Despite best clinical management, patients with meningiomas frequently experience tumor recurrence. During recent decades, efforts have been made to improve the prognostic stratification of meningiomas by incorporating molecular data. A subgroup of tumors harboring a homozygous CDKN2A deletion was identified, and a higher risk of tumor progression was observed, suggesting the potential use of cyclin-dependent kinases as biomarkers. In this retrospective single-center study, the immunohistochemical staining for the cyclin-dependent kinases p16, phosphoRB1 (pRB1), CDK4 and CDK6 was analyzed in 1751 paraffin-embedded meningioma samples. For the assessment of p16, CDK4 and CDK6, a semi-quantitative score was applied, whereas an automated quantification tool was used for pRB1. The distribution and association with histopathological results, clinical data and progression-free survival (PFS)—defined by radiographic tumor recurrence—were assessed. Of all meningioma samples, 14.9
Defective mitochondrial quality control is increasingly implicated in tau-mediated neurodegeneration, but how distinct tau lesions in different cell types interact with PINK1-PRKN-mediated mitophagy remains unclear. Phosphorylated ubiquitin at serine 65 (pS65-Ub) is the joint product of PINK1-PRKN signaling. Significant deposition of pS65-Ub has been previously demonstrated in autopsy brains from patients with Lewy body disease, Alzheimer disease, and MAPT mutation-associated frontotemporal lobar degeneration, where increased pS65-Ub signal was particularly strongly associated with early neuronal tau pathology. We here expanded the analyses to 92 postmortem human brains comparing neuropathologically normal controls and cases of primary age-related tauopathy (PART), Pick’s disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Using pS65-Ub and pS202-tau immunohistochemistry in selectively vulnerable regions, deep learning-based quantification of tau lesion subtypes, and single-cell co-localization analyses, we found considerable disease-, cell type-, and tau inclusion-specific differences in pS202-tau and pS65-Ub accumulation. Although pS202-tau burden was elevated across all primary tauopathies in their respective vulnerable regions, the extent of pathology and predominant tau inclusion types varied markedly among diseases. pS65-Ub positive cells were most abundant in the hippocampus of PART and PiD but were sparse in the primary motor cortex of PSP and especially in CBD, despite extensive tau pathology. In both PART and PiD, pS65-Ub primarily accumulated in neurons containing tau inclusions, with significantly greater intracellular burden and more frequent large vacuolar structures in PART. The density of pS65-Ub/tau double-positive cells strongly correlated with tau tangle burden in PART but not with Pick body burden in PiD. Together, our findings revealed marked heterogeneity in the distribution, density, intracellular abundance, and morphology of pS65-Ub deposits across affected brain regions in primary tauopathies, highlighting pS65-Ub as a potential marker for differential diagnosis of neuronal tau-associated disorders in tauopathies.
HIV remains a major global health concern, as does the connection between HIV infection and the opioid epidemic. Substance abuse increases the risk of HIV transmission and is linked to treatment non-compliance, rapid disease progression, HAND, and higher mortality rates. In recent years, epigenetic modifications have been linked to the development of opioid addiction and neurodegenerative diseases, but despite new insights, the long-term epigenetic effects of HIV and opioid co-occurrence on the severity, progression, and prognosis of HAND are not yet fully understood. In this study, we explored synaptic, immune, and epigenetic alterations associated with HIV and opioid exposure by integrating analyses from human postmortem brain tissue, peripheral blood mononuclear cells, and an EcoHIV-infected mouse model subjected to chronic morphine treatment. RT-PCR of human frontal cortex revealed differential expression of genes involved in synaptic transmission, innate immune activation, and chromatin regulation. In mice, behavioral assessments were combined with transcriptomic and proteomic approaches, including nanoscale liquid chromatography–tandem mass spectrometry, as well as biochemical assays such as RT-PCR, flow cytometry, ELISA, and Western blotting. Data from EcoHIV-infected, morphine-treated mice demonstrated sex-dependent differences in behavioral outcomes, histone modification profiles, and epigenetic regulator expression, along with disruptions in neuronal signaling and neuroinflammatory pathways. Proteomic analyses further identified widespread changes in histone post-translational modifications and altered expression of chromatin-modifying enzymes, indicating global epigenetic remodeling consistent with an altered chromatin state. Together, these findings suggest that HIV infection and opioid exposure cooperatively alter chromatin organization and transcriptional programs in the brain in a sex-dependent manner, potentially contributing to neuroimmune dysregulation and cognitive impairment.
In extreme cases of space-occupying lesions and elevated intracranial pressure, the dura has been documented to compress the brain, leading to trans-tentorial herniation. Even in individuals without traumatic brain injuries, edema or hydrocephalus, the tentorial cerebelli dura forms an impression, the tentorial notch (TN), on the surface of entorhinal cortex (EC). Given the EC’s role in memory formation and its known early vulnerability in Alzheimer’s disease, we aimed to determine whether the physical contact of the free edge of the tentorium cerebelli dura has a damaging effect on the tissue in non-injury related instances. We evaluated the severity of the TN on gross tissue (n = 55 cognitive controls) and the effect of the indentation in histology-stained sections. We developed two novel protocols: (1) to differentiate among TN severity, and (2) to examine the impact of the TN on cortical layers and individual neurons in the EC in Nissl stained sections. We observed a TN in 96
Papillary tumors of the pineal region (PTPR) are rare CNS neoplasms with adult and pediatric presentations, but whether age defines distinct molecular biology is unclear. We assembled a multicenter retrospective cohort of 86 histologically confirmed PTPR with genome-wide DNA methylation data, comprising 62 adult and 24 pediatric tumors. Molecular subgroup, array platform, sex, and tumor purity were incorporated into multivariable models. Analyses included DNA methylation class assignment, differential methylation, copy-number variation (CNV), epigenetic mitotic-clock scores, methylation-based tumor microenvironment deconvolution, and descriptive survival evaluation. Adult and pediatric tumors mapped within the established PTPR-A and PTPR-B methylation framework rather than forming age-defined methylation classes. Pediatric tumors were enriched for PTPR-B (22 of 24 tumors [91.7
Abstract Choroid Plexus tumors constitute 10–20% of brain tumors in infancy. Among these, Choroid Plexus Carcinomas (CPC) are highly aggressive and result in poor survival. Details on tumor initiation and oncogenic events remain largely unknown, aside from a high prevalence of TP53 mutations and marked chromosomal instability. We generated hGFAP-cre::lsl-MYCN::lsl-Gli2(N)::Tp53 fl/fl mice with recombination activity from embryonic day 13.5 onwards in CNS cells, leading to MYCN and Gli2 activation as well as TP53 inactivation. 84% of the mice developed ventricular tumors within 18 days of life, resembling human CPCs in histology and marker expression. We performed histological and molecular characterization of the resulting tumors and treated tumor cells in vitro. We demonstrate that aberrant Sonic Hedgehog (SHH) signaling during embryonic Choroid Plexus (CP) development triggers a dedifferentiation cascade that reverts mature epithelium to a progenitor-like state. Spatial transcriptomic analysis identifies a distinct cellular hierarchy, where differentiated plexus cells shed their secretory identity to adopt malignant progenitor states. This transformation is accompanied by a transition from multiciliated epithelial cells expressing mature, secretory CP markers to highly proliferative, monociliated progenitors expressing SOX2. This malignant reprogramming activates embryonic developmental programs and induces a critical dependency on cell cycle and DNA repair pathways. Consequently, we identify that these tumor cells cultivated in vitro are vulnerable to ATR and CDK inhibition.
Mutations in the VRK1 (Vaccinia-related kinase 1) gene have been implicated in neurodegenerative disease, primarily affecting motor neurons (MNs) and brain development. However, VRK1’s role in MN function and underlying disease mechanisms remain poorly understood. In this study, we investigated VRK1’s role in motor neuron disease (MND) by generating a conditional knockout (cKO) mouse model lacking VRK1 in cholinergic neurons. We created a Vrk1-targeted Cre-lox MND mouse model, in which Cre recombination resulted in a null mutation of Vrk1. Cre-recombinase was expressed in cholinergic neurons, including MNs, generating a cholinergic neuron-specific Vrk1 KO mouse (Vrk1 ChAT-cKO). The phenotype was analyzed by observation and motor testing; MN degeneration, neuromuscular junction (NMJ) denervation, and muscle atrophy were assessed using histological and immunostaining techniques. Vrk1 ChAT-cKO mice showed progressive motor degeneration, including weight loss, reduced grip strength, tail dragging, decreased mobility, tremors, kyphosis, and respiratory distress, leading to premature death by approximately 27 days. Histological analysis of spinal cord sections from postnatal day 24-27 cKO mice revealed significant MN degeneration, including vacuolation, chromatolysis, apoptosis and neuroinflammation, with a 40-50
Microglial hyperactivation contributes to Parkinson’s disease (PD) progression, yet the upstream microenvironmental cues that sustain this state remain incompletely understood. While α-synuclein (α-Syn) aggregation is a primary trigger, aging and PD are also associated with microvascular and perfusion abnormalities. However, how vascular-associated hypoxic stress interacts with protein toxicity in microglial fate determination remains unclear. We integrated human single-nucleus RNA sequencing (snRNA-seq) data, a chronic progressive transgenic mouse model (9-month-old A53T), and an in vitro “double-hit” model. Neuropathological and immunofluorescence analyses were employed to assess the neurovascular unit and microglial phenotypes. The snRNA-seq analysis of human PD brains revealed a Disease-Associated Microglia (DAM) subset characterized by enrichment of hypoxia and glycolysis pathways, with HIF1A acting as a central node. In vivo, 9-month-old A53T mice exhibited motor deficits and dopaminergic degeneration, accompanied by reduced CD31+ microvascular coverage in the substantia nigra. This reduction in CD31+ vascular coverage was associated with microglial HIF1A accumulation and increased IBA1-defined soma area. In vitro, physical hypoxia amplified α-Syn preformed fibril (PFF)-induced microglial reactivity, intracellular accumulation of phosphorylated α-Syn (p-αSyn). Our study supports a “double-hit” model in which hypoxia-associated stress may amplify α-Syn-induced microglial dysfunction through HIF1A-linked metabolic remodeling and impaired autophagy-related protein handling. Targeting neurovascular-immune interactions may offer therapeutic opportunities for advanced PD.
Riluzole is the most commonly prescribed among the few approved therapies for amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron degeneration and paralysis. Although believed to counteract excitotoxicity by suppressing motoneuron excitability and glutamate release, clinical studies show these effects diminish within weeks. Yet, riluzole still yields a modest but measurable survival benefit, raising the question of additional therapeutic mechanisms. We previously showed that homeostatic mechanisms in the SOD1G93A (mSOD1) mouse model of ALS are hyperactive and prone to overcompensation. Here, we tested whether such dysregulated homeostasis antagonizes the effects of riluzole. Wild-type (WT) and presymptomatic mSOD1 mice received therapeutic doses of riluzole in drinking water for 10 days, with untreated littermates of both genotypes serving as controls. Motoneuron excitability and synaptic inputs were then examined using intracellular recordings from the isolated sacral spinal cord. The data showed that extended riluzole treatment increased motoneuron excitability and polysynaptic inputs in mSOD1 mice but produced no detectable changes in WT motoneurons. These results are consistent with compensatory homeostatic adaptations in ALS counteracting the suppressive effects of riluzole. Notably, mSOD1 motoneurons exhibited larger membrane capacitance than WT, in line with their increased cell size at this disease stage. Riluzole treatment reduced motoneuron membrane capacitance in mSOD1 mice to the range observed in WT animals, suggesting a potential reduction in cell size. The functional significance of this size change remains uncertain. Together, our findings provide new insight into ALS pathology and demonstrates that dysregulated homeostasis can shape therapeutic responses in ALS.
Depression entails a range of pathological processes in the brain, typically characterized by altered microglial state, neural dysfunction, and vascular dysregulation. While it is well established that activated microglia inflict damage to neurons through direct and indirect microglia-neuron interactions, their interaction with vasculature and the associated regulation of vascular structure and function in depression remain poorly understood. Here, using a mouse model of depression induced by chronic unpredictable stress (CUS), we find that in stressed mice, activated microglia present reduced motility and decreased contact area with vasculature, which is accompanied by pathological vascular structure and function, characterized by reduced vessel density, narrowed vascular diameters, and sluggish blood flow velocity. We observe that vascular structure in the stressed mice is rapidly modified by the vessel-associated microglia (VAM). These VAM show upregulated angiotensin II type 1 receptor (AT1R) expression, which is not present in the vascular-uncontacted microglia. Furthermore, we demonstrate that AT1R signaling together with altered microglial state under chronic stress are critical mediators for the altered microglia-vascular interactions, vascular dysregulation, as well as the depression-like behaviors. Together, our findings reveal that under CUS, the aberrant microglial-vascular interaction, including the dysregulated microglial vasoregulation arising from AT1R signaling and altered microglial state, leads to depression, forging a new link between chronic stress and depression.
Tau assemblies, associated with tauopathies, are believed to self-propagate through prion-like mechanisms in the central nervous system, driving neurodegeneration. Recently, protein seed amplification assays have emerged as highly sensitive methods for detecting trace amounts of misfolded protein assemblies across various neurodegenerative diseases. In this study, we utilized protein misfolding cyclic amplification (PMCA) to demonstrate that tau assemblies from the brains of transgenic mice or human patients with tauopathies can be efficiently amplified. Amplification was achieved using complex matrix substrates, such as brain homogenates or cell lysates expressing aggregation-prone mutant tau proteins, with heparin as a cofactor. This assay enabled the highly sensitive detection of tau assemblies, even at 1-million-fold dilutions of brain homogenate from aged and symptomatic THY-Tau30 transgenic mice (a model of tauopathy) and human cases of frontotemporal lobar degeneration (FTLD-P301L). Tau assemblies from Alzheimer’s disease (AD) patients were also successfully amplified, albeit with lower sensitivity compared to other tauopathies. Critically, the PMCA-generated tau assemblies retained seeding competence, inducing further tau aggregation in reporter tau “biosensor” cells and in young THY-Tau30 mice following intracerebral injection. Together, our findings establish PMCA as an in vitro model for studying the seeded aggregation of tau assemblies, providing a powerful tool to advance research into tau aggregation mechanisms and the development of therapeutic interventions.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by chronic inflammation, neuronal loss, and continuous decline in memory and cognitive function. Raman Spectroscopy (RS) offers a powerful, label‑free approach for detecting early biochemical alterations in AD by generating highly sensitive molecular fingerprints, which is valuable for identifying subtle changes associated with protein misfolding, lipid dysregulation, and oxidative stress, key processes underlying AD onset and progression. In our study, full‑spectrum RS revealed clear biochemical distinctions between control and AD brain tissues, as well as between Braak IV and Braak VI AD stages. Multivariate analytical methods, including Singular Value Decomposition (SVD) and Linear Discriminant Analysis (LDA), were applied to manage spectral complexity and highlight the principal biochemical contributors to AD pathology. Multiple Raman bands in the 1200–1800 cm−1 region showed increased intensity in AD tissue, including 1296 cm−1 (lipid CH₂ deformation), 1440 cm−1 (lipid/cholesterol deformation), 1554 cm−1 (Amide II), 1585 cm−1 (protein‑folding–related vibrations), and 1640–1680 cm−1 (Amide I). These changes indicate enhanced protein aggregation, loss of ordered secondary structure, and extensive lipid membrane disorganization. Complementary gene‑expression analysis further demonstrated dysregulation of lipid homeostasis in AD, with altered expression of ABCA1, LIPE, CPT1A, PPARA, and SREBP‑1, indicating broad metabolic reprogramming. Together, the coordinated spectral and transcriptional shifts underscore lipid‑metabolic dysfunction as a central feature of AD. By capturing these molecular signatures, RS provides a promising tool for early detection and monitoring of AD progression.
Extracellular vesicles (EVs) are increasingly recognized as key mediators of intercellular communication in neurodegenerative disorders, yet their mechanistic contribution to Alzheimer’s disease (AD)-related molecular changes remains poorly understood. Neural progenitor cells (NPCs) are particularly relevant because deficits in their proliferation and differentiation impair neurogenesis and brain repair. To investigate how EVs may influence these processes, we isolated EVs through size exclusion chromatography (SEC) from induced pluripotent stem cells (iPSCs)- derived NPCs carrying the AD-associated PSEN1 ΔE9 mutation and from isogenic controls. EV formulations were characterized by nanoparticle tracking analysis, cryogenic transmission electron microscopy, immunoblotting, and liquid chromatography–tandem mass spectrometry-based proteomics. Their effects on iPSC-derived brain organoids (BOs) were assessed by transcriptomic profiling. AD NPC EVs showed increased 6E10-reactive Aβ-related signal and contained AD-associated protein signatures, including PZP, ALPL, POSTN, APOC3, and transferrin. Application of AD EV preparations to healthy BOs induced transcriptomic changes that partially overlapped with AD BO transcriptomic signatures, including altered developmental and synapse-associated gene programs and downregulation of metabolic pathways. Consistently, PSEN1 ΔE9 NPCs showed reduced oxidative phosphorylation and glycolysis in Seahorse extracellular flux assays, while PSEN1 ΔE9 EV-treated BOs displayed downregulation of TCA cycle and glycolytic pathways at the transcriptomic level. Together, our findings suggest that NPC-derived SEC-enriched EV preparations contain AD-associated molecular signatures that could affect developmental, synapse-associated, and metabolic gene programs in recipient BOs, providing insight into cell-cell communication in AD.
Traumatic brain injury (TBI) is associated with an increased risk of Parkinson’s disease (PD), yet the anatomical routes through which diffuse injury confers selective neuronal vulnerability remain poorly defined. The olfactory system occupies a critical peripheral–central interface: primary olfactory neurons project unmyelinated axons through the cribriform plate into the olfactory bulb, rendering this pathway susceptible to mechanical stress while overlapping with one of the earliest sites of α-synuclein pathology in PD. Here, we tested whether diffuse mild TBI produces spatially and temporally distinct neuropathological responses across the olfactory–nigrostriatal axis. Adult C57BL/6 mice underwent mild TBI using the Closed Head Impact Model of Rotational Acceleration and were assessed at 24 h, 1 month, and 6 months post-injury. Holocranioimmunohistochemistry preserving anatomical continuity between the olfactory epithelium (OE) and olfactory bulb enabled integrated analysis of peripheral and central structures. Diffuse injury produced acute axonal disruption of olfactory receptor neurons and was accompanied by transient immune cell accumulation and altered neuronal turnover in the OE. These changes largely resolved by one month, although a modest reduction in mature receptor neurons persisted. In contrast, central olfactory regions demonstrated sustained microglial elevation together with delayed increases in phosphorylated α-synuclein occurring without corresponding changes in total α-synuclein expression. Delayed vulnerability emerged within the substantia nigra, where dopaminergic neuron density was reduced at six months despite preserved striatal terminals. This was accompanied by increased total α-synuclein in the absence of phosphorylation at serine-129, consistent with altered protein handling rather than phosphorylation-dominant aggregation. Together, diffuse mild TBI produced early peripheral disruption followed by persistent region-specific neuroimmune activation and divergent alterations in α-synuclein biology, culminating in delayed nigral susceptibility without evidence of progressive synucleinopathy. These findings identify the olfactory–nigrostriatal axis as a site of trauma-related vulnerability and provide a neuropathological framework linking diffuse injury to processes relevant to later neurodegenerative disease.
Autoimmune autonomic ganglionopathy (AAG) is a disorder of the autonomic nervous system associated with autoantibodies against the α3 subunit of the ganglionic acetylcholine receptor (gnACHR). gnACHR antibodies exert their effects via receptor internalisation, but most current gnACHR diagnostic assays only detect antibody binding. Hence, we developed a new bioluminescent cell-based assay (BLIA) to measure internalising gnACHR antibodies. The BLIA was performed by incubating patient sera with live IMR-32 cells that express surface gnACHR. Remaining surface gnACHR was quantified using a novel split luciferase system with NanoBiT conjugated detecting antibodies. The percentage of receptor internalisation was calculated with comparison to cells incubated with reference sera, with > 20
Amyotrophic lateral sclerosis (ALS) involves TAR DNA-binding protein 43 (TDP-43) dysfunction, leading to cryptic splicing, including UNC13A cryptic exon inclusion and truncated STMN2 production. Pathologically, ALS is classified into three phosphorylated TDP-43 subtypes (Types 1, 2a, and 2b) based on the distribution of neuronal and glial cytoplasmic inclusions and the density of dystrophic neurites. However, the relationship between these pathological subtypes and TDP-43-associated cryptic splicing remains unclear. This retrospective postmortem study aimed to analyze motor cortex tissue from sporadic ALS cases (Type 1, n = 12; Type 2a, n = 12; Type 2b, n = 11) with previously described subtype-specific morphological features. UNC13A cryptic RNA and truncated STMN2 RNA levels were quantified using quantitative real-time PCR (qRT-PCR). Compared with Types 1 and 2a, Type 2b, characterized by abundant thread-, dot-, and grain-like dystrophic neurites, exhibited significantly higher levels of UNC13A cryptic RNA and truncated STMN2 RNA. Droplet digital PCR revealed a similar subtype-dependent trend and showed strong correlations with qRT-PCR measurements, providing partial support for the primary findings. UNC13A cryptic RNA and truncated STMN2 RNA levels were positively correlated (Spearman’s ρ = 0.58), indicating coordinated dysregulation of multiple TDP-43-dependent splicing targets. Our results demonstrate that the burden of TDP-43-associated cryptic splicing differs across ALS pathological subtypes. Additional analyses indicated that these subtype-dependent differences were not readily accounted for by disease duration, RNA quality, normalization strategy, or semiquantitative neuronal loss scores. These findings suggest that molecular heterogeneity parallels pathological heterogeneity in ALS and provide additional insight into the biological diversity of TDP-43 proteinopathy.
Blood-brain barrier (BBB) disruption is a key pathological event following traumatic brain injury (TBI), yet its molecular and spatial characteristics remain incompletely understood. Here, we developed a dual-tracer mapping system to assess the temporal and spatial dynamics of BBB permeability following controlled cortical impact (CCI) injury in EphA4f/f VE-Cadherin-CreERT2 (KO) and EphA4f/f (WT) mice. By tracking Evans Blue Dye (EBD), sodium fluorescein (NaFl), and endogenous IgG deposition, we identified distinct patterns of vascular tracer extravasation in the injured cortex and hippocampus. NaFl, a small-molecule tracer, continued to extravasate for 7 days post-injury, whereas EBD leakage diminished after 4 days. Notably, endothelial EphA4 deletion significantly reduced size-dependent vascular tracer extravasation. To further investigate molecular pathways associated with altered BBB permeability, we integrated spatial transcriptomics with tracer quantification, revealing that endothelial EphA4 ablation upregulates BBB-associated genes (Tjp2, Tjp3, Cldn1, and Ocln) and injury-responsive genes linked to injury-responsive genes (Nr4a1 and Npas4). Wnt signaling genes were similarly upregulated in the KO cortex, and pharmacological inhibition of Frizzled-4 (FZD4)/Wnt signaling attenuated the reduction in vascular tracer extravasation observed in KO mice. Conversely, pharmacological activation of Wnt signaling with the FZD4 agonist FZM1.8 in WT mice reduced lesion volume and vascular tracer extravasation. Overall, these findings demonstrate the utility of combining spatial transcriptomics with dual-tracer mapping to identify region-specific transcriptional programs associated with BBB permeability following CCI injury and to define the contribution of EphA4/Wnt signaling to vascular responses after TBI. Together, these findings identify Wnt signaling as a promising therapeutic pathway for reducing vascular permeability and limiting secondary brain injury following TBI.
IDH (isocitrate dehydrogenase) wild-type gliomas (glioblastomas) exhibit rapid progression and poor prognosis compared to their IDH mutant counterparts, highlighting an urgent need for novel, biology-informed therapies. We performed an integrative analysis combining tissue metabolomics and ex vivo drug screening in matched patient-derived tumor cells (PDCs) to uncover IDH-relevant vulnerabilities. IDH wild-type tumors showed metabolic reprogramming marked by upregulation of nucleotide metabolism, central carbon metabolism, fatty acid β-oxidation, and redox mechanisms relative to IDH mutant tumors, consistent with enhanced proliferation and tumor plasticity. Strikingly, microbiota-derived metabolites (p-cresyl sulphate and indoxyl sulphate) were enriched in IDH wt tumor tissues in relation to IDH mut, suggesting altered blood-brain barrier permeability. A machine learning classifier trained in metabolic profiles distinguished IDH status with high accuracy. Drug response profiles across 66 compounds revealed significantly higher efficacy (p < 0.05) of HDAC inhibitors (panobinostat, vorinostat), MDM2 inhibitors (AMG232, R7112) and nuclear export/mTOR inhibitors (selinexor, temsirolimus) in IDH wild-type PDCs. Importantly, drug responses aligned with metabolic signatures, indicating that metabolic context shapes therapeutic susceptibility. Our integrative approach reveals fundamental metabolic differences between IDH wild-type and mutant gliomas, and links these to differential drug responses. These findings underscore the potential of metabolism informed precision oncology strategies for glioblastomas.
Glaucoma is a leading cause of irreversible blindness worldwide, yet available treatments fail to prevent disease progression for all patients. It is characterized by a progressive dysfunction and loss of retinal ganglion cells. Neuroinflammation has been recognized as an underlying neurodegenerative mechanism of glaucoma in animal models and human post-mortem samples, and targeting neuroinflammation may provide additional means to neuroprotection. Galectin-3, a pro-inflammatory mediator encoded by the LGALS3 gene in humans, holds promise as a treatable target as its pharmacological and genetic inhibition is neuroprotective in multiple models of experimental glaucoma. However, the role of Galectin-3 in glaucoma remains unclear, particularly whether its emergence is a consequence of degeneration, or occurs at earlier time points. To address these knowledge gaps, we labeled IBA1, GFAP, and Galectin-3 in retina sections at early glaucoma stages in the rat bead glaucoma model, and in human retina from glaucoma donors. In the rat, IBA1 volume, but not GFAP, increased at an early, pre-degenerative timepoint. Accompanying this, we identified a significant increase of Galectin-3/IBA1 colocalization compared to control at the same timepoint, supporting the upregulation of Galectin-3 in early inflammation, preceding retinal ganglion cell degeneration in experimental glaucoma. However, a significant increase in Galectin-3/GFAP colocalization compared to control at the same timepoint in the rat additionally associates Galectin-3 production with astrocytes and Müller glia. This Galectin-3 to Müller glia relationship was significantly pronounced in human glaucomatous retina, predominating over microglia co-labelling. We further demonstarted that human MIO-M1 Müller glia in vitro express Galectin-3, but this is not altered in response to glaucoma relevant stimuli (TNF-α or mild-metabolic stress from rotenone). Instead, Galectin-3 expression was altered in phagocytosing states from exposure to E. coli particles, brain synaptosomes, or apoptotic neuronal debris. These findings provide further insight into Galectin-3 and gross inflammatory responses in glaucoma pathology.
