Search Results (574)

Optic neuritis (ON) has been recognized since antiquity, but its modern clinical identity emerged only in the late 19th century and was definitively shaped by the Optic Neuritis Treatment Trial (ONTT). The ONTT established the natural history, visual prognosis, association with multiple sclerosis (MS), and therapeutic response to corticosteroids, building the foundation for contemporary ON management. Subsequent discoveries—most notably aquaporin-4 IgG-associated ON (AQP4-ON), myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON), and double-negative ON—have fundamentally transformed this paradigm, shifting ON from a seemingly uniform demyelinating syndrome to a group of biologically distinct disorders. These subtypes differ in immunopathology, clinical course, MRI features, retinal injury patterns, CSF profiles, and long-term outcomes, making early and accurate differentiation essential. MRI provides key distinctions in lesion length, orbital tissue inflammation, bilateral involvement, and chiasmal or optic tract extension. Optical coherence tomography (OCT) offers complementary structural biomarkers, including severe early ganglion cell loss in AQP4-ON, relative preservation in MOG-ON, and variable patterns in double-negative ON. CSF analysis further refines diagnosis, with oligoclonal bands strongly supporting MS-ON. Together, these modalities enable precise early stratification and timely initiation of targeted immunotherapy, which is critical for preventing irreversible visual disability. Despite major advances, significant unmet needs persist. Access to high-resolution MRI, OCT, cell-based antibody assays, and evidence-based treatments remains limited in many regions, contributing to global disparities in outcomes. The understanding of the pathogenesis of double-negative optic neuritis, the identification of reliable biomarkers of relapse and visual recovery, and the determination of standardized cut-off values for multimodal diagnostic tools—including MRI, OCT, CSF analysis, and serological assays—remain unresolved challenges. Future research must expand biomarker discovery, refine imaging criteria, and ensure equitable global access to cutting-edge diagnostic platforms and therapeutic innovations. Four decades after the ONTT, ON remains a dynamic field of investigation, with ongoing advances holding the potential to transform care for patients worldwide. Together, these advances expose a fundamental tension between historically MS-centered diagnostic frameworks and the emerging biological heterogeneity of ON, a tension that underpins the structure and critical perspective of the present review. Full article

The aquaporin 0 (AQP0)/major intrinsic protein of eye lens (MIP) cDNA was cloned and sequenced. Initial studies of the tissue distribution of mRNA expression proved to be incorrect. Subsequent experiments showed that AQP0 mRNA is expressed strongly in the eye with moderately strong expression in the kidneys and some expression was seen in the brain and muscle tissue, and very low expression in the esophagus/fundic stomach. Another set of PCR reactions with five times the amount of cDNA additionally showed mRNA/cDNA expression in the liver, rectal gland, and a very low level in the intestine. Sporadic expression of different pieces of AQP0 cDNA was seen in various experiments in gill and pyloric stomach. A custom polyclonal antibody was produced against a region near the C-terminal end of the AQP0 protein sequence. The antibody gave a band of around the correct size (for the AQP0 protein) on the Western blot, which also showed a few other higher-molecular-weight bands. The antibody was also used in immunohistochemistry, and in the kidney, it showed staining in the proximal II (PII), intermediate segment I (IS I), and late distal tubule (LDT) parts of the sinus zone region of nephrons as well as some staining in the bundle zone tubule segments, suggesting a role for AQP0 as a water channel. In the rectal gland, the antibody showed weak apical membrane staining in a few secretory tubules near the duct, but also somewhat stronger staining in cells appearing to connect various secretory tubules, suggesting a role in cell–cell adhesion. In the spiral valve intestine side wall and valve flap, after signal amplification, weak antibody staining was seen in the apical and lateral membranes of epithelial cells adjacent to the luminal surface. There was also some staining in the intestinal muscle. In the rectum/colon, staining was seen in a layer of cells underlying the epithelium and in some muscle layers. In the gill, there was very weak staining in secondary lamellae epithelial cells and in connective tissue surrounding blood vessels and blood sinuses. The low level of transcript expression in the rectal gland, gill, and intestinal tissues suggests caution in the interpretation of the immunohistochemical staining in these tissues. Full article

Aquaporin 1 (AQP1) is a transmembrane protein that acts as a highly selective channel for the rapid passage of water across cell membranes, driven by osmotic gradients. The narrowest part of the water channel pore—the selectivity filter (SF)—plays a key role in ensuring selective and efficient water transport. In this study, density functional theory (DFT) at the M062X/6-311+G(d,p) level was used to identify the preferred position of the water molecule(s) inside the SF and to elucidate the forces that lead to its displacement during permeation. A systematic scan along the pore axis identified a well-defined energy minimum where a single water molecule was optimally stabilized by hydrogen bonds with SF residues. A second water molecule was introduced to study how the incoming water affects the translocation of the first water molecule. The resulting energy and force profiles reveal that the approaching water molecule gradually pushes the bound water forward, ultimately occupying its favorable binding site. These results provide an atomistic description of the positioning and displacement of water molecules in SF and offer a quantitative view of the fundamental interactions that govern water transport in AQPs. Full article

Depression represents a leading cause of global disability, yet its pathogenesis remains incompletely understood. This review synthesizes emerging evidence highlighting the multifaceted role of Aquaporin-4 (AQP4), the central nervous system’s predominant water channel, in the pathophysiology of depression. Preclinical studies frequently report AQP4 dysregulation in depression models, characterized by reduced perivascular expression and impaired polarization in mood-relevant brain circuits. We delineate how AQP4 impairment is implicated in depression through several interconnected mechanistic pathways: (1) exacerbating glutamate excitotoxicity by disrupting astrocytic glutamate clearance; (2) impairing monoaminergic neurotransmission and synaptic plasticity; (3) potentiating neuroinflammatory cascades; (4) inducing mitochondrial functional impairment and oxidative stress; and (5) participating in hypothalamic–pituitary–adrenal (HPA) axis dysregulation by disrupting perineuronal osmotic and ionic homeostasis in response to arginine vasopressin (AVP) signaling. Furthermore, we explore the therapeutic relevance of AQP4, noting that diverse antidepressant treatments appear to partly exert their effects by modulating AQP4 expression and function. Collectively, the evidence positions AQP4 not as a solitary causative factor, but as a critical contributing component within the broader astrocyte–neuron–immune network. We therefore propose AQP4 as a promising node for therapeutic intervention, whose modulation may help counteract core pathophysiological processes in depression, offering a potential avenue for novel treatment development. Full article

In this study, blood cell counts and serum C3, C4, and CH50 values at baseline and after more than 6-month drug use were measured to elucidate changes in blood cells and complements during relapse prevention therapies for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD). A total of 70 patients with AQP4+ NMOSD (87% female, median age 56 years) were enrolled. They were divided into the following treatment groups: glucocorticoids and/or immunosuppressants (GC/IS, n = 22), inebilizumab/rituximab (anti-CD19/20, n = 13), satralizumab (anti-IL-6R, n = 22), and eculizumab/ravulizumab (anti-C5, n = 13). At baseline, the blood counts and complement levels did not differ among the groups. At follow-up, the neutrophil and platelet counts in the anti-IL-6R group decreased from those at baseline (p < 0.0001 and p < 0.001, respectively). Compared with the GC/IS, anti-CD19/20, and anti-C5 groups, the anti-IL-6R group had lower levels of C3 (p < 0.0001, p < 0.01, and p < 0.05, respectively) and C4 (p < 0.0001, p < 0.01, p < 0.001, respectively). Furthermore, the anti-C5 group had significantly lower CH50 levels than the GC/IS, anti-CD19/20, and anti-IL-6R groups (p < 0.0001, p < 0.0001, p < 0.05, respectively). In addition, the anti-IL-6R group had lower CH50 levels than the GC/IS and anti-CD19/20 groups (p < 0.001 and p < 0.05, respectively). The present study demonstrated that anti-IL-6R therapy broadly and mildly suppressed the complement system and decreased the neutrophil and platelet counts. It also showed that anti-C5 therapy strongly suppressed total complement activity but did not affect the C3 and C4 levels or blood counts. These findings may have implications for the mode of action of the drugs and the risk of adverse drug reactions, including infections. Full article

Tremella mesenterica, commonly known as the yellow brain or golden jelly fungus, has been traditionally used for its medicinal properties. In this study, we elucidated the structural characteristics of T. mesenterica polysaccharide (TMP) and evaluated its potential moisturizing mechanism in vitro, comparing it to Tremella fuciformis polysaccharide (TFP) and hyaluronic acid (HA). TMP was isolated through enzyme assisted extraction and it has a molecular weight (MW) of approximately 143 kDa. We investigated the composition of mannose, xylose, glucuronic acid, and glucose as a ratio of 59.8 ± 0.3, 24.0 ± 1.2, 11.0 ± 0.8, 5.2 ± 0.0, respectively. Through methylation and GC-MS analysis, we discovered TMP was composed of a main chain of β-(1→3)-linked mannopyranoside, substituted with various side chains such as xylopyranoside, glucuronopyranoside, glucopyranoside at the C-2 or C-4 positions of the backbone. TMP upregulated the expression of key moisturizing-related factors compared to TFP and HA, such as aquaporin-3 (AQP3) with 55% and 57% at 25 and 50 μg/mL and hyaluronic acid synthase-2 (HAS2) with 22% at 25 μg/mL, as confirmed through qRT-PCR analysis. Additionally, TMP significantly enhanced the expression of filaggrin (FLG), a critical protein involved in skin barrier function, with 22% at 25 μg/mL. Immunocytochemistry (ICC) analysis further revealed that TMP achieved the highest improvement in hyaluronic acid synthase-3 (HAS3) protein levels by 475% at 50 μg/mL. While further in vivo studies are required to substantiate its functional moisturizing efficacy, these findings suggest that TMP serves as a promising moisturizing agent. The structural and functional properties of TMP provide a potential foundation for its application in diverse industries, including cosmetics, food, biopolymers, and pharmaceuticals. Full article

Water deprivation triggers coordinated physiological responses to preserve body fluid balance, yet the molecular mechanisms that regulate aquaporin-mediated water transport under dehydration remain incompletely understood. Aquaporin-4 (AQP4), the main water channel in the brain and a basolateral water pathway in the kidney collecting duct, exists in multiple isoforms, including the translational readthrough variant AQP4ex, whose regulatory role is only beginning to be defined. Here, we investigated the effects of acute water deprivation (6–12 h) on AQP4 isoform expression and phosphorylation in a mouse kidney and brain. While total AQP4 and AQP4ex protein levels remained largely unchanged in both tissues, dehydration induced a marked and divergent regulation of the phosphorylated form of AQP4ex. Levels increased in the kidney medulla, consistent with enhanced antidiuretic water transport, but decreased in the cerebral cortex, suggesting a protective reduction in perivascular water permeability. No changes were detected in the cerebellum. These findings identify phosphorylation of AQP4ex as a rapid, tissue-specific regulatory mechanism that adjusts water flux according to the physiological needs of each organ, revealing an additional layer of control in systemic water homeostasis and highlighting AQP4ex as a potential target in dehydration-related and osmotic disorders. Future studies could explore the signaling pathways regulating AQP4ex phosphorylation and investigate its potential involvement in pathological conditions, such as diabetes insipidus or cerebral edema. Full article

Background: Sudden, non-traumatic hearing loss has been associated with vascular or inflammatory disorders. Hearing loss in Neuromyelitis optica spectrum disorder (NMOSD) is a very rare presentation. Methods: In this paper, we describe the case of a 58-year-old female patient with aquaporin-4-positive NMOSD exhibiting bilateral tinnitus and right-sided deafness in the context of a relapse. The auditory brainstem responses pointed to a lesion of the right peripheral auditory pathway (cochlea and/or auditory nerve). The patient’s hearing failed to improve after high-dose intravenous steroids; however, it showed slight improvement after plasmapheresis. We also conducted a systematic literature review in databases MEDLINE and Scopus in English, searching for all reported cases of hearing loss in NMOSD. Results: We included 10 studies reporting 15 cases of NMOSD with hearing loss. The vast majority of patients were female (11 out of 15, 73.3%), with an age range of 26 to 70 years. Hearing loss, ranging from mild to severe, seems more frequent in AQP4-positive cases, and it can even be the presenting symptom. It can present isolated or in combination with tinnitus, ataxia, and/or intractable vomiting. The auditory pathway impairment in NMOSD seems to be localized either centrally, i.e., cochlear nuclei or higher brainstem levels, or peripherally, i.e., in the cochlea or cochlear nerve itself. Intravenous methylprednisolone in high doses, followed by oral tapering, was the most common treatment option, resulting in a gradual improvement. Conclusions: This paper describes a rare case of peripheral auditory pathway affection in NMOSD, which is an inflammatory astrocytopathy mainly affecting the central nervous system. Early recognition of hearing loss in the context of an NMOSD relapse and subsequent treatment have a crucial impact on the hearing outcome of NMOSD patients. This expands our knowledge of NMOSD as an autoimmune aquaporin-4 channelopathy. Full article

Background and Objective: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a significant component of demyelinating diseases in pediatric populations. Recently, diagnostic criteria for MOGAD were established. This study aims to evaluate and compare the diagnostic efficacy of the fixed-cell-based assay (Fixed-CBA) and the live cell-based assay (Live-CBA) in patients who meet the 2023 clinical diagnostic criteria for MOGAD. Methods: This retrospective study included patients suspected of having MOGAD who were enrolled between June 2023 and June 2024. Patients were selected based on the “core clinical demyelinating events” outlined in the 2023 proposed criteria of the International MOGAD Panel. Patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) with aquaporin-4 antibody-positive (AQP4-Abs-positive), and non-central nervous system (non-CNS) inflammatory diseases were chosen as controls. Serum samples were simultaneously tested for MOG-Abs using Fixed-CBA and Live-CBA. Results: A total of 86 patients were enrolled in the study: 52 in the suspected MOGAD group and 34 in the control group. Out of these patients studied, 16 presented with optic neuritis (ON), 5 with myelitis, 8 with acute disseminated encephalomyelitis (ADEM), and 7 with cortical encephalitis. Sixteen patients could not be classified by clinical phenotype. The highest MOG-Ab positivity rate was among patients with cortical encephalitis [85.7% (Live-CBA)/71.4% (Fixed-CBA)]. Both assays identified 22 positive samples, with Fixed-CBA and Live-CBA sensitivities at 44.2% and 55.8%, respectively, and a specificity of 97%. Of the patients suspected of having MOGAD, 19 cases were confirmed using the Fixed-CBA, while 28 cases were confirmed using the Live-CBA. This resulted in an upgrade in diagnostic classification for nine cases. This led to a diagnostic reclassification in nine cases. Conclusions: Both the Fixed-CBA and Live-CBA were associated with higher sensitivity for patients selected based on the 2023 MOGAD clinical diagnostic criteria. The Live-CBA exhibited an 11.6% increase in sensitivity, contributing to a 17.3% (9/52) enhancement in clinical diagnostic accuracy. Full article

Background: Large-scale production of poultry viral vaccines increasingly requires robust suspension cell platforms. However, most avian cell lines, including DF-1, are strictly anchorage-dependent, limiting scalability. Aquaporin-1 (AQP1) regulates cell–cell adhesion and membrane dynamics, making it a potential target for engineering suspension growth. This study aimed to generate a stable DF-1 suspension cell line via AQP1 disruption and evaluate its potential for enhanced infectious bursal disease virus (IBDV) production. Methodology: DF-1 cells were engineered using a CRISPR/Cas9 ribonucleoprotein system to create a truncated AQP1 gene. DF-1/AQP1⁻ cells were assessed for morphology, tumorigenicity in nude mice, and genetic stability across 20 passages. Suspension growth, cell density, and viability were measured. Cells were infected with IBDV strain BJQ902, and viral titers were compared with wild-type DF-1 and monolayer DF-1/AQP1⁻ cells. Results: DF-1/AQP1⁻ cells maintained normal morphology, were non-tumorigenic, and retained stable AQP1 mutations. They grew as true suspension cultures without adaptation, reaching 4.0 × 10⁶ cells/mL with >95% viability. Suspension DF-1/AQP1⁻ cells cells produced significantly higher viral titers (9.0 log TCID₅₀/mL; 8.63 log EID₅₀/mL) than both monolayer DF-1/AQP1⁻ and wild-type DF-1 cells. Virus production time was shortened in suspension cultures. Conclusions: Targeted AQP1 disruption converts DF-1 cells into a stable, non-tumorigenic suspension cell line with markedly enhanced IBDV production, providing a scalable platform for next-generation avian vaccine manufacturing. Full article

Entomopathogenic nematodes (EPNs), including Steinernema and Heterorhabditis, are obligate insect parasites widely used in biological pest control. However, their efficacy is often limited by susceptibility to environmental stresses like desiccation. Aquaporins (AQPs), channel proteins facilitating water and solute movement across membranes, are hypothesized to play a key role in the osmotic stress response of EPNs. This study identified and cloned three AQP genes (L596_g7661, L596_g18121, and XLOC_007750) from four strains of Steinernema carpocapsae. Bioinformatic analysis confirmed that these AQPs belong to the aquaglyceroporin subfamily and share high sequence homology across strains. Functional characterization in Xenopus oocytes demonstrated that AQP L596_g7661 facilitates glycerol transport. Expression patterns under osmotic dehydration revealed significant upregulation of L596_g7661 and XLOC_007750 in all strains, while L596_g18121 expression remained unchanged. These findings indicate that specific AQPs are involved in the molecular response of S. carpocapsae to osmotic stress, providing crucial insights for breeding resilient EPN strains and enhancing their field application. Full article

This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × Large, body weight = 2.58 ± 0.05 kg) were divided into three treatment groups based on similar body weights and equal numbers of males and females: the blank control group (CON group), the PEDV infection group (PEDV group), and the NG intervention + PEDV infection group (NG + PEDV group) (n = 6 per group). The experiment lasted for 11 days, comprising a pre-feeding period from days 0 to 3 and a formal experimental period from days 4 to 10. On days 4–10 of the experiment, piglets in the NG + PEDV group were orally administered NG (10 mg/kg). On Day 8 of the experiment, piglets in the PEDV and NG + PEDV groups were inoculated with PEDV (3 mL, 10⁶ 50% tissue culture infective dose (TCID₅₀) per milliliter). On day 11 of the experiment, piglets were euthanized for sample collection. PEDV infection caused significant intestinal damage, including a decreased (p < 0.05) villus height in the duodenum and ileum and an increased (p < 0.05) crypt depth in all intestinal segments. This intestinal damage was accompanied by an impaired absorptive function, as indicated by reduced (p < 0.05) serum D-xylose. Further results showed that PEDV compromised the intestinal antioxidant capacity by decreasing (p < 0.05) glutathione peroxidase and catalase activities, and it stimulated the intestinal inflammatory response by upregulating (p < 0.05) the expression of key inflammatory genes, including regenerating family member 3 gamma (REG3G; duodenum, jejunum, colon), S100 calcium binding protein A9 (S100A9; ileum, colon), interleukin 1 beta (IL-1β; ileum, colon), and S100 calcium binding protein A8 (S100A8; colon). PEDV also suppressed the intestinal lipid metabolism pathway by downregulating (p < 0.05) the ileal expression of Solute Carrier Family 27 Member 4 (SLC27A4), Microsomal Triglyceride Transfer Protein (MTTP), Apolipoprotein A4 (APOA4), Apolipoprotein C3 (APOC3), Diacylglycerol O-Acyltransferase 1 (DGAT1), and Cytochrome P450 Family 2 Subfamily J Member 34 (CYP2J34). Moreover, PEDV suppressed the intestinal antiviral ability by downregulating (p < 0.05) interferon (IFN) signaling pathway genes, including MX dynamin like GTPase 1 (MX1) and ISG15 ubiquitin like modifier (ISG15) in the duodenum; weakened intestinal water and ion transport by downregulating (p < 0.05) aquaporin 10 (AQP10) and potassium inwardly rectifying channel subfamily J member 13 (KCNJ13) in the duodenum, aquaporin 7 (AQP7) and transient receptor potential cation channel subfamily V member 6 (TRPV6) in the ileum, and TRPV6 and transient receptor potential cation channel subfamily M member 6 (TRPM6) in the colon; and inhibited intestinal digestive and absorptive function by downregulating (p < 0.05) phosphoenolpyruvate carboxykinase 1 (PCK1) in the duodenum and sucrase-isomaltase (SI) in the ileum. Notably, NG effectively counteracted these detrimental effects. Moreover, NG activated the IFN signaling pathway in the jejunum and suppressed PEDV replication in the colon. In conclusion, NG alleviates PEDV-induced intestinal injury by enhancing the antioxidant capacity, suppressing inflammation, normalizing the expression of metabolic and transport genes, and improving the antiviral ability. Full article

Around 85% of all land plants have symbiotic relationships with arbuscular mycorrhizal (AM) fungi, microscopic soil fungi that build extensive filamentous network in and around the roots. These links strongly influence plant development, water uptake, mineral nutrition, and defense against abiotic stresses. In this context, the use of AMF as a biological instrument to enhance plant drought resistance and phenotypic plasticity, through the formation of mutualistic associations, seems like a novel strategy for sustainable agriculture. This review synthesizes current understanding on the mechanisms through which AMF alleviates drought stress in agriculture. We focus on how AMF help maintain nutrient and water homeostasis by modulating phytohormones and signaling molecules, and by orchestrating associated biochemical and physiological responses. Particular emphasis is placed on aquaporins (AQPs) as key water-and stress-related channels whose expression and activity are modulated by AMF to maintain ion, nutrient, and water balance. AMF-mediated host AQP responses exhibit three unique patterns under stressful conditions: either no changes, downregulation to limit water loss, or upregulation to promote water and nutrient uptake. Nevertheless, little is known about cellular and molecular underpinnings of AMF effect on host AQPs. We also summarize evidence that AMF enhance antioxidant defenses, osmotic adjustment, soil structure, and water retention, thereby jointly improving plant drought tolerance. This review concludes by outlining the potential of AMF to support sustainable agriculture, offering critical research gaps, such as mechanistic studies on fungal AQPs, hormonal crosstalk, and field-scale performance, which propose future directions for deploying AMF in drought-prone agroecosystems. Full article

Background/Objectives: We evaluated Goreisan, a traditional Chinese medicine, for its effects on nephrotic syndrome in a rat model. Methods: Male Sprague–Dawley rats underwent right nephrectomy at 5 weeks of age, followed by adriamycin administration (5 mg/kg) at 6 and 8 weeks of age to induce nephrotic syndrome. At 10 weeks, rats were divided into three groups: vehicle (control), Goreisan 0.5 g/kg (GL), and Goreisan 1.0 g/kg (GH). Goreisan was administered daily for 4 weeks. At 14 weeks, blood, urine, mRNA expressions, and kidney histopathology were analyzed. Data were analyzed using one-way ANOVA followed by Tukey–Kramer post hoc testing. Results: Goreisan prevented worsening kidney function, with reduced glomerular and tubulointerstitial damage, lower systemic and intrarenal 8-hydroxy-2′-deoxyguanosine levels, and lower plasma aldosterone levels and expression of intrarenal renin–angiotensin–aldosterone system (RAAS)-related factors. Urine volume significantly increased in GL and GH groups compared with the control group. In the GH group, urine volume increased markedly (Δ urine volume: 10.0 ± 2.6 mL/day), whereas it tended to decrease in the Vehicle group (Δ urine volume: −1.3 ± 2.5 mL/day). Urine osmolality was lower in the GH group, with a larger decrease in Δ urine osmolality (−616.3 ± 132.8 mOsm/L). These changes occurred without an increase in urinary sodium excretion, suggesting an aquaretic effect independent of natriuresis. Creatinine clearance (CCr/kg) declined markedly in the Vehicle group but was significantly preserved in the GH group (Δ CCr/kg: −2.2 ± 0.19 vs. −0.7 ± 0.28), indicating renoprotective effects. No differences were found in serum arginine–vasopressin levels. Real-time PCR and immunohistochemical staining showed no significant differences in aquaporin (AQP) mRNA expression (AQP1, AQP2, AQP3, and AQP4), but AQP2 localization to the apical membrane in the collecting ducts was reduced with Goreisan treatment. Conclusions: Goreisan demonstrates kidney-protective and diuretic effects in nephrotic syndrome, potentially through reducing systemic oxidative stress, modulating RAAS activation, and altering AQP2 trafficking. Full article

Astrocytes and microglia constitute nearly half of all central nervous system cells and are indispensable for its proper function. Both exhibit striking morphological and functional heterogeneity, adopting either neuroprotective (A2, M2) or proinflammatory (A1, M1) phenotypes in response to cytokines, pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), toll-like receptor 4 (TLR4) activation, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Crucially, many of these phenotypic transitions arise during the earliest stages of neurodegeneration, when glial dysfunction precedes overt neuronal loss and may act as a primary driver of disease onset. This review critically examines glial-centered hypotheses of neurodegeneration, with emphasis on their roles in early disease phases: (i) microglial polarization from an M2 neuroprotective state to an M1 proinflammatory state; (ii) NLRP3 inflammasome assembly via P2X purinergic receptor 7 (P2X7R)-mediated K⁺ efflux; (iii) a self-amplifying astrocyte–microglia–neuron inflammatory feedback loop; (iv) impaired microglial phagocytosis and extracellular-vesicle–mediated propagation of β-amyloid (Aβ) and tau; (v) astrocytic scar formation driven by aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP)/vimentin, connexins, and janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling; (vi) cellular reprogramming of astrocytes and NG2 glia into functional neurons; and (vii) mitochondrial dysfunction in glia, including Dynamin-related protein 1/Mitochondrial fission protein 1 (Drp1/Fis1) fission imbalance and dysregulation of the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Sirt1/PGC-1α) axis. Promising therapeutic strategies target pattern-recognition receptors (TLR4, NLRP3/caspase-1), cytokine modulators (interleukin-4 (IL-4), interleukin-10 (IL-10)), signaling cascades (JAK2–STAT, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase–protein kinase B (PI3K–AKT), adenosine monophosphate-activated protein kinase (AMPK)), microglial receptors (triggering receptor expressed on myeloid cells 2 (TREM2)/spleen tyrosine kinase (SYK)/ DNAX-activating protein 10 (DAP10), siglec-3 (CD33), chemokine C-X3-C motif ligand 1/ CX3C motif chemokine receptor 1 (CX3CL1/CX3CR1), Cluster of Differentiation 200/ Cluster of Differentiation 200 receptor 1 (CD200/CD200R), P2X7R), and mitochondrial biogenesis pathways, with a focus on normalizing glial phenotypes rather than simply suppressing pathology. Interventions that restore neuroglial homeostasis at the earliest stages of disease may hold the greatest potential to delay or prevent progression. Given the complexity of glial phenotypes and molecular isoform diversity, a comprehensive, multitargeted approach is essential for mitigating Alzheimer’s disease and related neurodegenerative disorders. This review not only synthesizes pathogenesis but also highlights therapeutic opportunities, offering what we believe to be the first concise overview of the principal hypotheses implicating glial cells in neurodegeneration. Rather than focusing on isolated mechanisms, our goal is a holistic perspective—integrating diverse glial processes to enable comparison across interconnected pathological conditions. Full article