Search Results (2,284)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which amyloid β accumulation, tau pathology, chronic neuroinflammation, and metabolic stress converge to drive synaptic dysfunction and neuronal loss. Rather than resulting from a single mechanism, increasing evidence indicates that neurodegeneration in AD is mediated by the coordinated activation of multiple regulated cell death pathways. These pathways include apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, each characterized by distinct molecular mediators and execution programs. Evidence from human brain tissues, animal models, and in vitro systems demonstrates that core pathological drivers such as amyloid β and tau pathology, oxidative stress, and sustained neuroinflammation engage these death pathways in a spatially, temporally, and cell-type-dependent manner across neurons and glial populations. In this review, we synthesize the current knowledge on regulated cell death mechanisms in AD, emphasizing their molecular signatures, cellular specificity, and stage-dependent involvement, together with recent advances in immunohistochemical, imaging, and biofluid-based approaches for detecting neuronal death. By integrating evidence across molecular, cellular, and system levels, this review positions regulated cell death as a unifying framework for understanding neurodegeneration and developing pathway-specific biomarkers and combinatorial neuroprotective strategies. Full article

Glial cells, particularly astrocytes and microglia, are central to maintaining CNS homeostasis and coordinating responses to injury through tightly regulated metabolic, inflammatory, and mechanosensitive processes. Emerging evidence identifies the Hippo signaling pathway and its downstream effectors YAP/TAZ as key regulators of glial functions, influencing proliferation, polarization, intercellular communication, and the balance between neuroprotection and neurotoxicity. This review discusses the Hippo signaling pathway and its transcriptional co-activators YAP/TAZ as context-dependent hubs integrating mechanical, metabolic, and immune cues in astrocytes and microglia. Particular attention is given to MST1/2- and YAP/TAZ-dependent signaling in microglia, which governs inflammatory states, redox balance, mitophagy, and mechanosensing. In astrocytes, Hippo–YAP signaling emerges as a bidirectional regulator of reactive gliosis and neuroprotection, capable of constraining excessive scar formation. However, when chronically suppressed, it impairs glutamate clearance, metabolic support, and resistance to neurodegeneration. Disruption of Hippo signaling in glial tumors is also considered, with YAP/TAZ–TEAD complexes driving glioblastoma stemness, infiltrative growth, immune evasion, and therapy resistance. Finally, therapeutic perspectives are outlined that emphasize context-selective modulation of Hippo signaling in the CNS. Overall, Hippo–YAP/TAZ signaling is presented as a highly context-dependent regulator at the interface of glial inflammation, neurodegeneration, and glioma biology and as a promising but demanding target for future CNS therapies. Full article

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity affecting 30–40% of patients treated with neurotoxic chemotherapy. Sensory symptoms arise from injury to dorsal root ganglion (DRG) neurons and their axons; yet, the underlying mechanisms remain incompletely understood. While human induced pluripotent stem cell (iPSC)-derived sensory neuron (iSN) monolayers have provided mechanistic insight, they lack the three-dimensional architecture and cellular heterogeneity of native DRG tissue. Here, we generated human iPSC-derived DRG organoids (iDRGOs) containing mixed neuronal and peripheral glial populations and established a quantitative neurite outgrowth assay to model chemotherapy-induced neurotoxicity in a 3D context. iDRGOs from three healthy donors were exposed to bortezomib, vincristine, or paclitaxel. All three drugs caused dose-dependent neurite outgrowth impairment without significant short-term changes in organoid size, consistent with early axonal injury. Vincristine reduced MAP2 levels when normalized to total protein, whereas bortezomib and paclitaxel showed divergent microtubule-associated responses compared to monolayer cultures. The developmental stage significantly influenced the baseline neurite outgrowth, highlighting the need for age standardization. These results establish iDRGOs as a physiologically relevant human platform that complements monolayer models for mechanistic studies and therapeutic screening in CIPN. Full article

The Fukushima nuclear accident highlighted that evacuation-related psychosocial harm can outweigh direct radiation risks, underscoring the need to define the health impacts of chronic low-dose-rate (LDR) radiation and evidence-based thresholds for intervention. This study investigated the effects of continuous, postnatal LDR gamma irradiation (1.2 mGy/h, cumulative dose: 5 Gy) in male mice. While no changes in body weight, hippocampal neurogenesis, or major glial and neuronal populations were observed, persistent DNA damage (γ-H2AX foci) in dentate gyrus granule cells occurred in both irradiated male and female mice. Irradiated male mice developed anxiety-like behaviour, a phenotype not observed in a previously published study of female mice subjected to an identical irradiation protocol. Molecular profiling revealed two novel, dysregulated miRNA/mRNA axes in the hippocampus linking DNA damage to behaviour: a maladaptive miR-466i-5p/Tfcp2l1 pathway associated with genomic instability, and a potentially adaptive miR-101a-5p/BMP6 pathway promoting neuronal survival. Venn analysis further identified miR-124b-3p and novel-miR489-3p as conserved exposure biomarkers, altered in both the hippocampus and blood of irradiated animals. Our results show that a high cumulative dose of chronic LDR induces markedly less severe hippocampal pathology than has been reported for equivalent acute doses. These findings support the concept of dose-rate-dependent threshold dose and contribute to the evidence base for developing countermeasures following nuclear incidents or other radiation exposures. Full article

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults, but cell-type-specific molecular alterations in the epileptic cortex remain incompletely characterized. We performed single-nucleus RNA sequencing on temporal cortex from three patients with drug-resistant TLE and two non-epileptic controls, retaining 66,932 nuclei. Seven major cell types were annotated. Neuropeptide Y (NPY) was significantly upregulated in microglia and oligodendrocytes under stringent criteria (|log₂FC| > 1, adjusted p < 0.01), whereas changes in other cell types did not meet this threshold. Microglia showed enrichment of neuropeptide- and inflammatory-related pathways, together with reduced oxidative phosphorylation signatures. Oligodendrocytes showed altered lipid metabolism, together with reduced mitochondrial energy-related signatures. Inferred intercellular communication was globally reduced in the TLE samples. qPCR in an independent small set showed an upward trend of NPY expression, though not statistically significant. Given the limited cohort size, these results should be interpreted as exploratory. They provide a cell-type-resolved candidate framework for future mechanistic studies of glial-associated responses in human epilepsy. Full article

Neuroimplants represent an emerging medical technology, offering new therapeutic approaches for severe neurological and psychiatric disorders. One of the key limitations to long-term neuroimplant performance is the foreign body response elicited by intracortical implantation. Among the contributing cell types, astrocytes play a central role in glial scar formation around the implant, which can compromise device functionality. Immunofluorescence of glial fibrillary acidic protein (GFAP) provides a well-established marker of astrogliosis (neuroinflammation), yet quantitative and reproducible assessment of astrocyte morphology remains challenging due to the complexity and variability of image analysis approaches. Here, we aimed to quantitatively assess implantation-induced astrogliosis and to determine how classifier training strategy influences segmentation outcomes and morphometric measurements. We present a machine learning-assisted pipeline based on the LabKit plugin in Fiji for segmentation and morphometric analysis of GFAP-positive astrocytes in peri-implant scar versus distant cortical regions. Using this approach, we demonstrate an increase in GFAP expression, cell area, and astrocytic process length as well as the redistribution of GFAP signal along astrocytic processes within scar regions. We show that different classifier training strategies produce systematically distinct segmentation outcomes, with rule-compliant annotation improving agreement with manually defined ground truth. These findings highlight the critical role of annotation strategy in shallow learning-based segmentation and provide a practical framework for improving reproducibility of astrocyte morphometry in studies of neuroinflammation and neuroimplant biocompatibility. Full article

Alzheimer’s disease is a complex neurodegenerative condition characterized by progressive cognitive decline, neuroinflammation, metabolic dysregulation, and abnormal protein deposition. While genetic factors and amyloid-beta-focused hypotheses have been extensively investigated, they fail to fully account for the prolonged prodromal phase or the early susceptibility of olfactory and limbic regions. Emerging evidence suggests chronic peripheral and mucosal infections may influence disease risk; however, mechanisms by which microbial activity outside the central nervous system contributes to persistent neuropathology remain poorly understood. This review explores the emerging concept that bacterial outer membrane vesicles act as mobile, lipid-rich vectors linking peripheral microbial reservoirs to neuroimmune and metabolic dysfunction in the aging brain. We discuss evidence suggesting vesicles originating from oral, olfactory, and upper airway niches can access the central nervous system via vascular routes and direct neural pathways, including olfactory and trigeminal nerves, where they influence glial and endothelial cell function. We also propose the Accumulative Vesicle Load Hypothesis, which describes how cumulative lifetime exposure to bacterial vesicles shapes disease onset, anatomical vulnerability, and progression, and incorporates components of other hypotheses proposed for Alzheimer’s disease. This offers a system-level perspective for early diagnosis and upstream therapeutic strategies, including minimally invasive vesicle profiling in nasal fluid, saliva, blood, and cerebrospinal fluid. This work is a conceptual review that summarizes current evidence in a hierarchically organized manner and proposes a testable model; it does not assert causality where direct human evidence is currently limited. Full article

Neuroinflammation is determinant in the progression of neurodegenerative diseases. One of the main mechanisms underlying this process involves the persistent activation of glial cells. Persistent activation of glial cells induces proinflammatory transcription factors and the release of cytokines, chemokines, and reactive oxygen species that exacerbate cellular dysfunction. This neurotoxic environment promotes neuronal death, while the products of cellular damage feed back into glial activation, establishing a self-sustaining pathogenic cycle that drives neurodegeneration. Alkaloids present in Amaryllidaceae plants support the use of this resource in folk medicine, displaying potent effects as acetylcholinesterase inhibitors and allosteric modulators of nicotinic receptors (nAChR). In this study, a murine microglial cell (IMG) model of LPS-induced inflammation was used to evaluate the involvement of α7 and α4β2 nAChRs in glioprotection and neuroprotection of SH-SY5Y cells against 6-hydroxydopamine (OHDA). GC-MS analysis revealed differences in the alkaloid profile between in vitro cultures with fructose and wild-type Rhodophiala pratensis. Homolycorine-type, norbelladine-type and crinine-type alkaloids produced in vitro reduced LPS-induced inflammation (5 µg/mL), possibly via α7 and α4β2 nAChRs, and showed a protective effect against OHDA-induced oxidative stress (1–3 µg/mL) and inhibited AChE and BuChE (24–78 µg/mL). Full article

Oligodendroglial cells are the myelinating glial cells of the central nervous system (CNS), and their morphological differentiation is a prerequisite for efficient myelin formation, which is essential for proper neuronal function. While oligodendroglial morphological changes normally proceed through tightly regulated developmental transitions, disruption of the underlying molecular mechanisms can lead to aberrant cellular phenotypes characterized by either premature, insufficient, or excessive differentiation. Although the phosphatidylinositol 3-kinase (PI3K) and its downstream Akt kinase signaling are well established as major drivers of oligodendrocyte morphological differentiation, myelination, and CNS white matter formation, how its negative regulator, phosphatase and tensin homolog (PTEN), is involved in the regulation of oligodendroglial morphogenesis remains incompletely understood. Recent genetic studies have highlighted a spectrum of disorders caused by PTEN dysfunction, conceptually established but currently evolving as PTENopathy, which has been partially associated with white matter abnormalities. Here, we report that, in an experimental model using the FBD-102b cell line, a well-established model of oligodendroglial cell differentiation, chemical inhibition of PTEN enhances pronounced morphological changes characterized by widespread membranes, accompanied by increased expression of differentiation and/or myelin marker proteins. We then focused on Rho family small GTPases, central regulators of cell morphogenesis, and examined their potential involvement downstream of this signaling. Expression of the RhoG-binding domain (RBD) of engulfment and cell motility 1 (ELMO1) attenuated the increased morphological changes. Similarly, inhibition of downstream Akt signaling also reversed these changes. Taken together, these results provide insight into how balanced regulation between PTEN and downstream signaling molecules governs oligodendroglial cell differentiation and suggest that dysregulation of this signaling equilibrium may contribute to cellular phenotypes relevant to disease-associated cellular alterations. Full article

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article

Neuroinflammation is a hallmark of multiple sclerosis (MS). MS is marked by glial cell activation, autoreactive T cells, and the release of pro-inflammatory cytokines and free radicals. Current therapeutic strategies aim to modulate the immune response using disease-modifying therapies, to slow disease progression. The specific aims of this study were: (a) to investigate the effect of cannabinoid acids on the release of glial neuroinflammatory mediators, (b) to examine the effect of intraperitoneally administered cannabinoid acids on symptoms of MS, and (c) to evaluate their effects on microglial and astrocyte activation and CD4⁺ T cell infiltration into the spinal cords of MS mice. Exposure of BV2 microglia to cannabinoid acids attenuated lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase by 40–90% it also reduced the release of nitric oxide and interleukin-17A. Among the cannabinoid acids tested, cannabidiolic acid (CBDA) significantly increased tumor necrosis factor alpha (TNFα) secretion by up to 40% in LPS-stimulated BV2 cells. Intraperitoneal administration of CBDA also resulted in a twofold increase in TNFα secretion in splenocytes isolated from MS mice, compared to untreated MS controls. This study provides evidence that CBDA significantly reduces neurological scores, while both cannabinoid acids attenuate microgliosis, astrogliosis, and CD4+ T cell migration in lumbar spinal cord sections of MS mice. These compounds cross the blood–brain barrier (BBB) and act directly within the central nervous system. The consistent elevation of TNFα in the presence of CBDA across three experimental models suggests a distinctive immunomodulatory role for CBDA, with potential therapeutic implications in MS. Full article

Alphaherpesviruses, including Herpes Simplex Virus 1 (HSV-1) and Pseudorabies Virus (PrV), establish lifelong latency in the nervous system and can cause recurrent disease. While latency has classically been attributed to peripheral sensory ganglia, accumulating evidence indicates that the central nervous system (CNS) may also serve as a site of long-term viral persistence and reactivation. Here, we investigated the CNS as a viral reservoir using the attenuated mutant PrV-∆UL21/US3∆kin, which preferentially targets mesiotemporal brain regions. Following intranasal inoculation, mice were analyzed at 11–14, 21, 28, 42, 105, and 190 days post-infection (dpi). To assess the reactivation potential, a subset of animals received cyclophosphamide/dexamethasone at 170 dpi. Viral transcripts were detected by RNAscope™ in situ hybridization and RT-qPCR targeting the lytic gene UL19 encoding the major capsid protein and the latency-associated transcript (LAT). Histopathology included hematoxylin and eosin staining and immunohistochemistry for CD3, Iba1, GFAP, cleaved caspase-3 and viral glycoprotein gB. UL19 RNA signals displayed marked regional and temporal heterogeneity, with prominent detection in mesiotemporal structures. In contrast, LAT RNA levels remained low overall, with a transient peak during the acute phase. RT-qPCR confirmed high UL19 and LAT transcript levels during early infection, while LAT transcription returned to baseline levels thereafter. Histopathology showed a transition from acute necrotizing meningoencephalitis to prolonged low-grade inflammation with glial activation and focal apoptosis. Notably, UL19 RNA signals strongly correlated with T-cell infiltration, particularly at 42 dpi. Together, these findings define regional and temporal patterns of long-term PrV transcriptional activity and associated neuropathology in the murine CNS. Full article

Background/Objectives: Vascular inflammation and impaired endothelial regeneration contribute to chronic degenerative disorders, including ocular neovascularization and retinal degeneration. Nutritional bioactives that modulate molecular pathways governing angiogenesis and tissue remodeling represent promising adjunct strategies for vascular health. This study investigated whether cocoa powder (CP) regulates hypoxia-driven molecular signaling and attenuates vascular inflammation and degeneration. Methods: The vascular-modulatory effects of CP were examined in human umbilical vein endothelial cells (HUVECs) and in murine models of alkali-induced corneal neovascularization and N-methyl-N-nitrosourea (MNU)-induced retinal degeneration. Hypoxia-inducible factor-1α (HIF-1α) signaling and downstream angiogenic targets were assessed by Western blotting and quantitative PCR. Endothelial migration, tube formation, and transwell assays were performed to evaluate angiogenic responses. In vivo, oral CP (50 or 200 mg/kg) was administered, and vascular growth, inflammatory and remodeling markers, and retinal structural integrity were analyzed by histology, immunofluorescence, and protein expression. Results: At non-cytotoxic concentrations (0.1–1.0 μg/mL), CP suppressed hypoxia-induced HIF-1α protein stabilization without altering HIF-1α mRNA levels and reduced expression of VEGFA, EPO, and GLUT1. CP significantly inhibited VEGF-A-induced endothelial migration, network formation, and chemotactic invasion. In alkali-injured corneas, CP reduced the neovascularized area and downregulated VEGF, MMP2, MMP9, α-smooth muscle actin, and Ninj1, indicating attenuation of vascular inflammation and fibrotic remodeling. In the MNU model, CP preserved outer nuclear layer thickness, reduced glial activation (GFAP), maintained rhodopsin expression, and decreased MMP9 induction. Conclusions: CP functions as a nutritional modulator of hypoxia-responsive and inflammatory pathways, suppressing pathological angiogenesis while supporting structural preservation in degenerative vascular conditions. These findings highlight the translational potential of dietary polyphenol-rich interventions in regulating vascular inflammation and regeneration. Full article

Despite the remarkable success of antiretroviral therapy (ART) in suppressing human immunodeficiency virus type 1 (HIV-1) replication, viral persistence remains a major barrier to cure. This persistence is sustained by heterogeneous cellular reservoirs in which viral expression is tightly regulated by host-dependent molecular mechanisms. Beyond the canonical cluster of differentiation 4 (CD4+) T-cell reservoirs, HIV-1 establishes long-lived infection in myeloid cells, glial populations within the central nervous system (CNS), and additional non-canonical cellular niches, each characterized by distinct transcriptional, epigenetic, and immune environments. In this review, we synthesize recent advances in understanding how HIV-1 expression, latency, and reactivation are shaped across diverse susceptible cell types. We highlight cell-type-specific mechanisms governing viral integration, chromatin organization, transcriptional elongation, innate immune sensing, host restriction factors, and cytoskeletal regulation. Particular emphasis is placed on how host signaling pathways and immune microenvironments contribute to reservoir stability and heterogeneity, complicating eradication strategies. We further discuss immunomodulatory approaches that seek to modulate viral expression without exacerbating immune activation. By integrating molecular, cellular, and immunological perspectives, this review provides a framework for understanding HIV-1 persistence as a context-dependent process and underscores the need for cell-type-tailored strategies in HIV cure research. Full article

Background/Objectives: Naegleria fowleri is an opportunistic pathogen causing primary amoebic meningoencephalitis (PAM), a fatal neuroinflammatory disease with a high mortality rate of over 97%, in humans. Currently, there are no approved therapeutics for PAM, underscoring the urgent necessity of developing effective and safe drugs. This study aimed to evaluate the potential of ginsenosides Rb3 and Rc as alternative or supplementary drug candidates for PAM by assessing their anti-amoebic activities against N. fowleri. Methods: Anti-N. fowleri activities of ginsenosides Rb3 and Rc and their cytotoxicity to C6 glial cells were evaluated by cell viability assay. The underlying anti-amoebic mode of action of Rb3 and Rc was analyzed by a series of assays for apoptosis–necrosis, TUNEL, intracellular reactive oxygen species (ROS), mitochondrial dysfunction, ATP production, caspase-3, and autophagy. The expression profiles of apoptosis- and autophagy-related genes were also analyzed. Results: Rb3 and Rc effectively induced death of N. fowleri trophozoites with IC₅₀ values of 94.71 ± 1.63 μM and 126.99 ± 1.88 μM, respectively. However, Rb3 and Rc showed no significant cytotoxicities against C6 glial cells, suggesting their selective anti-N. fowleri activities. Typical apoptosis signals, such as apopxin staining and DNA fragmentation, were detected in amoebae upon treatment with Rb3 or Rc. These two ginsenosides enhanced ROS production and induced mitochondrial dysfunction in the amoebae. Enhanced caspase-3 activity and autophagy formation were also identified in amoebae treated with Rb3 or Rc. Conclusions: These results provide the first evidence that ginsenosides Rb3 and Rc induce apoptosis-like programmed cell death in N. fowleri, suggesting that they are potential candidates in developing novel therapeutic strategies against PAM. Full article