poor outcomes in neovascular age-related macular degeneration. Mouse models of subretinal fibrosis all possess a degree of invasiveness and tissue damage not typical of fibrosis progression. This project characterises JR5558 mice as a model to study subretinal fibrosis. Fundus and optical coherence tomography (OCT) imaging was used to non-invasively track lesions. Lesion number and area were quantified with ImageJ. Retinal sections, wholemounts and Western blots were used to characterise alterations. Subretinal lesions expand between 4 and 8 weeks and become established in size and location around 12 weeks. Subretinal lesions were confirmed to be fibrotic, including various cell populations involved in fibrosis development. Müller cell processes extended from superficial retina into subretinal lesions at 8 weeks. Western blotting revealed increases in fibronectin (4 wk and 8 wk, p

The number of people with dementia is increasing annually worldwide. Alzheimer's disease (AD), which accounts for the highest percentage of dementia-causing diseases, remains difficult to cure, and prevention of its onset is important. We aimed to discover new AD-preventive ingredients and investigate the inhibitory effects of ten different species of seafood digests prepared by protease treatment on β-secretase 1 (BACE1) activity. Substantial inhibition of BACE1 activity was observed in five species of seafood, and protease-digested whitebait (WPD) showed the highest inhibitory effect among the ten marine samples. We further examined the potential of WPD as an AD preventive component using a familial AD strain (5xFAD) murine model. The intraperitoneal administration of WPD for 28 days substantially decreased the insoluble amyloid β1–42 content and the expression of glial fibrillary acidic protein, a marker of astrogliosis, in the cerebral cortex of the 5xFAD mice. These results strongly suggest that WPD is a novel functional food-derived ingredient with preventive effects against AD. [ABSTRACT FROM AUTHOR]

Background: Amyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer's disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD. Results: Immunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid β (Aβ) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aβ load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model. Conclusion: Aged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender. [ABSTRACT FROM AUTHOR]

Astrogliosis is a process by which astrocytes, when exposed to inflammation, exhibit hypertrophy, motility, and elevated expression of reactivity markers such as Glial Fibrillar Acidic Protein, Vimentin, and Connexin43. Since 1999, our laboratory in Chile has been studying molecular signaling pathways associated with "gliosis" and has reported that reactive astrocytes upregulate Syndecan 4 and αVβ3 Integrin, which are receptors for the neuronal glycoprotein Thy-1. Thy-1 engagement stimulates adhesion and migration of reactive astrocytes and induces neurons to retract neurites, thus hindering neuronal network repair. Reportedly, we have used DITNC1 astrocytes and neuron-like CAD cells to study signaling mechanisms activated by the Syndecan 4–αVβ3 Integrin/Thy-1 interaction. Importantly, the sole overexpression of β3 Integrin in non-reactive astrocytes turns them into reactive cells. In vitro, extensive passaging is a simile for "aging", and aged fibroblasts have shown β3 Integrin upregulation. However, it is not known if astrocytes upregulate β3 Integrin after successive cell passages. Here, we hypothesized that astrocytes undergoing long-term passaging increase β3 Integrin expression levels and behave as reactive astrocytes without needing pro-inflammatory stimuli. We used DITNC1 cells with different passage numbers to study reactivity markers using immunoblots, immunofluorescence, and astrocyte adhesion/migration assays. We also evaluated β3 Integrin levels by immunoblot and flow cytometry, as well as the neurotoxic effects of reactive astrocytes. Serial cell passaging mimicked the effects of inflammatory stimuli, inducing astrocyte reactivity. Indeed, in response to Thy-1, β3 Integrin levels, as well as cell adhesion and migration, gradually increased with multiple passages. Importantly, these long-lived astrocytes expressed and secreted factors that inhibited neurite outgrowth and caused neuronal death, just like reactive astrocytes in culture. Therefore, we describe two DITNC1 cell types: a non-reactive type that can be activated with Tumor Necrosis Factor (TNF) and another one that exhibits reactive astrocyte features even in the absence of TNF treatment. Our results emphasize the importance of passage numbers in cell behavior. Likewise, we compare the pro-inflammatory stimulus versus long-term in-plate passaging of cell cultures and introduce them as astrocyte models to study the reactivity process. [ABSTRACT FROM AUTHOR]

The positive effect of cellular protein kinases blockade in diabetes and diabetic retinopathy (DR) justifies the need to clarify molecular mechanisms, among which the trigger regulatory role belongs to calcium-binding proteins S100. Aim: to establish the expression of S100 protein in retinal tissues and the effect of cellular protein kinases blockade with Sorafenib on it in experimental DR. Materials and methods. Diabetic retinopathy was modeled in male Wistar rats. For this purpose, they were administered a single injection of streptozotocin at a dose of 50 mg/kg (Sigma-Aldrich, Co, China). Experimental rats were divided into three groups: control; with the administration of insulin 30 U (NovoNordiskA/S, Bagsvaerd, Germany); with the administration of insulin and sorafenib at a dose of 50 mg/kg (Cipla, India). Monoclonal antibodies against S100 (ThermoFisher Scietific, USA) were used during immunohistochemical studies. Results. With the development of experimental DR, the expression of S100 protein significantly increased in the bodies and processes of astrocytes and Müller cells. The latter were mainly located in the inner nuclear layer, significantly increased in size and had a process-like shape (reactive gliosis). Intensely stained S100-positive astrocyte fibers were in close contact with microaneurysms that formed on the retina inner surface. The appearance of individual S100-positive cells in the outer layers of the retina was noted. Treatment of animals with insulin led to a decrease in the expression of the S100 protein, and the use of Sorafenib prevented the activation of the expression of the S100 protein, preventing the development of DR, reactive gliosis, and the formation of microaneurysms on the inner surface of the retina. Conclusions. One of the mechanisms of the positive effect of Sorafenib in DR was discovered – the prevention of reactive gliosis, which prevented early manifestations of DR. [ABSTRACT FROM AUTHOR]

Mutations in the PSEN genes are the major cause of familial Alzheimer's disease, and presenilin (PS) is the catalytic subunit of γ-secretase, which cleaves type I transmembrane proteins, including the amyloid precursor protein (APP) to release Aβ peptides. While PS plays an essential role in the protection of neuronal survival, PSEN mutations also increase the ratio of Aβ42/Aβ40. Thus, it remains unresolved whether PSEN mutations cause AD via a loss of its essential function or increases of Aβ42/Aβ40. Here, we test whether the knockin (KI) allele of Psen1 L435F, the most severe FAD mutation located closest to the active site of γ-secretase, causes age-dependent cortical neurodegeneration independent of Aβ by crossing various Psen mutant mice to the App-null background. We report that removing Aβ completely through APP deficiency has no impact on the age-dependent neurodegeneration in Psen mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases Aβ42/Aβ40 in the cerebral cortex while decreasing de novo production and steady-state levels of Aβ42 and Aβ40 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of Psen mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that Psen1 mutations cause age-dependent neurodegeneration independent of Aβ, providing further support for a loss-of-function pathogenic mechanism underlying PSEN mutations. [ABSTRACT FROM AUTHOR]

Subretinal fibrosis is a major untreatable cause of poor outcomes in neovascular age-related macular degeneration. Mouse models of subretinal fibrosis all possess a degree of invasiveness and tissue damage not typical of fibrosis progression. This project characterises JR5558 mice as a model to study subretinal fibrosis. Fundus and optical coherence tomography (OCT) imaging was used to non-invasively track lesions. Lesion number and area were quantified with ImageJ. Retinal sections, wholemounts and Western blots were used to characterise alterations. Subretinal lesions expand between 4 and 8 weeks and become established in size and location around 12 weeks. Subretinal lesions were confirmed to be fibrotic, including various cell populations involved in fibrosis development. Müller cell processes extended from superficial retina into subretinal lesions at 8 weeks. Western blotting revealed increases in fibronectin (4 wk and 8 wk, p < 0.001), CTGF (20 wks, p < 0.001), MMP2 (12 wks and 20 wks p < 0.05), αSMA (12 wks and 20 wks p < 0.05) and GFAP (8 wk and 12 wk, p ≤ 0.01), consistent with our immunofluorescence results. Intravitreal injection of Aflibercept reduced subretinal lesion growth. Our study provides evidence JR5558 mice have subretinal fibrotic lesions that grow between 4 and 8 weeks and confirms this line to be a good model to study subretinal fibrosis development and assess treatment options. [ABSTRACT FROM AUTHOR]

Objective: This study provides histological evidence of the combined effects of L-Carnitine, and Coenzyme Q10 on gliosis and anhedonia in a rat model of multiple sclerosis (MS). Methods: Fifty male Sprague Dawley rats were randomly divided into 5 groups of 10 rats each. Group 1 was the control group. The rest of the groups were disease models and were given 0.2% cuprizone w/w to induce MS. After 4 weeks, Group 3 started receiving L-Carnitine, Group 4 was given Coenzyme Q10, and Group 5 received both, while cuprizone poisoning continued. After 12 weeks sucrose preference test and tail suspension test were performed for anhedonia. Rats were euthanized and brains were dissected, and assessed for astrocytes, oligodendrocytes, and microglial count. Results: A significant increase in oligodendrocyte count, while a reduction in astrocyte and microglial count was seen in the synergistic group (p < 0.05). Synergism could not be proved in anhedonia. Conclusion: The combination of Coenzyme Q10 and L-Carnitine has a synergistic effect in controlling gliosis in a rat model of MS, but synergism could not be demonstrated on anhedonia. [ABSTRACT FROM AUTHOR]

Evidence shows that Autism Spectrum Disorder (ASD) stems from an interplay of genetic and environmental factors, which may include propionic acid (PPA), a microbial byproduct and food preservative. We previously reported that in vitro treatment of neural stem cells with PPA leads to gliosis and neuroinflammation. In this study, mice were exposed ad libitum to a PPA-rich diet for four weeks before mating. The same diet was maintained through pregnancy and administered to the offspring after weaning. The brains of the offspring were studied at 1 and 5 months postpartum. Glial fibrillary acidic protein (astrocytic marker) was significantly increased (1.53 ± 0.56-fold at 1 M and 1.63 ± 0.49-fold at 5 M) in the PPA group brains. Tubulin IIIβ (neuronal marker) was significantly decreased in the 5 M group. IL-6 and TNF-α expression were increased in the brain of the PPA group (IL-6: 2.48 ± 1.25-fold at 5 M; TNF-α: 2.84 ± 1.16-fold at 1 M and 2.64 ± 1.42-fold, at 5 M), while IL-10 was decreased. GPR41 and p-Akt were increased, while PTEN (p-Akt inhibitor) was decreased in the PPA group. The data support the role of a PPA-rich diet in glia over-proliferation and neuro-inflammation mediated by the GPR41 receptor and PTEN/Akt pathway. These findings strongly support our earlier study on the role of PPA in ASD. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation end products (RAGE) is a protein of the immunoglobulin superfamily capable of regulating inflammation. Considering the role of this receptor in the initiation and establishment of neuroinflammation, and the limited understanding of the function of RAGE in the maintenance of this condition, this study describes the effects of RAGE inhibition in the brain, through an intranasal treatment with the antagonist FPS‐ZM1, in an animal model of chronic neuroinflammation induced by acute intraperitoneal injection of lipopolysaccharide (LPS). Seventy days after LPS administration (2 mg/kg, i.p.), Wistar rats received, intranasally, 1.2 mg of FPS‐ZM1 over 14 days. On days 88 and 89, the animals were submitted to the open‐field test and were killed on day 90 after the intraperitoneal injection of LPS. Our results indicate that blockade of encephalic RAGE attenuates LPS‐induced chronic neuroinflammation in different brain regions. Furthermore, we found that intranasal FPS‐ZM1 administration reduced levels of gliosis markers, RAGE ligands, and α‐synuclein in the substantia nigra pars compacta. Additionally, the treatment also reversed the increase in S100 calcium‐binding protein B (RAGE ligand) in the cerebrospinal fluid and the cognitive‐behavioral deficits promoted by LPS—less time spent in the central zone of the open‐field arena (more time in the lateral zones), decreased total distance traveled, and increased number of freezing episodes. In summary, our study demonstrates the prominent role of RAGE in the maintenance of a chronic neuroinflammatory state triggered by a single episode of systemic inflammation and also points to possible future RAGE‐based therapeutic approaches to treat conditions in which chronic neuroinflammation and increased α‐synuclein levels could play a relevant role, such as in Parkinson's disease. [ABSTRACT FROM AUTHOR]

The neuroprotective effects of choline chloride, an essential nutrient, a precursor for the acetylcholine and synthesis of membrane phospholipids, have been associated with neurological and neurodegenerative diseases. Its contribution to autism spectrum disorder, a neurodevelopmental disorder, remains unknown. Thus, we aimed to evaluate the effects of choline chloride on social behaviours, and histopathological and biochemical changes in a rat autism model. The autism model was induced by administration of 100 μg/kg lipopolysaccharide (LPS) on the 10th day of gestation. Choline chloride treatment (100 mg/kg/day) was commenced on PN5 and maintained until PN50. Social deficits were assessed by three‐chamber sociability, open field, and passive avoidance learning tests. Tumour necrosis factor alpha (TNF‐α), interleukin‐2 (IL) and IL‐17, nerve growth factor (NGF), and glutamate decarboxylase 67 (GAD67) levels were measured to assess neuroinflammatory responses. In addition, the number of hippocampal and cerebellar neurons and glial fibrillary acidic protein (GFAP) expression were evaluated. Social novelty and passive avoidance learning tests revealed significant differences in choline chloride‐treated male rats compared with saline‐treated groups. TNF‐α, IL‐2, and IL‐17 were significantly decreased after choline chloride treatment in both males and females. NGF and GAD67 levels were unchanged in females, while there were significant differences in males. Histologically, significant changes in terms of gliosis were detected in hippocampal CA1 and CA3 regions and cerebellum in choline chloride‐treated groups. The presence of ameliorative effects of choline chloride treatment on social behaviour and neuroinflammation through neuroinflammatory, neurotrophic, and neurotransmission pathways in a sex‐dependent rat model of LPS‐induced autism was demonstrated. [ABSTRACT FROM AUTHOR]

Age‐related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short‐lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single‐cell RNA‐sequencing (scRNAseq) of three age groups (6‐, 12‐, and 18‐week‐old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in the ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age‐related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterized, confirming the presence of all typical vertebrate retinal cell types. Data integration from age‐matched samples between the bulk and scRNAseq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasizes the value of the fast‐ageing killifish in elucidating molecular signatures in age‐associated retinal disease and vision decline. This study contributes to the understanding of how age‐related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age‐related pathologies. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP), an inherited retinal disease, affects 1,5 million people worldwide. The initial mutation-driven photoreceptor degeneration leads to chronic inflammation, characterized by Müller cell activation and upregulation of CD44. CD44 is a cell surface transmembrane glycoprotein and the primary receptor for hyaluronic acid. It is involved in many pathological processes, but little is known about CD44's retinal functions. CD44 expression is also increased in Müller cells from our Pde6bSTOP/STOP RP mouse model. To gain a more detailed understanding of CD44's role in healthy and diseased retinas, we analyzed Cd44−/− and Cd44−/−Pde6bSTOP/STOP mice, respectively. The loss of CD44 led to enhanced photoreceptor degeneration, reduced retinal function, and increased inflammatory response. To understand the underlying mechanism, we performed proteomic analysis on isolated Müller cells from Cd44−/− and Cd44−/−Pde6bSTOP/STOP retinas and identified a significant downregulation of glutamate transporter 1 (SLC1A2). This downregulation was accompanied by higher glutamate levels, suggesting impaired glutamate homeostasis. These novel findings indicate that CD44 stimulates glutamate uptake via SLC1A2 in Müller cells, which in turn, supports photoreceptor survival and function. [ABSTRACT FROM AUTHOR]

Degenerative lesions specific to the basal nuclei have not been described as a background finding in Beagle dogs. This report comprises a documentation of seven cases. In the context of a nonclinical safety studies, the authors suggest documenting the lesion descriptively as degeneration neuropil, basal nuclei, bilateral as it is characterized by (1) vacuolation, neuropil; (2) gliosis (astro- and/or microgliosis); and (3) demyelination. This novel lesion is considered a potential new background change for several reasons: (1) It occurred in animals from test item–treated and also vehicle-treated groups; (2) no dose dependency was observed; (3) in one of six affected test item–treated dogs, the given compound was shown not to penetrate the blood-brain barrier; and (4) statistical comparison between the proportions of affected dogs in the treatment and control groups did not yield a statistically significant difference. The etiology remains unknown and is subject to further investigations. [ABSTRACT FROM AUTHOR]