Search Results (681)

Tumor necrosis factor receptor-associated factors (TRAFs) are a family of adaptor proteins that transmit signals from immunoregulatory receptors—such as TNF receptors, Toll-like receptors, and interleukin receptors—to coordinate immune and inflammatory responses. Among them, TRAF5 is highly expressed in lymphocytes and implicated in obesity-associated inflammation, but its role in secondary lymphoid organs during chronic low-grade inflammation remains unclear. We examined splenic B and T cell phenotypes in wild-type (WT) and Traf5-deficient (KO) mice fed a high-fat diet (HFD). Although lymphocyte composition was broadly comparable, KO mice showed reduced spontaneous immunoglobulin G2c (IgG2c) production ex vivo—about 1.5-fold lower than WT. Notably, despite elevated TNF-α and CD40 ligand (CD40L) expression in HFD-fed KO splenocytes, IgG2c production remained diminished—about 1.9-fold lower than WT—upon soluble CD40L stimulation, indicating impaired CD40-mediated class-switch recombination (CSR). Consistently, B cells from KO mice on a normal diet exhibited reduced activation-induced cytidine deaminase (AID) expression—about 4.4-fold lower than WT—after CD40L stimulation, and decreased IgG2c secretion—about 6.6-fold lower—upon CD40L and IFN-γ co-stimulation in vitro. Collectively, these findings suggest that TRAF5 is involved in CD40-dependent CSR in B cells under inflammatory conditions and may contribute to sustaining adaptive immune responses during obesity-associated chronic inflammation. Full article

Toll-like receptor 3 (TLR3) initiates antiviral and inflammatory responses exclusively through the adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β). In contrast, MyD88 (myeloid differentiation primary response 88), a central adaptor for most other TLRs, is traditionally considered dispensable for TLR3 signaling. Here, we demonstrate that MyD88 directly contributes to TLR3-mediated NF-κB activation and cytokine production in macrophages. Bone marrow-derived macrophages (BMDMs) from MyD88 deficient mice exhibited significantly attenuated NF-κB activation in response to the TLR3 agonist polyinosinic–polycytidylic acid (poly(I:C)) compared to wild-type cells, as evidenced by the reduced phosphorylation of NF-κB p65 and IκBα, as well as IκBα degradation. Consistently, pro-inflammatory cytokine production, including IL-6, TNF-α, and IFN-β, was attenuated in MyD88-deficient BMDMs in vitro following stimulation by poly(I:C) or poly(A:U), another TLR3 agonist. Blood concentrations of IL-6, TNF-α, and IFN-β were significantly reduced in both TRIF-deficient mice and MyD88-deficient mice challenged by the i.p. injection of poly(I:C). Mechanistic analyses revealed that MyD88 physically associates with activated TLR3 upon poly(I:C) stimulation, and that TLR3 engagement triggered MyD88 oligomerization, which was absent in TLR3 or TRIF deficient macrophages. Our findings highlight a previously unrecognized dual-adaptor mechanism for TLR3, wherein MyD88 recruitment amplifies NF-κB signaling dynamics by bridging TLR3 to the canonical NF-κB activation cascade and robust cytokine induction. This study expands the paradigm of TLR3 signaling by establishing MyD88 as a direct contributor to TLR3-driven innate immune responses, offering new insight into cross-talk between MyD88-dependent and -independent pathways. Full article

Background: Blast-induced spinal cord injuries (bSCI) account for 75% of all combat-related spinal trauma and are associated with long-term functional impairments. However, limited studies have evaluated the neuropathological outcomes in the spinal cord following blast exposure. Objectives In this study, we aimed to determine the acute and sub-acute neuropathological changes in the spinal cord of ferrets after blast exposure. Methods: An advanced blast simulator was used to expose ferrets to tightly coupled repeated blasts. The Catwalk XT system was used to detect gait performances in ferrets at 24 h and 1 month post-blast exposure. After euthanasia, the cervical spinal cord samples were collected at 24 h or 1 month post-blast. A quantitative real-time polymerase chain reaction was performed to evaluate changes in the gene expression of multiple Toll-like Receptors (TLR), Cyclooxygenase (COX-1 and COX-2) enzymes and cytokines. Western blotting was performed to investigate markers of axonal injury (Phosphorylated-Tau, pTau; Phosphorylated Neurofilament Heavy Chain, pNFH; and Neurofilament Light Chain present in degenerating neurons, NFL-degen) and neuroinflammation (Glial Fibrillary Acidic Protein, GFAP; and Ionized Calcium Binding Adaptor Molecule, Iba-1). Results: Blast exposure significantly affected the gait performances in ferrets, especially at 24 h post-blast. Multiple TLRs, COX-2, Interleukin-1-beta (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α) were significantly upregulated in the spinal cord at 24 h after blast exposure. Although only TLR3 was significantly upregulated at 1 month, non-significant increases in TLR1 and TLR2 were observed in the spinal cord at 1 month post-blast. Phosphorylation of Tau at serine (Ser396 and Ser404) and threonine (Thr205) increased in the spinal cord at 24 h and 1 month post-blast exposure. The increased expression of pNFH and NFL-degen proteins was evident at both time points. The expression of GFAP, but not Iba-1, significantly increased at 24 h and 1 month following blast exposure. Conclusions: Our results indicate that blast exposure causes acute and sub-acute neuroinflammation and associated axonal injury in the cervical spinal cord. These data further suggest that inhibition of TLRs and/or COX-2 enzyme might offer protection against blast-induced injuries to the spinal cord. Full article

Ultraviolet B (UVB) radiation triggers DNA damage and immune suppression, establishing conditions favorable for skin carcinogenesis. Previous studies have shown that a downstream adaptor for Toll-like receptors (TLRs), myeloid differentiation primary response 88 (MyD88), plays a role in UVB-induced DNA damage and immunosuppression. However, specific mechanisms for the effects on dendritic cells and T cells remain poorly understood. The objective of this study is to determine the role of MyD88 and TIR-domain-containing adaptor inducing interferon-β (TRIF), another key TLR downstream adaptor, in UVB-induced suppression of dendritic cell activity and T cell function. MyD88−/−, Trif−/−, and wild-type (WT) mice were evaluated for UVB-induced effects on dendritic cell, T cells, and contact hypersensitivity responses in skin. MyD88−/− mice exhibited significant resistance to UVB-induced immune suppression, compared to Trif−/− mice and wild-type controls. The MyD88 deficiency significantly reduced UVB-induced Treg cells that were CD4⁺CD25⁺Foxp3⁺ and produced interleukin (IL)-10. Moreover, it significantly inhibited the UVB-induced suppression of IL-12/IL-23 producing CD11c⁺ dendritic cells. Further experiments confirmed that MyD88 conditional knockout (MyD88fl/flXCD11c.Cre) mice were protected against UVB-induced immune suppression. Dendritic cells from MyD88 genomic or conditional knockout mice were resistant to UVB-induced reduction of major histocompatibility complex (MHC) class II antigens. These findings show that MyD88 plays a key role in UVB-induced immune suppression. The deficiency in the MyD88 gene inhibits UVB-induced suppression of CD11c+ dendritic cell (DC) activity and reduces UVB-induced development of Treg cells. Our studies demonstrate a new mechanism for MyD88-mediated regulation of UVB-induced immune suppression. Full article

Chemotherapy-induced senescence (CIS) contributes to tumor persistence and relapse. In this study, we investigated the senolytic activity of piceatannol (PCT) in 5-fluorouracil (5FU)-induced senescent colorectal cancer (CRC) cells. Senescence was established in P53-proficient HCT116 cells and normal colon fibroblasts (CCD18Co) following prolonged 5FU exposure, as shown by increased SA-β-gal activity, upregulation of P16, P21, and P53, mitochondrial depolarization, and enhanced oxidative stress. Subsequent PCT treatment selectively induced apoptosis in senescent populations, while non-senescent or p53-mutant, senescence-resistant HT29 cells were minimally affected. This effect was prevented by N-acetylcysteine, indicating a redox-sensitive mechanism. Mechanistically, PCT triggered mitochondrial depolarization and AIF-associated, caspase-independent apoptosis without increasing ROS. Morphological analysis with MitoTracker and quantitative morphometry using Fiji confirmed a fragmented mitochondrial network, characterized by reduced form factor, length, and number per cell. Western blotting revealed downregulation of fusion proteins (MFN1, MFN2), decreased FIS1, stable DRP1, and marked upregulation of the DRP1 adaptor MFF, consistent with suppressed fusion and enhanced fission competence. Together, these findings demonstrate that PCT selectively targets chemotherapy-induced senescent CRC cells through mitochondrial fragmentation and AIF-dependent apoptosis, highlighting its potential as an adjuvant strategy to limit the long-term burden of therapy-induced senescence. Full article

Microtus ochrogaster, monogamous prairie voles, serve as translational animal models for studying monogamy and pair bonding. Microglia, the resident immune cells of the brain, are one of several cell types still poorly understood in non-classical animal models including prairie voles. Microglia are known to play mechanistic roles in mediating social behaviors using inflammatory signaling, but the relationship between microglia reactivity and pair bonding has not yet been investigated. The present study first developed a robust protocol for quantitative histological visualization of microglia in Microtus ochrogaster. Second, it investigated differences in microglia morphology, a reliable index of microglia reactivity and function, in pair-bonded vs. unpaired voles. Sections containing prefrontal cortex (PFC) and anterior cingulate cortex (ACC) were stained for ionized calcium-binding adaptor molecule I (Iba1) using immunohistochemistry (IHC). IHC results provided evidence for the successful use of murine histological protocols in prairie voles. Quantification results revealed a sexually dimorphic effect of pair bonding on microglia: somas were significantly larger in pair-bonded vs. unpaired females, and somas were significantly smaller in pair-bonded vs. unpaired males. Additionally, somas were significantly larger in unpaired males than females, with larger somas indicating higher microglia reactivity. While conclusions are limited due to the small sample size, results provide novel characterization of microglia morphology in the frontal cortex and elucidate how pair bonding may influence microglia function in a sexually dimorphic manner. Full article

Adaptors, self-touching movements that supposedly lack communicative significance, have often been overlooked by researchers focusing on co-speech gestures. A significant complication in their study arises from the somewhat ambiguous definition of adaptors. Examples of these movements include self-manipulations like scratching a leg, bringing a hand to the mouth or head, and fidgeting, nervous tics, and micro hand or finger movements. Research rooted in psychology indicates a link between adaptors and negative emotional states. However, psycholinguistic approaches suggest that these movements might be related to the communicative task. This study analyzes adaptors in forty Cantonese speakers of English as a second language in monologues and dialogues in face-to-face and online contexts, revealing that adaptors serve functions beyond emotional expression. Our data indicate that adaptors might have cognitive functions. We also identify micro-movements, flutter-like adaptors or “flutters” for short, that may have interactive functions conveying engagement. These findings challenge the traditional view of adaptors as purely non-communicative. Participants’ self-reports corroborate these interpretations, highlighting the complexity and individual variability in adaptor use. This study advocates for the inclusion of adaptors in gesture analysis, which may enrich understanding of gesture–speech integration and cognitive and emotional processes in communication. Full article

MicroRNAs (miRNAs), as an integral component of gene regulatory networks, play a critical role in post-transcriptional regulation, maintaining a dynamic balance between miRNA biogenesis and turnover essential for maintaining cellular homeostasis. The regulation of miRNA turnover, particularly through target-directed microRNA degradation (TDMD), is emerging as a key mechanism in gene expression control in response to physiological, developmental, and environmental changes. This process is mediated by the ubiquitin–proteasome system (UPS), where the E3 ligase ZSWIM8 functions as an adaptor to facilitate the recognition and degradation of Argonaute (AGO) proteins, essential components of the miRNA-induced silencing complex (miRISC), thus negatively regulating gene expression. The ZSWIM8–UPS axis contributes to the precise modulation of miRNA levels by targeting AGO proteins for degradation, thereby influencing miRNA stability and function. This review summarizes the mechanisms underlying ZSWIM8-mediated TDMD, its molecular interactions, and the potential therapeutic applications of targeting miRNA turnover pathways. By understanding the regulation of miRNA degradation, we aim to inform future strategies for the clinical manipulation of miRNA-based therapeutics. Full article

Swiprosin-1 (SWS1/EFhd2) is a calcium-binding adaptor protein involved in cytoskeletal regulation, but its physiological role in bone homeostasis remains largely undefined. To elucidate its function in osteoclast biology, we examined SWS1 expression and activity during osteoclastogenesis using primary murine bone marrow-derived macrophages, siRNA-mediated knockdown, and SWS1 knockout (KO) mice. SWS1 was predominantly localized to the nucleus in precursor cells and redistributed to the F-actin ring in mature osteoclasts. Receptor activator of nuclear factor-kappa B ligand stimulation significantly downregulated SWS1 mRNA expression. Loss of SWS1 enhanced osteoclast formation, F-actin ring integrity, and bone resorption, accompanied by elevated expression of osteoclastogenic markers. In vivo, male SWS1 KO mice exhibited deteriorated trabecular bone microarchitecture with increased osteoclast numbers. Mechanistically, SWS1 deficiency intensified αvβ3 integrin-associated cytoskeletal signaling and upregulated Akt, MAPK, NF-κB, and PLCγ2 pathways. These results indicate that SWS1 negatively regulates osteoclast differentiation and function by restraining cytoskeletal reorganization and downstream signaling. Collectively, our findings establish SWS1 as a novel modulator of osteoclast activity and a potential therapeutic target for osteolytic bone disorders. Full article

Spinal cord injury (SCI) results in significant motor, sensory, and autonomic dysfunction. The pathophysiology of SCI develops during the primary and secondary phases. Inflammation contributes to the secondary phase through the non-specific activation of the innate immune response. Glial scar formation (gliosis), a reactive cellular mechanism facilitated by astrocytes, also occurs during this phase. Synthetic steroids such as tibolone (Tib) have been proposed as a treatment for SCI since they exert neuroprotective effects in various models of central nervous system (CNS) injury. We studied the effect of Tib on locomotor functional recovery and the regulation of neuroinflammation and gliosis in an SCI model. We performed an SCI at the thoracic vertebrae nine in male Sprague Dawley rats. The animals received daily doses of Tib (1 or 2.5 mg per kg of body weight) administered orally. We quantified pro- and anti-inflammatory cytokine levels at the injury site and determined motor recovery using the Basso, Beattie, and Bresnahan (BBB) scale. Finally, we investigated the effect of Tib on the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1), two markers of gliosis, using an immunohistochemistry assay. Our findings showed that Tib regulated pro- and anti-inflammatory cytokine levels at 3 h and 3, 7, and 14 days post-SCI. Furthermore, Tib administered orally for 15 days reduced gliosis markers and favored tissue preservation and motor function recovery after SCI. Full article

Obesity is an epidemic that currently impacts many nations. The persistence of this disease is shaped by both genetic and epigenetic factors that extend beyond calorie balance. Research in the past year has revealed that epigenetic and cellular memory within adipose tissue can predispose individuals to weight regain after initial fat loss, as shown by studies indicating persistent transcriptional and chromatin changes even after fat mass reduction. Independent studies also demonstrate long-lasting metabolic shifts, such as those triggered by glucose-dependent insulinotropic polypeptide receptor (GIPR)-induced thermogenesis and sarcolipin (SLN) stabilization that also support a form of “metabolic memory” that is associated with sustained weight loss. At the neural level, rare variants in synaptic genes like BSN (Bassoon presynaptic cytomatrix protein), a presynaptic scaffold protein, and APBA1 (amyloid beta precursor protein binding family A member 1), a neuronal adaptor involved in vesicular trafficking, disrupt communication in feeding circuits, elevating obesity risk and illustrating how synaptic integrity influences food intake regulation. Similarly, the spatial compartmentalization of metabolic signaling within neuronal cilia is emerging as crucial, with cilia-localized receptors G protein-coupled receptor 75 (GPR75) and G protein-coupled receptor 45 (GPR45) exerting opposing effects on energy balance and satiety. Meanwhile, genome-wide association studies (GWAS) have advanced through larger, more diverse cohorts and better integration of environmental and biological data. These studies have identified novel obesity-related loci and demonstrated the value of polygenic risk scores (PRS) in predicting treatment responses. For example, genetic variants in GLP-1R (glucagon-like peptide-1 receptor) and GIPR (glucose-dependent insulinotropic polypeptide receptor) may modulate the effectiveness of incretin-based therapies, while PRS for satiation can help match individuals to the most appropriate anti-obesity medications. This review focuses on studies in the last two years that highlight how advances in obesity genetics are driving a shift toward more personalized and mechanism-based treatment strategies. Full article

This study investigated whether self-adaptor behaviours, defined as non-communicative bodily actions such as touching one’s face or clasping one’s hands, facilitate lexical retrieval. Sixty Japanese-speaking adults were assigned to one of three conditions: a self-adaptor condition (instructed to hold their cheeks), a suppression condition (hand movements inhibited), and a control condition in which participants were allowed to move their hands freely. Participants completed a lexical retrieval task designed to elicit tip-of-the-tongue (TOT) states, followed by a recall task. Responses were categorised as successful retrieval, retrieval failure, TOT success, or TOT failure. Results showed that the self-adaptor condition achieved significantly more correct responses than the suppression condition, indicating that self-adaptor behaviour supports lexical access during retrieval difficulty. However, self-adaptor behaviour did not enhance the resolution of TOT states or improve recall performance. Video-based analysis further revealed that gestures increased markedly during TOT states, while self-adaptor behaviours were more frequent overall. These findings suggest that self-adaptor behaviour contributes to general lexical retrieval processes but does not directly facilitate the resolution of TOT states. The distinction between the functions of spontaneous bodily movements is therefore essential. This study extends the understanding of how embodied behaviours interact with verbal processes and underscores the cognitive significance of non-communicative bodily actions in speech production. Full article

We previously demonstrated that the activation of FGFR signaling in GIST may be a mechanism of GIST resistance to imatinib mesylate (IM). We show here that IM-resistant GIST cells lacking secondary KIT mutations overexpress claudin-1 on both transcriptional and translational levels. In contrast, a knockdown of CLDN1 or inhibition of its activity by PDS-0330 effectively restored GIST’s sensitivity to IM both in vitro and in vivo. This was evidenced by the increased expression of apoptotic markers (e.g., cleaved PARP and caspase-3) and the decreased proliferation rate of IM-resistant GIST T-1R cells treated with a combination of IM and PDS-0330 (or siRNA CLDN1). In concordance with these findings, a significant synergy was observed between IM and PDS-0330 in GIST T-1R cells. Importantly, decreased tumor size and weight were observed in IM-resistant GIST xenografts treated with a combination of IM and PDS-0330. Furthermore, the combined treatment of IM-resistant tumors induced an increase in intratumoral apoptosis and other changes, as defined by the histopathologic response rate. Based on the co-immunoprecipitation and immunofluorescence microscopy data, we also demonstrated the strong interaction pattern between CLDN1 and FGFR2. Of note, the inhibition or knockdown of CLDN1 effectively decreased the phosphorylation of FGFR2 and FRS-2, a well-known FGFR adaptor protein, thereby illustrating CLDN1’s ability to regulate FGFR-signaling and thereby promote FGFR-mediated survival in KIT-inhibited GIST. Consequently, CLDN1 inhibition in GIST effectively disrupted the FGFR-mediated pathway and re-sensitized tumor cells to IM. In concordance with these data, molecular profiling of CLDN1-inhibited GIST T-1R cells illustrated a significant decrease in the majority of FGFR transcripts, including FGFR2, 3, and 4. Additionally, several FGFR ligands (e.g., FGF14, -19, and -23) were also down-regulated in PDS-0330-treated GIST. Notably, exogenous FGF-2 increased CLDN1 expression in a time-dependent manner. In contrast, pan-FGFR inhibitors effectively reduced CLDN1 levels in IM-resistant GIST T-1R cells, thereby illustrating a cross-talk between CLDN1- and FGFR-mediated pathways in IM-resistant GIST. Based on subcellular fractionation and immunofluorescence microscopy data, we also observed partial relocalization of CLDN1 into the cytoplasm in IM-resistant GIST. Notably, PDS-0330 effectively abrogated this relocalization, suggesting that changes in CLDN1 subcellular distribution might also impact GIST resistance to IM. Lastly, based on our small cohort clinical study (n = 24), we observed the increased expression of CLDN1 in most “high-risk” primary GIST known to be associated with poor prognosis and aggressive behavior, thereby illustrating the prognostic value of increased CLDN1 expression in GIST and providing a further rationale to evaluate the effectiveness of CLDN1 inhibition for GIST therapy. Full article

Background: Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal primary brain malignancies, characterized by rapid proliferation, extensive invasiveness, and a dismal prognosis. Emerging evidence implicates nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor, as a potential driver of GBM progression. This study investigates NOD2’s role in promoting glioblastoma through its effects on the epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) markers. Methods: NOD2 expression levels and survival outcomes were assessed using TCGA data from GBM tumor samples (n = 153) and normal brain tissues (n = 5). NOD2 protein expression was validated in glioma cell lines using Western blot and immunofluorescence analyses. Functional studies employed siRNA-mediated NOD2 knockdown to evaluate effects on cellular proliferation, migration, invasion, and colony formation, while correlations between NOD2 and EMT/CSC markers were assessed. Results: The analysis of TCGA data revealed a significantly elevated NOD2 expression in GBM tumors compared to normal brain tissue, with a high NOD2 expression correlating with a reduced disease-free survival in GBM patients. All tested glioma cell lines demonstrated robust NOD2 expression. Functional analyses demonstrated that NOD2 depletion substantially impaired cellular proliferation, migration, invasion, and the colony-forming capacity. Mechanistically, siRNA-mediated NOD2 knockdown significantly decreased the expression of EMT (Snail, SLUG, Vimentin) and CSC markers (CD44, CD133) at both protein and mRNA levels. Conclusions: Our results indicate that NOD2 contributes to GBM progression by influencing EMT and CSC pathways. These findings suggest NOD2’s potential as a therapeutic target in glioblastoma, highlighting the need for further mechanistic studies and therapeutic exploration. Full article

Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization—spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways—including PI3K–AKT–mTOR, MAPK, Wnt/β-catenin, and integrated stress response cascades—undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome–lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3–CR3 axis), and excitatory–inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network “meaning-making”—a collapse of coordinated signal interpretation, triage prioritization, and adaptive response—the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning—a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration. Full article