搜索结果：Translational neurodegeneration

The key pathological mechanisms in diabetes and neurodegeneration generally involve a progressive accumulation of reactive carbonyl species (RCS), accompanied by increased oxidative stress and the accumulation of inflammatory mediators. Thus, a clear understanding of the Glo1-Nrf2-RAGE axis is crucial as it plays a key role in redox imbalance, regulation of cell responses to methylglyoxal (MG)-induced glycation, and chronic inflammation. Even though glyoxalase I (Glo1) detoxifies MG to mitigate advanced glycation end product (AGE) formation, the transcription of antioxidant enzymes by nuclear factor erythroid 2-related factor 2 (Nrf2) is reactivated. Conversely, persistent activation of the receptor for AGE (RAGE) further amplifies inflammatory cascades and tissue damage. A continuous dysregulation of "this axis" can contribute to the pathogenesis of several complications, including diabetes and neurodegeneration. Nevertheless, polyphenols have emerged as nutraceutical candidates that may modulate the Glo1-Nrf2-RAGE axis due to their specialized structural features. Key polyphenols, such as quercetin, resveratrol, curcumin, epigallocatechin gallate, luteolin, and apigenin, enhance Glo1 expression and activity, promote Nrf2 nuclear translocation via Keap1 modification, and lower RAGE expression and ligand binding. However, numerous challenges, such as limited bioavailability, metabolic instability, and "interindividual variability," hinder their clinical translation. We have tried to fill the research gap by combining recent evidence from preclinical, clinical, and molecular studies, with the aim of highlighting the pleiotropic effects of these metabolites. In addition, the molecular effects of polyphenolics with reference to modulation of mitochondrial function, regulation of epigenetic mechanisms, and interactions with the gut-brain axis are detailed.

Neurotrophic factors (NTFs), including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and vascular endothelial growth factor (VEGF), play a central role in neuronal survival, plasticity, and regeneration. Despite their distinct etiologies and temporal profiles, stroke (both ischemic and hemorrhagic), traumatic brain injury (TBI), and neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), converge on a common pathophysiological phenotype characterized by excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal apoptosis. Neurotrophic factors modulate these pathological cascades through tropomyosin receptor kinase (Trk) receptors, p75 neurotrophin receptor (p75NTR), and related signaling pathways, thereby supporting neuroprotection, neurogenesis, and synaptogenesis. Experimental evidence from preclinical models demonstrates robust beneficial effects of neurotrophin-based interventions in stroke, TBI, AD, and PD across protein, gene, and cell-based strategies. However, clinical translation remains severely limited. Early-phase clinical trials of adeno-associated virus (AAV)-mediated GDNF and neurturin gene therapy for PD, ex vivo NGF gene therapy for AD, and BDNF gene therapy for AD have confirmed acceptable safety profiles but yielded modest or inconsistent efficacy, largely due to constraints in brain delivery, the need for invasive neurosurgical procedures, restricted target coverage, suboptimal control of expression, and marked patient heterogeneity. Consequently, the principal barrier to clinical success is not biological validity, but the lack of safe, effective and scalable delivery platforms capable of bypassing or functionally modulating the BBB. In this review we synthesize shared pathophysiological mechanisms linking stroke, TBI and NDDs; examine the biology, receptor systems, and signaling pathways of key neurotrophic factors; summarize preclinical evidence for their therapeutic potential; and critically evaluate current delivery strategies, including viral vectors, lipid nanoparticles, exosomes, cell-based therapies, small-molecule mimetics, and intranasal administration. We conclude that overcoming delivery barriers through development of improved viral and non-viral platforms, minimally invasive administration routes, controllable expression systems, and rational patient stratification based on disease stage and biomarkers will be essential to fully realize the neuroprotective and neuroregenerative potential of neurotrophin-based therapies for acute and chronic brain disorders.

Maintenance of proteostasis is essential for cellular and organismal homeostasis, and disruption of protein quality control (QC) networks underlies numerous human diseases. The endoplasmic reticulum (ER) functions as a central organelle for the synthesis, folding, maturation, and trafficking of secretory and membrane proteins, and serves as a central hub of intracellular proteostasis. Recent studies have established that the ER membrane serves not only as a site of protein translocation but also as a dynamic platform integrating translational regulation, RNA surveillance, and multiple QC pathways. During ER-associated translation, cells continuously monitor ribosome dynamics, mRNA integrity, nascent-chain folding, and transmembrane protein insertion processes to prevent the accumulation of aberrant proteins. These surveillance systems include the PKR-like ER kinase (PERK)-mediated integrated stress response (ISR), regulated IRE1-dependent decay (RIDD), nonsense-mediated mRNA decay (NMD), RNA silencing, ribosome-associated QC (RQC), ubiquitin-fold modifier 1 conjugation (UFMylation), ER-phagy, and ER stress-induced pre-emptive QC (ERpQC). Although these pathways were originally characterized independently, increasing evidence indicates that they function cooperatively on or near the ER membrane to coordinate translational attenuation, mRNA degradation, ribosome recycling, nascent-chain elimination, and organelle remodeling. In particular, UFMylation has emerged as a central mechanism linking ER-associated RQC, translocation-associated QC (TAQC), and ER-phagy. Dysfunction of these ER-localized translational QC pathways contributes to neurodegeneration, inflammation, fibrosis, cancer, and aging-related disorders. In this review, we summarize recent advances in ER-localized translational control and discuss how integrated QC networks on the ER membrane maintain proteostasis and influence disease pathogenesis.

Neurodegenerative diseases are increasingly linked to systemic metabolic dysfunction, with brain insulin resistance (BIR) positioned as a central mediator. Yet translating this insight into effective therapies has proven remarkably difficult. This review argues that BIR-driven neurodegeneration should be interpreted at two distinct but interconnected levels: cell-type-specific disruption of brain homeostasis by BIR, and the direct, mechanistic role of BIR in driving the proteinopathies that define Alzheimer's and Parkinson's diseases. We first show how BIR produces distinct functional deficits across neurons, astrocytes, microglia, and oligodendrocytes, impairing synaptic plasticity, metabolic coupling, immunometabolic homeostasis, and myelination, resulting in a cellular milieu that favors proteinopathy. We then map molecular pathways through which BIR directly distrubs the metabolism of amyloid-β, tau, and α-synuclein. We further examine how islet amyloid polypeptide cross-seeds cerebral amyloid pathology, suggesting a direct molecular interaction between the peripheral drivers of BIR and protein aggregation. In this framework, BIR functions not as a passive risk factor, but as an active, upstream driver of proteostatic collapse. Cellular dysfunction combined with proteostatic failure, defines the therapeutic target space. We evaluate interventions accordingly, distinguishing those that primarily restore cellular function from those that enhance protein clearance, and those that achieve both. For each strategy, we assess the translational evidence, critically appraising the barriers that have limited their clinical success, including patient heterogeneity, narrow therapeutic windows, and inadequate central nervous system delivery. By integrating cell-type-specific biology with proteostatic mechanisms and a clinically oriented therapeutic framework, this review aims to provide a foundation for multi-target strategies that address the BIR-neurodegeneration axis at its mechanistic roots.

Cognitive impairment increasingly emerges at the intersection of type 2 diabetes mellitus, vascular brain injury, chronic kidney disease, heart failure, and neurodegeneration, prompting interest in therapies that modify shared metabolic and inflammatory drivers of brain vulnerability. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor widely used in type 2 diabetes and cardiorenal disease, has attracted attention as a candidate modulator of cognitive decline because its established peripheral pharmacology extends beyond glucose lowering to include natriuresis, blood pressure reduction, weight loss, improved insulin resistance, reduced oxidative and inflammatory stress, and favorable cardiorenal effects. In this review, we examine the pharmacological basis by which these systemic actions could influence the neurovascular unit, mitochondrial homeostasis, glial activation, autophagy-related signaling, and synaptic plasticity pathways implicated in cognitive impairment. We summarize preclinical evidence suggesting that dapagliflozin can improve cognitive performance and modulate pathways such as AMPK-mTOR, Wnt/β-catenin, CREB/BDNF, oxidative stress responses, and neuroinflammatory signaling in experimental models, while also critically evaluating the limitations of these models. We then assess the current human evidence, distinguishing observational studies that suggest lower dementia risk from randomized clinical evidence that has not yet established a definitive cognition-related benefit. We argue that dapagliflozin should currently be viewed not as a proven cognitive therapeutic, but as a mechanistically plausible metabolic-neurovascular intervention whose relevance may be greatest in metabolically vulnerable phenotypes. Finally, we outline key translational challenges, including uncertainty regarding direct central target engagement, the need for biomarker-enriched trial designs, and the importance of integrating pharmacological, vascular, and neurodegenerative frameworks in future studies.

Olfactory impairment is a well-established prodromal marker of neurodegeneration. However, the synergistic role of combined olfactory and gustatory dysfunction remains under-investigated in geriatric clinical practice. This scoping review aims to synthesize current evidence on the relationship between dual chemosensory decline and cognitive deterioration in aging. Following PRISMA-ScR guidelines, we conducted a comprehensive search across PubMed, Scopus, Web of Science, and Cochrane databases for studies published between 2015 and 2025. Inclusion criteria focused on clinical research evaluating both smell and taste functions in the context of cognitive impairment and neurodegenerative diseases. Our analysis of the identified literature suggests that combined chemosensory deficits are significantly correlated with cognitive decline. Our findings indicate that the concurrent loss of olfactory and gustatory sensitivity could serve as potential biomarker of cortical and subcortical neurodegenerative progression, reflecting a breakdown in central multisensory integration centres critical for geriatric cognitive homeostasis. Dual assessment of olfaction and gustation may represent a promising candidate biomarker of neurodegenerative progression compared to isolated olfactory testing. We propose the integration of standardized chemosensory protocols into routine geriatric assessments as a pragmatic strategy for early cognitive risk stratification and follow-up. This approach holds significant translational potential for monitoring neurodegenerative trajectories in older adults.

In recent years, a considerable body of research has increasingly underscored the critical roles that protein Post-Translational Modifications (PTMs) play in the pathogenesis of Alzheimer's Disease (AD). However, a comprehensive bibliometric analysis of this field is still lacking. This study aims to systematically map research trends and hotspots and to identify promising directions for future work. The data in this study were extracted from the Web of Science Core Collection (WOSCC) and visualized using CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel 2016 to analyze bibliometric indicators including countries, institutions, authors, journals, citations, production categories, and keywords. A collection of 1,170 articles was retrieved, spanning the publication period from January 1, 1990, to December 31, 2024. The top three countries in terms of publications were the United States, China, and Germany. The most productive institution was the University of California System in the United States, contributing 57 articles. The leading authors identified were Mitkevich Vladimir, Perry George, and Makarov Alexander A. The Journal of Alzheimer's Disease was the top-ranked journal in terms of published papers. The most frequently cited article was "The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation," published in the International Journal of Molecular Sciences. Finally, the most prolific research category was neuroscience, with 432 papers published. High-frequency keywords included Alzheimer's disease, phosphorylation, tau, and neurodegeneration. The study's findings suggest that PTM research in AD continues to revolve around the core pathological hallmarks represented by Aβ and tau protein. At the same time, some studies have reported aberrant modifications of α-synuclein and its potential role in AD. By systematically cataloging diverse PTM types and the molecular mechanisms involving Aβ and tau throughout AD progression, this analysis paves the way for a reassessment of AD pathogenesis from a "modification-function-pathology" perspective and provides a basis for identifying potential PTM-related targets and intervention strategies. This bibliometric analysis highlights the growing scholarly attention devoted to the relationship between PTMs and AD. The significant contributions and emerging trends emphasize the pivotal role of PTMs in the pathogenesis of AD, which may guide future biomarker discovery.

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal destruction. MS impacts about 2.6 million individuals worldwide, typically presenting a wide array of clinical manifestations, such as motor, sensory, visual, and dementia, often leading to progressive disability. This progressive condition and the accumulation of handicaps draw attention to a crucial unmet need for therapies able to preserve neurons, encourage myelin regeneration, and restore neurological function. Although present conventional treatments mostly target the inflammatory aspects of MS, their effectiveness in treating the underlying neurodegeneration and supporting central nervous system repair is still limited. Recently, stem cell-based therapy and regenerative medicine have become some of the most promising approaches for treating MS. However, progress is subject to challenges and achievements are limited. The current study thoroughly investigates the findings of preclinical and clinical studies on neural stem cell (NSC)-based therapies for MS and highlights the related challenges. Study investigates its possible modes of action, treatment effectiveness, major earlier challenges, and emerging questions in transferring NSC-based therapies into clinical practice, aiming to improve neuroprotection, promote remyelination, and facilitate the repair of damaged CNS tissue. NSC-based therapies hold great potential as a regenerative therapy for MS, however, fundamental questions remain about the optimal delivery, long-term survival, functional integration, and potential immunological responses. To sum up, NSC-based therapies represent a promising new frontier in the next generation of treatments for MS. However, further comprehensive studies are required to conclusively confirm their safety, effectiveness, and long-term advantages.

Amyloid-related imaging abnormalities (ARIA) represent a significant iatrogenic complication of anti-amyloid monoclonal antibody therapies. To address this, we propose the Impedance Mismatch Theory as a theoretical framework and hypothesis, reframing neurodegeneration as a network-level thermodynamic failure characterized by localized thermal runaway (Neural Physiological Load Index (NLI) greater than or equal to 1.0). Within this framework, amyloid-β (Aβ) is modeled not only in its established biological context, but as a potential thermodynamic heat sink and bio-conductive electrical shunt deployed to protect hyper-metabolic neural hubs. Utilizing the Pennes bioheat equation, we formalize the NLI and map its theoretical values to absolute 1H-magnetic resonance spectroscopy thermometry signatures. Our model suggests that clearing Aβ in the setting of unresolved energetic mismatch could contribute to localized mechanical and thermal instability. We hypothesize that these upstream physical dynamics precipitate the downstream inflammatory cascades clinically observed as ARIA. If validated, these theoretical considerations suggest that effective disease modification may require thermodynamic normalization as a prerequisite to, or in parallel with, plaque clearance.

Mitochondrial dysfunction is a central feature of neurodegenerative diseases, yet the molecular mechanisms governing mitochondrial protein synthesis remain insufficiently understood. Mitochondrial ribosomal proteins (MRPs), essential for the translation of mitochondrial-encoded components of the oxidative phosphorylation system, are emerging as critical regulators of neuronal homeostasis and survival. In this mini-review, we examine current knowledge on mitochondrial ribosomes with a focused analysis of three mitochondrial ribosomal proteins-MRPL44, NAM9, and GEP3-highlighting their structural and functional roles in maintaining mitochondrial integrity. We discuss evidence linking alterations in these proteins to key pathogenic processes relevant to neurodegeneration, including impaired oxidative phosphorylation, increased oxidative stress, and defective mitochondrial quality control. Importantly, we propose an integrative research perspective that positions these MRPs as potential modulators of tissue-specific vulnerability in neurodegenerative disorders. By synthesizing available data and identifying critical knowledge gaps, we outline future directions aimed at elucidating their contribution to neuronal dysfunction and disease progression. This work underscores mitochondrial ribosomal proteins as underexplored determinants of neurodegenerative pathology and suggests that their systematic investigation may reveal novel mechanistic insights and therapeutic opportunities.

Niemann-Pick type C1 (NPC1) disease is a rare neurodegenerative disorder linked to defective cholesterol biosynthesis. Because olfactory dysfunction frequently precedes clinical manifestations in neurodegenerative conditions, we investigated whether the olfactory system might provide early insights into disease processes in NPC1. Using a knock-in mouse model carrying the human I1061T mutation, we investigated the olfactory epithelium in wild-type, heterozygous, and mutant mice to analyze neurodegeneration at 36 and 60 days after birth. Mutant mice showed reduced density of mature olfactory sensory neurons, increased apoptosis, and infiltration of macrophage/microglia. These structural alterations were accompanied by reduced odor-evoked responses and impaired odor-guided behavior. Finally, we assessed olfaction in a family with a child carrying biallelic NPC1 mutations and two heterozygous carrier parents, finding hyposmia of different severity in all three individuals. Our work extensively characterized the OE structurally and functionally, proposing it as a sentinel to monitor disease progression.

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Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of aggregated α-synuclein (α-syn), including Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. These diseases are marked by locomotor and non-motor impairments, as well as mitochondrial dysfunction and the loss of dopaminergic (DA) neurons. We have developed several anti-α-syn single-domain antibodies (sdAbs) and demonstrated the diagnostic imaging potential of two of them and the acute therapeutic benefit of one in clearing α-syn in a mouse model. However, whether these sdAbs can suppress α-syn-mediated neuronal loss and locomotor impairment in vivo remains unclear. We evaluated the therapeutic potential of five anti-α-syn sdAbs to clear pathological α-syn in mouse neuronal culture and then demonstrated their in vivo efficacy in a Drosophila model of synucleinopathy. The sdAbs differed in their efficacy to lower levels of phospho-serine 129 α-syn, prevent loss of DA neurons, alleviate mitochondrial dysfunction, improve motor function, and prolong survival in synucleinopathy flies. The most effective sdAb, 2H1, has not been reported before. It binds strongly to the aggregation prone region of α-syn and robustly improves all these disease parameters. Additionally, that sdAb is associated with α-syn in the fly neurons, as shown through proximity dependent turboID biotinylation assays. The sdAb-turboID also biotinylated α-syn-associated proteins involved in synapse/vesicle trafficking pathways, pinpointing the location of their intracellular interaction. Our findings provide an insight into the therapeutic mechanism of action of these sdAbs and strongly support their clinical development.

Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks global cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global increase in start codon stringency in neurons as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with a cytoplasmic redistribution of eIF1 in neurons and is reversed with neuronal overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and selectively enhances cap-dependent RAN translation. Taken together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis and neuronal translational regulation.

TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.

Background: Accumulating evidence suggests that environmental light cues influence brain function and neurodegenerative processes; however, the underlying cellular mechanisms remain incompletely understood. Methods: Here, using a Tau-overexpressing Drosophila model, we investigated how light exposure modulates neurodegeneration-associated phenotypes, with a particular focus on adenosine signaling and mitochondrial homeostasis. We performed behavioral assays, biochemical measurements, genetic interference targeting the adenosine receptor, and mito-QC reporter analysis to assess mitochondrial quality control. Results: We show that light exposure ameliorates Tau-induced behavioral impairments and neuropathological features, reducing climbing time by approximately 29% in males and 45% in females, and extending median lifespan by ~29% in males and ~26% in females. Notably, biochemical analyses revealed that light exposure significantly increases brain adenosine levels at ZT12 by approximately 5 to 6 nmol/L in both sexes (p < 0.01), suggesting a light-dependent modulation of adenosine availability. To further examine the role of adenosine signaling, we performed genetic interference experiments targeting the adenosine receptor. These results indicate that adenosine receptor-associated signaling is functionally involved in the beneficial effects of light, as disruption of this pathway attenuates the light-induced improvements in behavioral and mitochondrial phenotypes. Using a mito-QC reporter system, we further show that light exposure enhances mitochondrial quality control, as reflected by a ~2.3-fold increase in mitolysosome density (p < 0.001). Importantly, this effect is modulated by the functional state of adenosine signaling, suggesting a potential interaction between these processes. Conclusions: Together, our findings indicate that light exposure is associated with coordinated changes in adenosine signaling and mitochondrial quality control, which may contribute to the attenuation of Tau-induced deficits in Drosophila. This work provides insight into how environmental light cues may influence neurodegeneration-related cellular processes and highlights the potential relevance of light-based interventions for future mechanistic and translational studies.

Retinal ganglion cells (RGCs) exhibit high bioenergetic demands, rendering them vulnerable to mitochondrial dysfunction and metabolic collapse during glaucomatous neurodegeneration. Therapeutic strategies capable of restoring mitochondrial homeostasis in human RGCs remain limited. We established a human retinal ganglion-like cell (RGLC) model of mitochondrial injury and evaluated neuroprotective efficacy of small extracellular vesicles (sEVs) derived from either undifferentiated BRN3B-H9 cells or differentiated lineage-tailored RGLCs. RGLC-derived sEVs (RGLC-sEVs) conferred robust neuroprotection, significantly enhancing neuronal survival, preserving neurite architecture, and mitigating mitochondrial stress following injury. These effects were reproducible in mixed retinal cultures and in an ocular hypertension mouse model of glaucoma, with neuroprotective benefits observed throughout the retinal landscape. Mechanistically, untargeted metabolomic profiling revealed extensive metabolic reprogramming involving oxidative phosphorylation, amino acid utilization, lipid metabolism, and redox regulatory pathways. In vitro tracking studies confirmed efficient uptake of sEVs by injured RGLCs, confirming effective vesicular cargo delivery under conditions that promote neuroprotection and metabolic recovery. Functional bioenergetic analysis further validated restoration of mitochondrial-glycolytic coupling and improved cellular energetic resilience. Collectively, our findings establish lineage-tailored RGLC-sEVs as a potent, cell-specific therapeutic candidate capable of reprogramming metabolic networks and restoring bioenergetic homeostasis in glaucomatous neurodegeneration, highlighting their translational potential for neuroprotective intervention in optic neuropathies.

Metabotropic glutamate receptor subtype 5 (mGlu5) is an important regulator of excitatory neurotransmission and remains a therapeutic target for neuropsychiatric and neurological disorders, including substance use disorders, depression, Fragile&#x202f;X&#x202f;syndrome, Parkinson's disease-related dyskinesia, and other movement disorders. However, the clinical development of mGlu5 negative allosteric modulators (NAMs) has been limited by translational challenges, inconsistent efficacy, and safety concerns, particularly hepatotoxicity associated with early acetylene-containing scaffolds such as ADX10059. The study provides an updated assessment of the mGlu5 NAM patent landscape and related medicinal chemistry advances from 2018 to the present. The post-2018 period is characterised as a phase of translational and medicinal chemistry refinement, marked by a shift from metabolically unstable aryl-alkyne and acetylene-based chemotypes towards more stable heterocyclic, bicyclic, and non-acetylene frameworks. Key strategies include scaffold hopping, structure-based drug design, receptor occupancy assessment, and pharmacokinetic optimisation to reduce the risk of bioactivation, improve brain exposure, and enhance clinical translatability. Recent patent-linked compounds such as TMP-301/HTL0014242, VU0424238, VU6031545, VU6024945, and AE90015 are presented alongside unconventional approaches, including GET-73, LCGM-10, antibodies, and nanobodies. It also covers clinical progress, including the repurposing of mavoglurant/STP7 for cocaine use disorder. Overall, the field aims for safer, more selective, and better-controlled mGlu5 modulation strategies, but challenges related to efficacy, tolerability, and patient selection continue to hinder clinical success.

Traumatic brain injury (TBI) is a major cause of neurological dysfunction and long-term neurodegeneration, yet the intrinsic neuronal contributions to TBI pathophysiology remain incompletely defined. Here, we present a novel Neuron-on-Chip microfluidic device and weight-drop impactor&#xa0;platform that can be used to mechanically injure mature human prefrontal cortex neurons (hPFCs) embedded in three-dimensional (3D) hydrogels, enabling the study of injury responses in pure neuronal cultures. We assessed real-time calcium dynamics across 13 metrics of single-cell and network activity, revealing a biphasic injury response: an early phase (0.5-24&#xa0;h) characterized by excitotoxicity, hyper-synchronized bursting, and network collapse; and a late phase (8 d) marked by sustained depolarization and structural remodeling. Secretome profiling revealed progressive elevations in extracellular pT181 and total Tau from days 1 to 5 post-injury. Cytokine analysis identified early (24&#xa0;h) elevations in IP-10, IL-10, IFN&#x3b1;2, and NCAM, and late increases (8 d) in CXCL9 and MPO, linking neuronal activity changes to stage-specific inflammatory signaling. Immunocytochemistry and immunoblotting confirmed temporally ordered upregulation of calpain-1 and active caspase-3 (days 1-3), phosphorylated Tau (AT8+, days 5-8), and neurofibrillary tangle-like Tau aggregates (NFT+, day 8). These findings establish our platform as a scalable microphysiological model for probing the dynamic cellular and molecular sequelae of neuronal response to injury, offering insights into neurodegeneration and opportunities for therapeutic discovery.