Abstract
The annual conference held by the American Society for Neural Therapy and Repair (ASNTR) is a premier venue for exchanging scientific findings and ideas for cell therapies and brain repair following injury and disease. The Society consists of leading scientists and physicians, as well as postdoctoral fellows and students, all actively engaged in research and education in the field of neural therapy and repair.
This annual conference is at the forefront of translational medicine, and the abstracts included in this volume reflect the diverse and innovative research being conducted in the field of neural therapy and repair. Topics range from disease mechanisms and basic development of stem cell therapies to clinical trials using cutting-edge technologies. With an emphasis on translation, presentations will discuss innovations in discovery as new techniques in data science and -omics emerge and lead to clinical application. The collegial exchange of ideas during our annual conferences have led to many fruitful collaborations over the years, resulting in truly pioneering discoveries in the field of neural therapy.
The 2026 annual conference is being held at the Sheraton Sand Key Resort, Clearwater Beach, Florida. Without the continued support of NIH and our private and corporate sponsors, and our members, none of this would be possible. Special thanks to our current President John Stanford, President-Elect Julien Rossignol, the 2026 Program Committee, Education Committee, Fundraising Committee, Donna Morrison, Inger Mills, and our staff for all their efforts in planning what will, without a doubt, be an exciting meeting.
Early Carvacrol Treatment Attenuates Acute Neuropathology Following Traumatic Brain Injury in Rats
1University of South Florida Morsani College of Medicine, Center of Excellence for Aging and Brain Repair, Tampa, FL 33612 USA
2Center for Neurotrauma, Multiomics & Biomarkers, Department of Neurobiology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310 USA
Traumatic brain injury (TBI) affects ~2.5 million Americans annually, with over 60,000 TBI-associated deaths reported. TBI is a leading cause of long-term disability, with ~5.3 million individuals in the United States living with persistent or late-onset TBI-related impairments. Carvacrol (CAR), a low-molecular-weight monoterpenoid abundant in oregano and Satureja species and widely used as a food additive, readily crosses the blood-brain barrier (BBB), and exhibits anti-inflammatory, anti-apoptotic, and anti-edematous properties; however, its efficacy as an early intervention for post-TBI neuropathology had not been evaluated. Male Wistar rats (250–300 g) underwent TBI using the Marmarou weight-drop model. Experimental groups included sham, TBI+vehicle, TBI+CAR (200 mg/kg, i.p.), and TBI+Satureja essential oil (SKEO) (200 mg/kg, i.p.), with treatments administered 30 min post-injury. Neurological status was measured at 4 and 24 hours post-injury using the Veterinary Coma Scale (VCS). At 24 hours post-injury, BBB permeability, edema, inflammation, oxidative stress, and cell death markers were assessed using Evans blue extravasation, Western blotting, and immunohistochemistry. Compared to sham animals, TBI significantly increased brain edema, BBB disruption, neuroinflammatory cytokines (IL-1β, TNF-α, IL-6), oxidative stress markers (MDA, ROS), and MMP-9 and NF-κB p65 levels, while reducing antioxidant capacity (SOD, T-AOC) and tight junction proteins (ZO-1, occludin, and claudin-5). TBI also enhanced apoptosis (cleaved caspase-3, Bax/Bcl-2), increased neuron-specific enolase-positive neuronal death, and worsened VCS scores. Early treatment with CAR or SKEO largely prevented or markedly reduced the development of neuropathological changes, with outcomes comparable to sham controls. CAR consistently demonstrated superior efficacy relative to SKEO across all measured endpoints, including VCS scores, likely due to greater purity and fewer constituents. These findings support CAR as a promising, inexpensive, and widely available early therapeutic intervention for acute post-TBI neuropathology. Further studies are warranted to determine whether early CAR administration confers sustained protection against chronic and late-onset TBI-related pathophysiology.
Targeting Glioblastoma via Co-delivery of Kif23 and Kif18a siRNAs Using G4 70/30 PAMAM Dendrimers
1Field Neurosciences Institute Laboratory for Restorative Neurology
2Program in Neuroscience
3Department of Psychology
4College of Medicine
5Department of Chemistry and Biochemistry, Central Michigan University, The National Dendrimer & Nanotechnology Center
6Mount Pleasant, MI, 48858, USA.
Glioblastoma (GB) is the most aggressive primary brain tumor in adults, characterized by rapid cellular proliferation, therapeutic resistance, and an exceptionally poor prognosis. Aberrant expression of kinesin motor proteins, particularly Kif23 and Kif18a, is frequently observed in GB and plays a critical role in tumor cell division, survival, and invasive behavior. RNA interference (RNAi) using small interfering RNAs (siRNAs) represents a highly specific strategy to silence these oncogenic drivers; however, its clinical translation is hindered by challenges related to siRNA instability, limited cellular uptake, and off-target toxicity. Fourth generation (G4) 70/30 poly(amidoamine) (PAMAM) dendrimers have emerged as a promising nanocarrier platform, offering efficient siRNA protection, enhanced cellular internalization, and improved brain-targeted delivery.
This study investigates the co-delivery of Kif23 and Kif18a siRNAs using G4 70/30 PAMAM dendrimers in vitro and in vivo. Dendrimer–siRNA complexes formed stable nanostructures at an optimal N/P ratio of 1.5:1 and displayed minimal cytotoxicity in normal brain astrocytes. In GL261 mouse glioma cells, co-delivery resulted in significant knockdown of BCL2 gene and upregulation of BAX, indicating increased apoptosis. Wound healing assays revealed a marked reduction in cell migration, and the expression of migration markers MMP2, MMP7, and MMP9 was reduced significantly. A GB mouse model was established via intrastriatal implantation of GL261/luc2-tdtomato cells, with tumor growth confirmed through IVIS imaging and luciferase immunohistochemistry. Kif23 and Kif18a siRNA–loaded dendrimers were administered intracranially to the tumor site, and therapeutic efficacy was evaluated by analyzing animal survival as well as molecular markers associated with proliferation, apoptosis, migration, and stemness. These findings support the use of G4 70/30 PAMAM dendrimers as a safe and effective platform for co-delivering therapeutic siRNAs, reducing GB cell migration and advancing targeted nanomedicine for glioblastoma.
Support for this study was provided by the Neuroscience program, the College of Medicine, Office of Research and Sponsored Program, the E. Malcolm Field and Gary Leo Dunbar Endowed Chair, and the John G. Kulhavi Professorship in Neuroscience at CMU.
Extracellular Vesicles from hiPSC-Derived Neural Stem Cells Mitigate Tau Pathology and Neurogenesis Impairment in PS19 Mouse Model of Tauopathy
Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University College of Medicine, College Station, Texas, USA.
Tauopathies are neurodegenerative diseases characterized primarily by the hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles within neurons. Extracellular vesicles (EVs) shed by human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) carry a cargo of miRNAs and proteins capable of promoting antioxidant, antiinflammatory, neurogenic, and neuroprotective effects, as well as inhibiting tau phosphorylation. This study investigated the efficacy of hiPSC-NSC-EVs in alleviating tau hyperphosphorylation, a hallmark of tauopathy, and hippocampal neurogenesis decline, using the PS19 mouse model. Three-month-old female PS19 mice received four intranasal doses of hiPSC-NSC-EVs (15 billion EVs per dose, administered once every two weeks over 1.5 months). After completing the treatment regimen, the animals were assessed for hippocampus-dependent cognitive function using an object location task (OLT) and episodic-like memory using a behavioral pattern separation task (PST). The untreated PS19 mice failed to form an object location memory in the OLT, and their pattern separation ability was impaired compared to the naïve control mice. In contrast, the PS19 mice that received hiPSC-NSC-EVs treatment demonstrated proficiency in forming object location memory formation and pattern separation, suggesting better maintenance of hippocampus- dependent cognitive function and episodic memory encoding. The improved brain function in hiPSC- NSC-EVs-treated PS19 mice was associated with a significant reduction in tau phosphorylation, as measured through AT8 quantification using ELISA and western blot. Furthermore, analysis of hippocampal neurogenesis, measured through 5’- bromodeoxyuridine (BrdU) labeling of newly born cells and dual immunofluorescence with BrdU and neuron- specific nuclear antigen, revealed that hiPSC-NSC-EVs-treated PS19 mice displayed higher levels of neurogenesis than untreated PS19 mice, implying better preservation of hippocampal neurogenesis processes with hiPSC-NSC-EVs treatment. Thus, intermittent hiPSC-NSC-EVs treatment commencing from the early stage of tauopathy can maintain better cognitive function for extended periods, associated with significantly reduced tau phosphorylation and improved hippocampal neurogenesis.
Impaired Mitophagy’s Relationship with Alzheimer’s Disease Pathogenesis
University of Kansa Medical Center. Kansas City, Kansas, 66160, USA
Alzheimer’s disease (AD) is a common neurodegenerative disorder marked by amyloid beta (Aβ) plaques and neurofibrillary tangles. Studies have revealed that damaged mitochondria accumulate across various AD disease models, suggesting disrupted mitochondrial quality control pathways. Mitophagy—the cellular process that removes dysfunctional mitochondria—has been shown to be impaired in AD, though its exact relationship to disease mechanisms remains unclear. This study investigates the relationship between mitophagy mechanisms and AD pathophysiology. Whole brain from 5xFAD and wild-type (WT) mice was use to collect whole cell, mitochondrial, and autophagosome components (AP). Mitochondrial DNA (mtDNA) copy number was measured from whole brain and AP fractions using qPCR. iPSC-derived cerebral organoid models were generated from both non-AD and sporadic AD (sAD) sources. These models were then separated into AP fractions and mtDNA copy number was measured using qPCR. Postmortem human brain was fractionated to collect whole cell, mitochondrial, and AP fractions from non-demented (ND) and sAD subjects. Aβ levels were measured in fractions using ELISA kits. iPSCs where used to derive neurons from ND and sAD subjects and lysosome number and autophagosome events were measured using LysoTracker and DAPRed fluorescent dyes. We observed a significant reduction in AP mtDNA content from 5xFAD mice from 2 months of age, while whole brain mtDNA was elevated in 5xFAD mice at 2 months of age but reduced at 12 months of age. Organoids derived from sAD iPSC donors also had reduced AP mtDNA content. Aβ levels were increased in whole and AP fractions in 5xFAD mouse samples, cerebral organoid models, and human postmortem brain. iPSC derived neurons from sAD donors had reduced lysosome content and autophagy events. Overall mitophagy is impaired across mouse and iPSC models of AD. Associations with Aβ pathology and other underlying mechanisms requires further investigation.
The Brain Does Not Heal Alone: Neuroplasticity and Social Context Operationalizations
1Department of Emergency Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, 33613, USA
2Department of Anthropology, College of Arts and Sciences, University of South Florida, Tampa, Florida, 33620, USA
3Department of Neurosurgery, Brain and Spine, Morsani College of Medicine, University of South Florida, Tampa, Florida, 33613, USA
Innovations in neural repair have advanced understanding of biological and psychological mechanisms underlying recovery following traumatic brain injury (TBI), yet outcomes remain variable and difficult to predict. The biopsychosocial ecological (BPSE) framework provides a comprehensive model for explaining this variability by emphasizing interactions among biological, psychological, social, and environmental processes. However, neurotrauma research has largely operationalized BPSE components in isolation, limiting insight into how these domains jointly shape neuroplasticity. This study addresses two research questions: (1) How can social context be operationalized in ways that are mechanistically meaningful for neuroplasticity research following traumatic brain injury? (2) How do biological, psychological, social, and environmental domains co-evolve during recovery from mild-to-moderate TBI? An integrative methodological approach grounded in neuroanthropology is used within an ongoing hyperbaric oxygen therapy (HBOT) study of Veterans with mild-to-moderate TBI. Biological processes are assessed using repeated electrophysiological measurements (EEG) capturing cortical function. Psychological and functional change is tracked longitudinally using global impression of change and outcomes including the Mayo Portland Adaptability Inventory (MPAI). Social and environmental processes are operationalized through position-generator social network assessments quantifying access to social roles, resources, and support embedded in recovery contexts. For analysis, social network measures are overlaid with longitudinal neurophysiological and clinical data to examine how BPSE domains interact. Drawing on neuroanthropology, social networks are conceptualized as culturally patterned systems of meaning, practice, and expectation that structure cognitive demands, shape identity reconstruction after injury, and organize participation in recovery. These socially embedded experiences constitute a cognitive ecology through which neuroplasticity is elicited and stabilized, linking social context to measurable brain function. Aligned with Innovating Neural Repair: From Lab to Life, this study advances a basic science framework for integrating BPSE principles into neurotrauma research by specifying how socially embedded experience functions as a mechanistic driver of neuroplasticity.
High-Throughput Identification of Mitochondrial-Targeted Therapeutics for Alzheimer’s Disease Using Human iPSC Neurons and Astrocytes
1University of Kansas Medical Center Department of Neurology
2University of Kansas Medical Center Medical Scientist Training Program
3University of Kansas Medical Center Cell Biology & Physiology
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Amyloid-β (Aβ) plaques, hyperphosphorylated tau (p-tau), neuroinflammation, and mitochondrial dysfunction are interconnected features of AD pathology. However, clinical trials targeting Aβ with monoclonal antibodies have shown only modest efficacy and frequent adverse effects, underscoring the need for alternative therapeutic strategies. Mitochondrial dysfunction is observed across multiple AD-relevant cell types, with neurons and glia displaying altered respiration, reduced mitochondrial membrane potential (MMP), and elevated reactive oxygen species (ROS). Here, we conducted a high-throughput screen of 583 mitochondrial-protective compounds to identify agents capable of restoring mitochondrial function in human iPSC-derived neurons and astrocytes from sporadic AD patients and sex- and age-matched non-demented (ND) controls. Mitochondrial health was assessed using Seahorse XF oxygen consumption rate (OCR) measurements, MMP and ROS probes, and mitochondrial mass assays. Primary screening identified compounds that rescued OCR deficits to within ±20% range of ND neurons and astrocytes. Secondary validation confirmed reproducibility, and prioritized hits based on improved mitochondrial parameters and reductions in AD-related phenotypes. Tertiary studies will assess dose responsiveness and evaluate top compounds in neuron-astrocyte co-cultures. Several compounds exhibited strong cell type- and sex-specific rescue profiles, revealing distinct mitochondrial vulnerabilities in AD neurons versus glia. This work provides a prioritized set of mitochondrial-targeted therapeutic candidates and highlights mitochondrial restoration as a promising avenue for drug discovery and repurposing in AD and related neurodegenerative diseases.
Spinning Bioreactor Growth Method Allows for Faster Midbrain Organoid Maturation
1Gateway Institute for Brain Research, Davie, FL 33314, USA
In the amount of time that it takes to grow mature midbrain organoids, roughly 410,000 people will be diagnosed with Parkinson’s disease (PD) globally. Most midbrain organoid growth protocols require upwards of 100 days for organoids to display the midbrain dopaminergic phenotype. This time requirement for 3D modelling of Parkinson’s disease slows the progress of finding a cure. Given this obstacle, we sought to compare two different Induced Pluripotent Stem Cell (iPSC)-derived midbrain organoid growth protocols. Using PD patient and healthy control iPSC lines, we investigated a plate-based growth protocol (PB) and a spinning bioreactor (BR) protocol. Samples were collected at various time points throughout each protocol and used for transcriptomics, dopamine quantification, and electrophysiology. The BR midbrain organoids had peak expression of the following dopaminergic markers by day 31: Dopamine Receptor D1 (DRD1), Dopamine Receptor D2 (DRD2), DOPA Decarboxylase (DDC), Tyrosine Hydroxylase (TH), and Alpha-synuclein (SNCA). Conversely, the PB midbrain organoids did not develop peak expression of the same markers until day 80. Dopamine levels followed a similar trend, there was a significant increase in dopamine production occurring around day 54 for PB and day 31 for BR midbrain organoids when compared to baseline iPSCs. We further characterized the BR protocol by growing organoids on Microelectrode array (MEA) plates and recorded spontaneous electrical activity. The BR midbrain organoids developed complex network bursting as early as day 37. Given our findings, we have concluded the spinning bioreactor protocol produces an enhanced organoid-based model for Parkinson’s disease.
Modulating Microglial and Monocyte/Macrophage Responses in Chronic Traumatic Brain Injury: Transcriptomic insights into SCF+G-CSF-induced Brain Repair
Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA
Previous studies have demonstrated that combined treatment with stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) enhances brain repair and functional recovery during the chronic phase of severe traumatic brain injury (TBI). However, the mechanism underlying SCF+G-CSF-mediated repair remains unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) to identify SCF+G-CSF-induced transcriptomic alterations in brain immune cells in chronic severe TBI. In a controlled cortical impact mouse model of severe TBI, SCF+G-CSF was administered subcutaneously for 5 consecutive days beginning at 8 months post-injury. CD11b-positive brain cells, comprising microglia and monocytes/macrophages (Mo/Mac), were isolated one day after the final injection for scRNA-seq analysis.
Analyses performed using both the Seurat R package and Partek Flow revealed that SCF+G-CSF exerted a more pronounced effect on Mo/Mac than on microglia. Flow cytometry confirmed this observation by demonstrating an increased CD11b+/CD45high Mo/Mac population following treatment. In microglial clusters, genes such as S100a8, S100a9, Mir682, and Rpl37rt were modestly upregulated. In contrast, Mo/Mac clusters exhibited robust upregulation of genes, including Wfdc17, Ifitm1/2/3, Tspo, Lrg1, and Igfbp6, following treatment. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified interleukin-17 (IL-17) signaling as a central mediator. Additionally, SCF+G-CSF upregulated genes involved in protein synthesis machinery and detoxification processes, while also promoting glial cell development and astrocyte differentiation.
These findings indicate that SCF+G-CSF reprograms brain CD11b+ cells toward reparative phenotypes, generating a microenvironment supportive of chronic TBI repair. Collectively, this work uncovers previously unrecognized immunomodulatory mechanisms of SCF+G-CSF and lays the groundwork for targeted therapeutic strategies, opening new avenues for enhancing recovery from chronic TBI.
This study was supported by the NIH/NINDS (R01NS118166).
Periodic Treatment of Extracellular Vesicles from Human iPSC-derived Astrocytes Can Restrain Neuroinflammation and Maintain Better Brain Function in a Model of Alzheimer’s Disease
Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University Naresh K. Vashisht College of Medicine, College Station, TX 77840, USA.
Alzheimer’s disease (AD) is a progressive disease where dementia symptoms worsen over several years. Neuroinflammation plays a crucial role in the development and progression of AD. Extracellular vesicles (EVs) shed by human-induced pluripotent stem cell (hiPSC)-derived astrocytes (hA-EVs) could be a promising therapeutic approach for neuroinflammation in AD, as they carry anti-inflammatory molecules. This study examined the efficacy of multiple intranasal (IN) administrations of hA-EVs, purified through chromatographic methods from cultures of hiPSC-derived astrocytes, for reducing neuroinflammation and maintaining better cognitive function for extended periods in 5xFAD mice. Three-month-old 5xFAD female mice received IN administrations of hA-EVs (30 x 10^9 EVs) or the vehicle (once monthly for 5-months). A month after the final dose of EVs, brain function wes assessed through a series of neurobehavioral tests, and animals were euthanized for brain tissue harvesting and quantification of markers of neuroinflammation and amyloid plaques. 5xFAD mice receiving monthly treatment to hA-EVs displayed improved proficiency to discern minor changes in the environment in an object location test, object recognition memory in a novel object recognition test, and associative recognition memory in an object in place test, compared to 5xFAD mice receiving vehicle treatment. Brain tissue analyses revealed that 5xFAD mice receiving hA-EVs exhibited reduced microglial clusters, astrocyte hypertrophy, and NLRP3 inflammasome complexes within microglia in the hippocampus, compared to vehicle-treated 5xFAD mice. 5xFAD mice receiving hA-EVs also displayed significant reductions in concentrations of mediators (NLRP3, ASC, and cleaved caspase-1) and end products (IL-1β and IL-18) of NLRP3 inflammasome activation. Additionally, the concentrations of proteins linked to the activation of cGAS-STING signaling, such as phosphorylated STING and interferon-alpha, were reduced. The results suggest that periodic IN administrations of hA-EVs can maintain better brain function for prolonged periods in an early-onset model of AD by significantly restraining the progression of neuroinflammation.
Single nucleus RNA sequencing identifies early transcriptional changes to midbrain and striatum neuronal populations following the selective loss of tyrosine hydroxylase in adult rat midbrain dopaminergic neurons
Intramural Research Program, National Institute on Drug Abuse, Baltimore MD 21224
Parkinson’s disease (PD) is the 2nd most common neurodegenerative disease, characterized by disruptions to motor function such as tremors and rigidity. A hallmark of PD pathology is loss of dopaminergic neurons in the substantia nigra (DANs), and subsequent dysregulation of dopamine signaling. By the time patients present with motor symptoms, they have already lost on average 50-60% of their dopaminergic neurons in the SN, meaning that dopaminergic degeneration can be occurring for years, if not decades prior to diagnosis. Studying the early consequences of dopamine loss is critical to understanding mechanisms of disease progression and identifying biomarkers for earlier diagnosis. While many models of PD seek to mimic the disease progression through transgenic animals that express PD relevant genetic mutations or are deficient in dopaminergic neuron function, they do not account for the possibility of developmental compensation, which may not accurately recapitulate the phenotype of sporadic PD, which occurs in late-stage adulthood. With this in mind, we aimed to study the early transcriptional changes that occur after adult loss of dopamine signaling. We knocked down tyrosine hydroxylase (TH), a protein required for dopamine synthesis, in the adult rat midbrain through injection of TH specific guide RNAs into transgenic rats expressing Cas9 nuclease specifically in dopamine transporter positive neurons and performed single nucleus RNA sequencing on midbrain and dorsal striatum samples two weeks after injection. Our data identified alterations to genes involved in synaptic signaling, organization, and function in both midbrain and striatal neuron populations. This data demonstrates that disrupting dopamine signaling has detectable transcriptional consequences on a variety of neuronal populations prior to total neuron degeneration and may provide new insights into the early cellular changes that occur in Parkinson’s disease.
Development of Citrate-Based Bioresorbable Flow Diverters for Intracranial Aneurysm Therapy
1Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA
2Biomedical Engineering Department, University of Florida, Gainesville, FL 32608, USA
3Biomedical Engineering Department, Northwestern University, Evanston, IL 60208, USA
4Mechanical Engineering Department, Northwestern University, Evanston, IL 60208, USA
Intracranial aneurysms affect ~6.8 million Americans, with ~30,000 annual ruptures causing subarachnoid hemorrhage and high morbidity. Current metallic flow diverters promote occlusion but require permanent implantation, leading to chronic inflammation, in-stent thrombosis, and prolonged antiplatelet therapy. Citrate-based polymers offer a biocompatible alternative to metallic implants, enabling bioresorbable flow diverters (BFDs) with tunable degradation, antioxidant properties, and native endothelial support. This has been demonstrated in orthopedic and peripheral vascular applications but untested in neurovascular contexts. This study hypothesizes that citrate-based BFDs fabricated from methacrylated poly(1,8-octanediol-co-citrate) (mPOC) and methacrylated poly(1,12-dodecanediol citrate) (mPDC) will match the mechanical performance of metallic flow diverters while enabling endothelial repair and safe resorption. Methods encompass fabrication of BFD variants via stereolithographic 3D-printing with varied porosity and strut geometry to evaluate structural similarity to metallic devices and iteratively optimize strut design for matching force properties. Mechanical characterization will include testing of radial force, fatigue resistance, and flexibility using Instron testing, plus degradation kinetics in pulsatile PBS flow over 12 weeks. Endothelial and smooth muscle cell responses including adhesion, ICAM-1 expression, and IL-6 secretion will be assessed on BFDs versus metallic controls under static and dynamic flow conditions. Optimized BFDs will be implanted in a murine elastase-induced aneurysm model for 4, 8, and 12 weeks, evaluating healing via CD31, F4/80, and α-SMA immunohistochemistry alongside inflammation and polymer resorption. Expected outcomes include BFDs demonstrating superior endothelialization with reduced inflammation compared to metallic devices, and >50% resorption by 12 weeks, The eventual goal of the study is to define design parameters to facilitate clinical translation while mitigating long-term implant risks
Investigating Golgi apparatus morphology in dopaminergic neurons of the rat midbrain
Intramural Research Program, National Institute on Drug Abuse, Baltimore MD 21224
The Golgi apparatus plays a central role in the modification, sorting, and trafficking of proteins, lipids, and carbohydrates within cells. Although dopaminergic neurons possess distinct functional properties, the morphology of the Golgi apparatus in these neurons has not been systematically characterized. Preliminary observations from our laboratory suggested that dopaminergic neurons may exhibit unique Golgi structure compared to other midbrain cell types. The objective of this study was to describe and quantify Golgi apparatus morphology in dopaminergic neurons of the rat midbrain, with an emphasis on regional differences between the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). Dopaminergic neurons were identified by tyrosine hydroxylase (TH) expression, and Golgi structure was visualized using the cis-Golgi marker GM130. Golgi volume was quantified and compared between TH-positive and TH-negative cells across midbrain regions. Our results demonstrate that TH-positive neurons in the SNc exhibit significantly larger Golgi volume compared to TH-negative cells in the midbrain. Furthermore, Golgi volume in TH-positive neurons appears to be significantly greater in the SNc than in TH-positive neurons in the VTA. No significant differences in Golgi volume were observed between TH-positive neurons in the VTA and TH-negative cells. These findings reveal region-specific differences in Golgi morphology among dopaminergic neurons and suggest that SNc neurons may have increased secretory or membrane trafficking demands. Ongoing studies aim to further characterize Golgi structure across additional neuronal and glial populations and to examine how Golgi morphology is influenced by neuronal activity, Parkinson’s disease risk factors and psychostimulant exposure.
Adropin Reduces Early Brain Injury and Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage in a Mouse Model
1University of Florida College of Medicine, Department of Neurosurgery, Gainesville, Florida, 32611, USA
2University of Florida, Gainesville, Florida, 32611, USA
3Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Florida, 32610, USA
4Department of Pharmacology and Physiological Sciences, Saint Louis University, Saint Louis, MO 63104, USA
Psilocybin Alleviates Chronic Stress-Mediated Cognitive and Mood Impairments
Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University College of Medicine, College Station, Texas, USA.
Major Depressive Disorder (MDD) affects over 280 million individuals globally and remains a leading cause of disability worldwide. Approximately 30-40% of patients with MDD exhibit treatment-resistant depression and fail to respond to standard pharmacological therapies. Psilocybin (PS), a 5-hydroxy tryptamine 2A (5-HT2A) receptor agonist, has been effective in promoting rapid antidepressant effects in early-phase clinical trials. PS modulates large-scale neural networks involved in emotional regulation and executive function, such as the default mode network and hippocampal-prefrontal circuitry. To investigate the efficacy of PS in preventing chronic stress-mediated MDD, we developed a rat model of chronic stress that exhibits cognitive and mood deficits akin to that observed in MDD. Wistar rats were subjected to 6 hours of restraint stress per day for 21 consecutive days. Psilocybin (1 mg/kg, oral) was administered five times, with three doses delivered on chronic stress days 7, 14 and 21 and three doses thereafter on post-stress days 7 and 14. Following the completion of the treatment, animals were assessed using a battery of neurobehavioral tests designed to evaluate both hippocampus-dependent cognitive function and affective symptoms relevant to MDD, including anhedonia, and anxiety-like behavior. PS treatment significantly improved hippocampus-dependent cognitive function in an object location test (OLT) and recognition memory function in a novel object recognition test (NORT), compared to chronically stressed rats receiving vehicle treatment, which exhibited impairments. In the Sucrose Preference Test, PS-treated chronically stressed rats spent preferred sucrose to water compared to the chronically stressed vehicle group that could not distinguish between sucrose and water. Similarly, improvements were observed in the Novelty Suppressed Feeding Test suggesting a reduction in anxiety-like behavior and anhedonia. Brain tissues analysis shows that microgliosis and astrocyte hypertrophy may be mitigated by PS treatment. These findings suggest that psilocybin has the potential to prevent chronic stress-mediated MDD.
Modulation of Neural Plasticity Improves Cognitive Performance in Aging and Neurodegeneration
Institute of Experimental Medicine, Czech Academy of Sciences, Vídeňská, 1083 14200 Prague, Czech Republic
Cognitive decline in aging and neurodegenerative disease is increasingly viewed as a consequence of constrained neural plasticity rather than irreversible neuronal loss alone. Key contributors to these constraints include excessive accumulation of perineuronal nets (PNNs), which limit synaptic remodeling, and chronic neuroinflammation, which further destabilizes circuit function. Understanding how these mechanisms interact across physiological aging and tauopathy remains incomplete. Here, we examined the impact of sustained modulation of extracellular matrix–associated plasticity constraints in two complementary models: natural aging and P301S tauopathy. Aged mice (20–22 months) received long-term oral administration of 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis and a core structural component of PNNs, while P301S mice were treated for one month followed by a washout period. Cognitive performance was assessed using recognition memory paradigms, and histological analyses focused on PNN density, glial reactivity, immune cell infiltration, and tau pathology. Aging was associated with pronounced accumulation of PNNs and increased astrocytic and microglial activation across cortical and hippocampal regions, coinciding with impaired recognition memory. Long-term 4-MU administration normalized PNN abundance and attenuated neuroinflammatory markers, paralleling improved cognitive performance. In P301S mice, short-term 4-MU treatment reduced PNN density in the brain and spinal cord and led to sustained improvements in recognition memory that persisted beyond treatment cessation, despite the continued presence of tau aggregates. Together, these findings support a mechanistic framework in which excessive extracellular matrix stabilization and neuroinflammatory signaling act as convergent constraints on circuit plasticity in both aging and tauopathy. Modulating these constraints is sufficient to improve cognitive function without directly targeting disease-specific protein pathology.
Multi-color 19F MR imaging of immune cells infiltrating ECM hydrogel implanted into a stroke cavity
A. Kisel1, N. Didwischus1, G. Hussey2, T. K. Hitchens3, K. Tang4, E.T. Ahrens4, and
1Department of Radiology, University of Pittsburgh
2Department of Surgery, University of Pittsburgh
3Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
4University of California San Diego, Department of Radiology, California, USA
The infiltration of immune cells after implantation of an extracellular matrix (ECM) hydrogel in a stroke cavity is essential for its structural remodeling and eventual replacement by de novo tissue. To map this dynamic process, ideally both the immune cell infiltration and ECM scaffold are visualized non-invasively over time. Multi-color 19F magnetic resonance imaging (MRI) permits the separate visualization of different perfluorocarbon (PFC) molecules, such as perfluoro-tert-butyl-cyclohexane (PFTBC) and perfluoro-15-crown-5-ether (PFCE). Tagging of blood circulating myeloid cells, such as macrophages, was achieved using a systemic tail vein injection of PFCE nanoemulsions during the implantation of PFTBC-labeled ECM hydrogel into the tissue cavities caused by a middle cerebral artery occlusion (MCAo) stroke. The distribution of PFTBC-ECM hydrogel was visualized using 19F MRI and demonstrate complete coverage of the tissue defect 1-day post-implantation, as well as a gradual degradation at days 2, 6, 7, and 14 post-implantation. PFCE-labeled immune cells were observed on 19F MRI to invade through the peri-infarct tissue into the bioscaffold. At 7 days, labeled cells were distributed throughout the remnants of the scaffold. Over the same time period, conventional 1H T2-weighted MRI revealed a transformation of the hyperintense tissue cavity into an isointense tissue, suggesting that immune cell-mediated remodeling of the ECM hydrogel implant produced a new tissue. Overall, spatio-temporal mapping using multi-color 19F MRI offers unique insights into the interactions between immune cells and bioscaffolds in tissue regeneration and improves our mechanistic understanding of these processes prior to clinical translation.
Workshop Title: Medical Anthropology, Artificial Intelligence, and Neural Therapy and Repair
1Department of Anthropology, College of Arts and Sciences, University of South Florida, Tampa, Florida, 33620, USA
2Bellini College of Artificial Intelligence, Cybersecurity, and Computing, University of South Florida, Tampa, Florida, 33620, USA
3Department of Emergency Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, 33613, USA
This workshop will introduce participants to medical anthropology, neuroanthropology, and AI-driven clinical anthropology. Anthropology offers a comparative approach to the study of people using data ranging from human biology to social, cultural, and economic systems, and matches well with biopsychosocial ecological frameworks.
The workshop will take participants through (1) how medical anthropology and neuroanthropology connect with basic science around neural therapy and repair, (2) how these biosocial approaches help to investigate the neural and social factors that impact clinical and translational outcomes, and (3) how anthropology can combine with AI to facilitate interdisciplinary efforts in clinical trials and beyond. Overall, this workshop aims to show how the combination of interdisciplinary approaches with AI technologies can help with research, collaboration, and generating real-world impact.
The uses of medical anthropology and neuroanthropology will be illustrated through three different examples: (1) a clinical study of Veterans with mild-to-moderate TBI examining the impact of hyperbaric oxygen therapy, (2) applied research on how neurorehabilitation works in practice to foster improved patient outcomes, and (3) combining qualitative and AI methodologies to examine chronic pain.
AI is rapidly entering into multiple domains of work, research, and dissemination. This workshop will take participants through key principles of working with AI, cover how the tools of AI can help with research tasks, and how to work with AI to address complex and localized tasks within institutional settings. Throughout the workshop, we will cover basic uses of AI for research (including navigating problems with hallucinations). We will also address (1) differences between general-purpose AI models such as ChatGPT and lower-parameter AI models that can be run locally and (2) how to use AI for automating research or job tasks while including humans in the loop for both design and verification.
The Use of DCS as a Predictive Model for the Development of DCI Following aSAH – Preliminary Experience
1Department of Neurosurgery, Brain and Spine, University of South Florida, Tampa, FL 33606
2Tampa General Hospital, Tampa, FL 33606
3College of Electrical Engineering, University of South Florida, Tampa, FL 33606
Delayed cerebral ischemia (DCI) remains the leading cause of morbidity and mortality in patients with subarachnoid hemorrhage (SAH). DCI results in focal neurological deficits in 30-50% of patients within 4-10 days following aneurysm rupture. Given the shortcomings of the current technologies in identifying Delayed Cerebral Ischemia (DCI) (mainly transcranial dopplers), the current study employed the use of non-invasive optical measurements of cerebral blood flow (CBF) using a custom-built diffuse correlation spectroscopy (DCS) device. This research is supported by a R01 NINDS funding mechanism.
We preformed daily bilateral cerebral blood flow measurements using a custom built DCS device in twelve patients following aneurysmal SAH until discharge from our facility. Daily collection of transcranial doppler readings, NIHSS and GCS scores, in conjunction with other relevant clinical and angiographic procedural data were collected daily from admission until day 14 (or later if the patient remained symptomatic). In patients who underwent intra-arterial vasospasm treatment in the angio suite, DCS recordings were obtained immediately before, after, and throughout the infusion.
Recordings were successfully obtained in twelve patients. No safety concerns or interference with standard workflow procedures were noted. Correlation of daily DCS measurements with changes in clinical exam and occurrence of DCI are being finalized and prepared for the ASNTR conference.
Preliminary analysis have demonstrated that the use of DCS optical measurements is safe and effective in the clinical setting with minimal interruptions to standard clinical operations. By enabling continuous, individualized assessment of cerebral perfusion, this approach directly supports translational neural therapy and repair by informing intervention timing, monitoring treatment response, and improving clinical decision-making after aSAH.
Stem cell factor and granulocyte colony-stimulating factor treatment increases oligodendrocyte progenitors and enhances remyelination in the chronic phase of severe traumatic brain injury
Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
Severe traumatic brain injury (TBI) results in long-term white matter degeneration and persistent neurological deficits, with progressive demyelination serving as a major pathological driver. Chronic TBI is characterized by a sustained loss of oligodendrocyte progenitor cells (OPCs), leading to insufficient endogenous remyelination. In this study, we investigated whether combined treatment with stem cell factor and granulocyte colony-stimulating factor (SCF+G-CSF) administered during the chronic phase of severe TBI promotes white matter repair by generating new myelin from OPC-derived oligodendrocytes. Young adult mice were subjected to controlled cortical impact-induced severe TBI and subsequently received subcutaneous SCF+G-CSF or vehicle injections for 7 days, beginning 3 months post-injury. Sham-operated mice served as healthy controls. SCF+G-CSF treatment significantly increased OPC density and proliferation in the ipsilateral corpus callosum and external capsule, reversing chronic OPC loss. Furthermore, lineage tracing using NG2-Cre: ROSAmT/mG reporter mice demonstrated that SCF+G-CSF markedly enhanced newly formed OPC-derived myelin (mG+/MBP+) in the ipsilateral white matter, whereas TBI-vehicle control mice showed minimal mG+/MBP+ colocalization. Collectively, these findings provide direct evidence that SCF+G-CSF treatment enhances remyelination via OPC-derived oligodendrocytes, contributing to structural white matter repair during chronic TBI. This study highlights a regenerative therapeutic strategy with potential for long-term repair following severe TBI.
This study was supported by the NIH/NINDS (R01NS118166).
Intranasal delivery of small extracellular vesicles derived from human adipose tissue is a potential therapy for traumatic brain injury
Center of Excellence for Aging and Brain Repair, Departments of Neurosurgery and Brain Repair and Molecular Pharmacology & Physiology, University of South Florida; James A Haley VA Hospital
Traumatic brain injury (TBI) results from rapid acceleration, deceleration, or impact and affects over 2 million people annually in the United States each year. Despite the high prevalence, effective therapeutic interventions are limited and to address this issue, our lab investigates the use of small extracellular vesicles (sEV) derived from human adipose tissue (hASC) as a potential therapy for TBI. Previous research has demonstrated therapeutic efficacy of sEVs across various disease models, including TBI. Our lab has previously shown that treatment at 48 hours post injury significantly improves motor and cognitive outcomes. However, the primary objective of this study is to extend the therapeutic window to seven days post injury, a clinically relevant time-point given that many patients are unable to receive treatment within the acute phase. Additionally, we examine potential sex-specific responses to treatment, as biological differences between males and females may influence injury progression and therapeutic efficacy. To model TBI, mice were anesthetized and placed on a stereotaxic frame and receive either sham surgery or a controlled cortical impact. Baseline motor asymmetry was assessed using the elevated body swing test (EBST), after which animals were placed evenly based on bias into four groups: Sham+PBS, Sham+sEV, TBI+PBS, and TBI+sEV. After injury, mice underwent behavior of catwalk gait analysis and EBST. Seven days post injury(dpi), sEVs or PBS were administered intranasally. Behavioral assessments were repeated and cognitive performance was evaluated using radial arm water maze and novel object/place recognition. Molecular and immune-related changes were assessed using flow cytometry, with a focus on sex- and treatment-dependent effects. Our results demonstrated that sEV administration at seven days post-injury significantly improves motor and cognitive function and reduced brain injury in both male and female mice, supporting the feasibility of extending the therapeutic window for TBI treatment.
Systemic Inhibition of Hyaluronan Synthesis as a Strategy for Neural Repair after spinal cord injury
Institute of Experimental Medicine, Czech Academy of Sciences, Vídeňská, 1083 Prague 142 20, Czech Republic
Spinal cord injury (SCI) induces upregulation of chondroitin sulfate proteoglycans (CSPGs) in the glial scar and perineuronal nets (PNNs), which restrict axonal regeneration and neural plasticity. 4-Methylumbelliferone (4-MU) is a small molecule inhibitor of hyaluronan (HA) synthesis that has been proposed as a potential therapeutic agent for neurological diseases, but its effects in SCI and systemic impact remain underexplored.
In uninjured rats, eight weeks of oral 4-MU (1.2 g/kg/day) reduced spinal HA and downregulated chondroitin sulfate glycosaminoglycans (CS-GAGs), demonstrating effective extracellular matrix modulation under physiological conditions. To evaluate therapeutic potential in chronic SCI, rats received oral 4-MU starting six weeks after thoracic contusion injury, combined with rehabilitation. 4-MU reduced astrocytic HA synthesis around the lesion, attenuated astrogliosis, and promoted axonal sprouting, including enhanced serotonergic fibre growth into the ventral horn. Higher 4-MU dosing (2 g/kg/day) additionally enhanced extracellular matrix remodelling, vascularisation, and M2 macrophage/microglia infiltration, increased excitatory synapse density, and was associated with improved sensorimotor function.
Systemic effects of long-term 4-MU were assessed in healthy rats treated for ten weeks followed by a wash-out period. Treatment induced widespread HA and CSPG downregulation, transient increases in circulating bile acids, blood glucose, total protein, and elevated interleukins IL-10, IL-12p70, and IFN-γ, all of which fully normalized after wash-out.
These findings demonstrate that oral 4-MU creates a plasticity-permissive environment and supports structural and functional improvement after chronic SCI, with reversible systemic effects, highlighting its potential as a translational therapeutic strategy.
Development of cell-responsive Granular Hydrogels for brain repair after Stroke
Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV, 89154, USA.
Ischemic stroke results in extensive neuronal and vascular damage driven by inflammation, tissue loss, and limited endogenous regeneration. Biomimetic hydrogel biomaterials have emerged as promising strategies to support tissue repair after injury. We have recently developed injectable spherical hydrogel building blocks (microgels) capable of annealing upon contact to form microporous scaffolds with microscale interconnected pores that facilitate cell infiltration into the implant. Our preliminary in vivo data show that injecting microgels into the stroke cavity reduces local inflammation by disrupting the astrocytic scar architecture and reducing microglia activation. However, existing annealing chemistries primarily rely on enzymatic annealing or irreversible covalent bonding, which is limited by enzyme diffusion, batch-to-batch variability, and the formation of static networks that fail to adapt to the dynamic post-stroke environment. To address these limitations, we propose to develop a next-generation granular hydrogel platform based on
Cross-Cohort Blood Gene Signature Linked to 90-Day Stroke Recovery
1Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV, 89154, USA.
2Nevada Institute of Personalized Medicine (NIPM), University of Nevada, Las Vegas, NV, 89154, USA.
Functional recovery after ischemic stroke is influenced by early systemic responses, reflected in peripheral blood transcriptomic changes, yet few human transcriptomic signals reliably predict outcome. We hypothesize that an early, conserved suppression of adaptive immune signaling in peripheral blood represents a reproducible post-stroke transcriptional response, and that greater magnitude and persistence of this suppression predict poor functional recovery at 90 days. To test this hypothesis, we applied a covariate-aware meta-analytic framework to whole-blood microarray data from three independent Gene Expression Omnibus (GEO) stroke cohorts. This approach enabled identification of robust, directionally consistent differentially expressed genes (DEGs) while accounting for available clinical variables, including age, sex, and comorbidities. Across cohorts, we identified 33 genes consistently downregulated after stroke, associated for adaptive immune and lymphocyte signaling, forming a compact cross-platform candidate panel. To assess relevance to long-term recovery, we compared these genes to published data on acute outcome-associated DEGs and co-expression hub genes linked to 90-day modified Rankin Scale (mRS) scores. Our candidates overlapped with published outcome-associated DEGs at 3 h (9 genes), 5 h (12 genes), and 24 h (3 genes), and with co-expression hub genes at 3 h (5 genes) and 24 h (4 genes). Recurrent overlapping genes included key lymphocyte signaling mediators (ZAP70, SKAP1, PLCG1, UBASH3A), B-cell receptor components (CD79A, CD79B), and immune regulators (CXCR5, P2RY10), supporting a conserved early suppression of adaptive immune signaling associated with poorer recovery trajectories. This cross-cohort approach builds on prior single-cohort studies by focusing on signals that are consistent across datasets and validated against independent outcome measures. These findings point to immune network nodes that may affect recovery through ongoing immune–brain interactions that limit repair. Ongoing work will use cell-type–aware deconvolution and integrated epigenomic and proteomic analyses to link peripheral immune signals to neurorepair pathways and to test their ability to predict long-term recovery and rehabilitation response.
Targeting CCL20–CCR6 Limits Microglial Synaptic Pruning in rTBI
K. Mayilsamy1,2, A. Willing4, S.S. Mohapatra1,3 and
1James A Haley VA Hospital, Tampa, FL, USA
2Department of Molecular Medicine
3Department of Internal Medicine
4Department of Neurosurgery, Brain and Spine, Center of Excellence for Aging and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
Repetitive traumatic brain injury (rTBI) induces a long-lasting, self-perpetuating neuroinflammatory state marked by chronically activated microglia, persistent cytokine release, complement dysregulation, and progressive neurodegeneration. This is especially concerning in high-risk groups such as contact-sport athletes and military personnel, where repeated impacts are associated with enduring cognitive and psychological impairment. Following rTBI, the brain frequently transitions into a chronic inflammatory milieu driven by sustained production of pro-inflammatory cytokines.
A key mediator of this prolonged immune response is C-C motif chemokine ligand 20 (CCL20), which signals through its sole receptor, CCR6. CCR6 is expressed on Th17 cells, dendritic cells, B cells, and other immune populations, and CCL20 serves as a potent activator of glial cells, thereby amplifying neuroinflammation after TBI. In our previous rTBI mouse study, we showed that CCL20 significantly contributes to neurodegeneration, gliosis, and retinal injury, while concurrently suppressing brain-derived neurotrophic factor (BDNF).
Building on that work, our new findings demonstrate that prolonged upregulation of CCL20, persisting up to 30 days after rTBI, disrupts synaptic architecture, indicating a broader and more enduring role for CCL20 in rTBI-induced synaptic pathology. We additionally observed sustained activation of complement components, including C1q in the brain and C5a in serum, up to 30 days post-injury, underscoring the contribution of chronic complement signaling to synaptic loss.
Importantly, rTBI mice treated with shCCL20-CCR6 dendriplexes (DPX, a nanoparticle- mediated RNA therapy) showed markedly reduced expression of CCL20 and CCR6, accompanied by decreased glial activation (IBA1 and GFAP), reflecting attenuation of neuroinflammation. This reduction was associated with improved expression of synaptophysin, NMDAR2, and PSD95, indicating better preservation of pre- and postsynaptic structures. Behaviorally, shCombo-DPX treatment mitigated rTBI-induced anxiety-like phenotypes and improved cognitive performance 30 days after injury. Serum biomarkers of injury and inflammation, including GFAP and C5a, were also reduced, indicating that therapy lessens both CNS and systemic inflammatory responses.
Together, these findings support a model in which microglia, an important source of CCL20 under pathological conditions such as rTBI, drive synaptic pruning and synapse-specific degeneration. Although CCL20 does not directly dismantle synapses, it promotes a neuroinflammatory environment that heightens microglial reactivity and accelerates complement-mediated synaptic elimination. Overall, our results identify downregulation of CCL20–CCR6 signaling as a promising therapeutic strategy to reduce detrimental microglial responses and synaptic pathology after rTBI.
uPAR Expression and Disease Associated Microglial Transcripts Are Increased in Mice with Alzheimer’s Disease-like Pathology
1Wisconsin National Primate Research Center, University of Wisconsin–Madison, Madison, WI, 53715, USA
2Wisconsin Institute for Discovery, University of Wisconsin–Madison, Madison, WI, 53715, USA
3Cellular and Molecular Pathology Graduate Program, University of Wisconsin–Madison, Madison, WI, 53705, USA
4Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, Madison, WI, 53705, USA
5Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin–Madison, Madison, WI, 53792, USA
6Department of Biomedical Engineering, University of Wisconsin–Madison, Madison, WI, 53706, USA
7Department of Medical Physics, University of Wisconsin–Madison, Madison, WI, 53706, USA
The urokinase-type plasminogen activator receptor (uPAR) is a cell surface protein that regulates proteolysis, cell adhesion, and immune signaling. In the central nervous system, uPAR is expressed across multiple cell types during neurodevelopment, neuronal injury responses, and neuroinflammation, including in Alzheimer’s disease (AD) brains. However, progression of uPAR expression in AD and its relationship with immune condition remains incompletely defined. Here, we systematically characterized the age-, sex-, brain region-, and immune status-dependent expression of uPAR in mouse models of AD pathology and assessed its relationship with microglial senescence transcripts. Coronal brain sections from immunocompetent C57BL/6J (WT) and 5xFAD mice, as well as immunodeficient Rag2/Il2rg-/- (Rag) and Rag2/Il2rg-/--5xFAD (Rag-5xFAD) mice, were immunostained for uPAR and analyzed across cortical, hippocampal, striatal, and thalamic regions at 2, 4, and 6 months of age. uPAR-ir (immunoreactivity) was significantly influenced by age, sex, brain region, and immune status. While uPAR levels were comparable across genotypes at 2 months, 5xFAD and Rag-5xFAD mice exhibited robust age-dependent increases, with Rag-5xFAD mice demonstrating an accelerated accumulation. Female mice showed earlier and greater increases in uPAR than males. At the cellular level, uPAR expression was most prominent in glia-like cells and strongly enriched in Iba1-ir microglia, particularly those clustered around amyloid-β plaques, with the subiculum exhibiting the earliest and highest regional accumulation. Limited but consistent uPAR-ir was also observed in select neuronal populations, matching prior reports of context-dependent neuronal uPAR expression. Bulk RNA sequencing of Rag-5xFAD brains revealed upregulation of innate immune, phagocytosis, and disease-associated microglia (DAM) transcriptional programs, with modest changes in Plaur transcript abundance. These findings identify uPAR as a marker of glial populations undergoing transcriptional and functional changes associated with a DAM-like state in AD-pathology mouse models and indicate that adaptive immune deficiency accelerates the accumulation of uPAR+, DAM-like glial populations in AD-like mice.
Effect of APOE4 iPSC derived astrocytes on blood brain barrier integrity and amyloid clearance
1Nanoscience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL 32826, USA
2Hesperos, Inc. 3459 Progress Dr. Orlando, FL. 32826, USA
Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which amyloid-β (Aβ) peptide accumulation in the central nervous system is a dominant pathological hallmark pivotal to the progression of AD. While the exact mechanisms of Aβ are not fully understood, the blood brain barrier (BBB) clears around 85% of all Aβ through the low-density lipoprotein receptor-related protein 1 (LRP1). Apolipoprotein E ε4 (APOE4) gene is the strongest AD genetic risk factor that actively participates in the pathogenesis of AD. This research utilized an iPSC-derived microphysiological BBB model to investigate the effect of APOE4 variant expressed in astrocytes on BBB integrity, function, and clearance mechanisms. Astrocytes differentiated from both APOE2/3 and AD-like APOE4/4 iPSC lines were integrated into the BBB model, which was established by co-culturing astrocytes with iPSC-brain microvascular endothelial cells (BMECs) separated by a synthetic membrane under a microfluidic condition. The identity of the cells forming BBB as well as the expression of efflux and influx transporters in the model were characterized by immunocytochemistry. BBB barrier integrity, permeability, and nutrient transport function were analyzed by Trans-endothelial electrical resistance (TEER) measurements, Fluorescein Isothiocyanate (FITC)-Dextran 70kDa permeability assessment, and facilitative glucose transporter GLUT-1 assays respectively. To analyze the amyloid clearance function, the systems were dosed with varying concentrations of Aβ42 monomers and oligomers on the CNS or PNS side of the BBB for 24 hours, and the transported amyloid was quantified with ELISA. A significantly lower TEER and GLUT-1 transport was observed in the APOE4/4 system compared with the APOE2/3 variant condition. The CNS-to-PNS clearance of Aβ42 in the APOE4/4 systems was reduced compared with those in APOE2/3 conditions even when the TEERs maintained similar to controls. This research contributes to the understanding of AD pathogenesis while providing a drug evaluation platform for future toxicity & effectiveness studies.
A Bioluminescent Kinase Sensor (Blinks) Platform for Monitoring and Controlling Neuroinflammation
1CMU Biochemistry, Cell and Molecular Biology Program
2CMU College of Medicine
3CMU Neuroscience Program
Chronic inflammation underlies numerous pathological conditions, including autoimmune and neurodegenerative diseases. In the central nervous system, sustained inflammatory signaling exacerbates disorders such as Alzheimer’s and Parkinson’s disease. Although anti-inflammatory therapies such as JAK inhibitors are clinically available, their lack of cellular specificity often results in systemic toxicity and severe side effects. To address these limitations, we are engineering a genetically encoded Bioluminescent Kinase Sensor (BlinKS) platform coupled to a synthetic gene circuit for real-time detection and autonomous regulation of inflammatory signaling.
BlinKS is designed to sense activation of key inflammatory pathways, including JAK/STAT and NF-κB, and convert kinase activity into a bioluminescent output that drives light-dependent gene expression via the optogenetic transcription factor EL222. The sensor architecture consists of a split luciferase reconstituted upon phosphorylation-dependent intramolecular interactions between a phospho-amino acid binding domain (PAABD) and pathway-specific kinase substrates. We have generated and experimentally validated BlinKS variants targeting JAK1, JAK2, STAT1, STAT3, and candidate kinases within the NF-κB pathway, demonstrating pathway-responsive bioluminescent output in cell-based assays.
To enhance sensitivity, specificity, and dynamic range, we are systematically optimizing luciferase variants, linker composition and length, and PAABD–substrate pairings, while expanding the repertoire of inflammatory kinase targets. We further demonstrate that BlinKS-generated bioluminescence is sufficient to activate EL222-based transcriptional circuits, enabling regulation of downstream anti-inflammatory gene expression, including IL-10.
Collectively, this work establishes BlinKS as a modular platform for monitoring inflammatory signaling and implementing self-regulating therapeutic responses. This approach provides a powerful tool for dissecting inflammation dynamics and lays the groundwork for precision, cell-specific interventions in neuroinflammatory and other inflammatory diseases. Support for this study was provided by the NIH R21EB034494.
Establishment of a Fully Human iPSC-Derived Model of Peripheral Myelination
1NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, Florida 32826, United States
2College of Medicine, University of Central Florida, 6850 Lake Nona Blvd, Orlando, Florida 32827, United States
3Hesperos Inc., 12501 Research Parkway, Suite 100, Orlando, Florida 32826, United States
Myelination and node of Ranvier formation play an important role in the rapid conduction of nerve impulses along axons in the peripheral nervous system (PNS). We report a fully human model of peripheral myelination using human induced pluripotent stem cell (iPSC) -derived Schwann cells (SCs), and motoneurons in a fully defined serum-free medium, allowing disease modeling, drug discovery, and potentially a platform for personalized medicine. iPSC-derived SCs were characterized for their myelination potential, and after 30 days in coculture with motoneurons, hallmark features of myelination, myelin segment and node of Ranvier formation were investigated. Myelin segments were observed surrounding motoneuron axons, with formation of clusters of voltage-gated sodium channels and the paranodal protein contactin-associated protein 1, indicating node of Ranvier formation. Using high resolution confocal microscopy, 3D reconstructions of multiple myelin segments were created, allowing the measurement of myelin g-ratio, a readout which typically has only been collected using transmission electron microscopy, a technique prohibitive to 2D cellular models. The average g-ratio of myelin segments in the wildtype iPSC-derived model of myelination was seen to be .65, which matches the value range reported in literature. Establishment of this iPSC based disease model provides a platform to test various drugs and therapeutics that could potentially ameliorate PNS diseases such as Charcot–Marie Tooth disorder, Guillian–Barre syndrome, and anti-myelin-associated glycoprotein peripheral neuropathy, with greater translatability to human patients than animal models allow. The adaptation of this system onto a microelectrode array system would provide a functional readout in addition to the collected biomarker information which would be extremely useful when it comes to testing of drugs to treat diseases where the myelination and therefore action potential conduction is impaired.
Engineered pro-angiogenic hydrogel for neural stem cell transplantation after stroke
1Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV, 89154, USA.
2College of Osteopathic Medicine, Touro University California, Vallejo, CA, 94592, USA.
+equal contribution
Stroke is a leading cause of long-term disability in the United States, and no clinical trials to date have successfully reduced neurological impairment in stroke survivors. While stem cell transplantation has shown promise in activating brain repair mechanisms in preclinical models of cerebral ischemia, its clinical translation has been limited by poor cell survival and insufficient control over cell fate and differentiation. We have recently developed a Hyaluronic Acid (HA)-based biomimetic hydrogel platform specifically designed to enhance control over NPC survival and differentiation post-implantation. We hypothesize that incorporating pro-angiogenic properties to this material will further enhance its regenerative capabilities. To test this hypothesis, we integrated into our HA platform a slow controlled-release system for the delivery of Vascular Endothelial Growth Factor (VEGF) prior to loading NPCs and brain injection into the lesion site of a mouse model of cerebral ischemia. We found that this combination increased peri-lesional angiogenesis, reduced the injury-associated inflammatory response, and greater promoted functional recovery compared with NPC-loaded hydrogel and pro-angiogenic hydrogel alone. Our findings indicate that pro-angiogenic functionality within stem cell–loaded hydrogels plays a key role in supporting cell-mediated motor recovery.
Role of Hemispheric Dominance in Stem Cell–Mediated Restoration of Motor Function in the 6-OHDA Model of Parkinson’s Disease
*
1Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA, 43614.
2College of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA, 43614.
3Department of Neurology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA, 43614.
4Department of Biology, Ohio Northern University, Ada, OH, USA, 45810.
5Department of Neurology, Howard University, Washington DC, USA, 20059.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor deficits. A hallmark of PD is its asymmetric onset, with symptoms typically emerging on one side of the body, suggesting hemispheric differences in nigrostriatal vulnerability. While stem cell transplantation has shown promise in restoring motor function, the influence of hemispheric dominance on graft-mediated recovery remains poorly understood. This study examined whether transplantation of human embryonic stem cell (hESC)-derived dopaminergic progenitors into the dominant versus non-dominant hemisphere differentially affects behavioral recovery in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinsonism.
Adult Sprague Dawley rats (N = 15) were assessed for paw preference to determine motor dominance prior to lesioning. Unilateral 6-OHDA lesions were stereotaxically delivered to the substantia nigra pars compacta (SNpc) to induce hemiparkinsonism. Lesion efficacy was confirmed using apomorphine-induced rotational and a rodent behavioral battery of tests (RBBT). hESC-derived dopaminergic progenitors were then transplanted into the lesioned striatum of either the dominant (n = 3) or non-dominant (n = 3) hemisphere. Motor performance was assessed using the RBBT for up to 26 weeks of post-transplantation. At the end, brains were collected for histological and immunohistochemical analyses.
Both transplant groups showed significant motor improvement compared to pre-transplant baselines (p < 0.05). However, no significant differences were observed between dominant and non-dominant hemisphere transplants at any time point (p = 0.27–0.91). Histological analyses revealed graft survival and differentiation, with transplanted cells expressing midbrain dopaminergic markers.
These findings indicate that hESC-derived dopaminergic progenitor transplantation produces comparable functional recovery regardless of hemispheric dominance. The absence of lateralized effects may reflect limited sample size. Future studies with larger cohorts and advanced circuit-level analyses are needed to clarify whether hemispheric specialization influences graft–host interactions and therapeutic outcomes in PD.
Preliminary evaluation of AneuScreenTM: a blood-based assay to predict intracranial aneurysm rupture risk
1Canon Stroke and Vascular Research Center, University at Buffalo, Buffalo, NY, USA 14203
2Neurovascular Diagnostics, Buffalo, NY, USA 14203
3Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14203
4Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14203
5Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 19104
6Department of Neurosurgery, Brain and Spine, University of South Florida, Morsani College of Medicine, Tampa, FL, USA 33602
7Interventional Neuroradiology/Endovascular Neurosurgery Division Department of Neurology, Neurosurgery and Radiology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA 52242
Intracranial aneurysm (IA) is a cerebrovascular disease that affects ~3-5% of the US population. An IA can rupture, causing subarachnoid hemorrhage, which is associated with high rates of morbidity and mortality. Therefore, it is critical to assess rupture risk so clinicians can treat those likely to rupture, while sparing those at low risk from the complications of surgery. Currently, risk assessment is based on the patient’s medical history and imaging, but cerebral imaging is expensive and carries its own risks. To overcome this, we are developing a low-cost, non-invasive RNA biomarker, AneuScreenTM, that uses circulating blood to assess IA rupture risk. Using results from previous RNA sequencing studies and feature ranking, we identified a panel of genes associated with IA risk assigned by the widespread clinical metric PHASES. We then designed probes and validated them using pooled control human blood. Subsequently, we tested the assay on clinical samples collected from four IRB-approved sites in the US. The assay expression data was combined with basic clinical data to bolster the prediction model. Multiple feature selection strategies were independently evaluated across 500 stratified, random splits (80/20 train-test). Features selected in at least 50% of iterations were deemed stable and used to train four classifiers, each optimized via 5-fold cross-validation in 500 randomizations in the training set. Model performance was assessed using receiver operating characteristic area under the curve (ROC AUC), sensitivity, specificity, and accuracy, averaged across bootstraps. Finally, SHapley Additive eXPlanations (SHAP) were used to evaluate feature importance. Ultimately, we identified 15 features, both genes and clinical datapoints, that were used in a logistic regression model to predict aneurysm risk, achieving an average AUC>0.8. Additional validation in larger cohort is necessary, but this work demonstrates the potential of using circulating blood to assess intracranial aneurysm rupture risk.
The Epileptogenicity of Single Pulse Electrical Stimulation for Corticocortical Evoked Potentials in Stereotactic EEG
1University of Alabama at Birmingham, Department of Neurology, Birmingham, AL
2University of Alabama at Birmingham, School of Engineering, Birmingham, AL
3Birmingham VA Medical Center, Neurology Service, Birmingham, AL
Single-pulse electrical stimulation (SPES) using stereo-EEG (sEEG) electrodes generates corticocortical evoked potentials (CCEPs) and is increasingly used to investigate brain connectivity and identify the seizure-onset zone in drug-resistant epilepsy. It is important to assess whether SPES affects the seizure network. We applied SPES in 36 patients undergoing sEEG for seizure localization, delivering stimulation between all paired electrode contacts at 5 mA, 1 Hz, 300 μs over 30 seconds. One-hour sEEG segments before and after stimulation were reviewed. Stimulation-induced seizures were assessed in all patients. Interictal spike rates (spikes/min) and seizure counts before and after stimulation were manually counted in 27 patients with available baseline recordings. Colocalization of stimulation-induced seizures with spontaneous seizures was noted. Wilcoxon signed-rank test compared pre- and post-stimulation spike rates, and McNemar’s test assessed changes in seizure occurrence.
Spike rates did not significantly differ from pre-SPES (mean 28.2 spikes/min) to post-SPES (mean 25.4 spikes/min), with a mean decrease of 2.8 spikes/min (P = 0.38; Figure 1). Within the hour before and after SPES, 2 patients had seizures only before SPES, 2 patients had seizures only after SPES, and 21 patients had no seizures in either period. The difference in seizure frequency was not significant (P = 1.00). Eleven patients had SPES-induced seizures (5 subclinical, 4 clinical, 2 both), with an average of 1.45 subclinical and 0.63 clinical seizures. All SPES-seizures colocalized with spontaneous seizures except in two patients—one in the early propagation zone and one in a non-involved area.
This study provides preliminary evidence that SPES does not significantly alter interictal spike rates or seizures. Despite the limited sample, further research in larger groups is needed. Demonstrating SPES safety remains a key step toward wider clinical and research use.
Large-Scale Deep Proteomic Analysis in Alzheimer’s Disease Brain Regions Across Race and Ethnicity
1Emory University School of Medicine, Atlanta, Georgia, USA
2Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA
3Sage Bionetworks, Seattle, Washington, USA
4Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
5Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York, USA
6New York Genome Center, New York, New York, USA
7Banner Sun Health Research Institute, Sun City, Arizona, USA
8Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania, USA
9University of Florida, Gainesville, 100 Academic Advising Center, Gainesville, Florida, USA
10Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, USA
11Columbia University Irving Medical Center, New York, New York, USA
12Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, yet most molecular studies have focused on non-Hispanic White (NHW) populations, limiting understanding of disease biology across diverse racial and ethnic groups. We performed a large-scale deep proteomic analysis of two cortical brain regions harmonized across multiple centers using uniform neuropathological criteria. The study included 998 unique donors, of whom 273 self-identified as African American, 229 as Latino American, and 434 as NHW. Approximately 10,000 proteins were quantified in the dorsolateral prefrontal cortex and superior temporal gyrus. While amyloid precursor protein and microtubule-associated protein tau showed increased abundance in AD brains and correlated with Consortium to Establish a Registry for Alzheimer’s Disease and Braak stages, no significant race-related differences were observed in global protein abundance or in focused analyses of specific amyloid beta species and tau domains. Proteome-wide AD-associated changes were highly concordant between African American and NHW individuals. These findings indicate that racial differences in AD risk and clinical presentation are not driven by large differences in the brain proteome, suggesting that other biological or social determinants underlie observed disparities.
Testing the link between intrinsic fitness and disease onset, phenotype, and progression in the SOD1-G93A rat model of ALS
N. Shahlari1, M.O. Rupp1, and
1Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, United States
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that targets motor neurons in the brain and spinal cord. Initial symptoms of muscle weakness resulting from neuromuscular denervation progress rapidly to muscle atrophy and paralysis. Increasing evidence supports a hypermetabolic state in ALS. Given the heterogeneity of symptom onset and progression in ALS, identifying metabolic factors that interact with disease processes should improve treatment strategies. A key knowledge gap is differentiating intrinsic (genetic) and extrinsic (lifestyle) fitness, which is exceedingly difficult in humans given decades-long exposure to lifestyle and diet. To address this gap, we mated male SOD1-G93A (SOD1+) rats with female rats selectively bred for low (LCR) or high (HCR) aerobic capacity. As adults, LCR rats exhibit greater body weight, greater adiposity, and a poor metabolic profile. We compared LCR-SOD1+ and HCR-SOD1+ rats with their wildtype LCR and HCR littermates and a group of female and male SOD1+ rats. At this stage, changes in body composition are greatest in female SOD1+ rats, with no difference in survival between and their male SOD1+ counterparts. Interestingly, changes were less in LCR-SOD1+ and HCR-SOD1+ females than in SOD1+ females and the other SOD1+ groups. These rats are still being tested, and disease onset, phenotype, and progression will be reported.
Mechanisms Underlying Huntington’s Disease Onset Delay by the DNA Ligase 1 K845N Variant
1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA,
2Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA,
3Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
4Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, 48109, USA,
5CHDI Management Inc., Princeton, NJ, 08540, USA,
6Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA
The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS
1Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
2Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
3School of Life Sciences, Tsinghua University, Beijing 100084, China
4Center for Stem Cells and Regenerative Medicine, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
5Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA
6Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
7School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
8Technion Rappaport Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 3109601, Israel
9Department of Pathology, University of California San Diego, La Jolla, CA 92037, USA
10Drexel University, Philadelphia, PA 19104, USA
11Gladstone Institutes, San Francisco, CA 94158, USA
#X.S., H.J., Q.M., X.F., K.S.S. and J.Z. contributed equally to this work.
*Co-senior/corresponding authors
G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of functions, offering targets for several therapeutic interventions. One such GPCR, CXCR4, participates in many normal and abnormal processes. CXCR4 antagonists have been used extensively for treating cancer, blocking HIV intracellular entry, etc. CXCR4 agonism, however, has been less often explored. We unveiled such a novel therapeutic use by elucidating CXCR4’s molecular structure using cryogenic electron microscopy. In 2004, we reported that a mechanism underlying neural stem cell (NSC) “pathotropism” was expression of inflammatory cytokines, (like SDF1α) in neuropathological regions which, in turn, upregulate receptors (like CXCR4) on the NSC surface, promoting their directed homing to lesions. While engagement by SDF1α of CXCR4’s binding pocket promotes desirable chemoattraction and homing by directing NSC migration, SDF1α binding to CXCR4’s signaling pocket initiates inimical inflammatory cascades. However, by chemical mutagenesis of SDF-1α, we designed synthetic peptides (“SDV1a” and “SDVX1”) that maximally engage CXCR4’s binding pocket while minimally triggering actions downstream of its signaling pocket – i.e., a dual moiety compound and new class of drugs. We demonstrated therapeutic benefit of SDV1a in the SOD1G93A mouse model of ALS in which we had previously published (2012) that the degree of motor neuron (MN) neuroprotection conferred by transplanted NSCs correlated directly with the expanse of diseased neuroaxis traversed. Co-administration of SDV1a with human NSCs (hNSCs) not only promoted broader neuroprotective coverage but also enabled a minimally-invasive route of hNSC administration (via the cisterna magna) which could be atraumatically repeated whenever symptoms recurred (re-treatment itself constitutes a novel approach to cell-based treatment of neurologic disease). Taken together, symptom-free lifespan was extended at least 3-times longer than that of untreated ALS mice (experiments we artificially terminated at that point) with concomitant host MN survival. Such drug + cell approaches may be applied to other CNS diseases.
Early Short-Term α2δ-1 Modulation is Associated with Thalamic Synaptic Remodeling and Late-Onset Behavioral Outcomes after Traumatic Brain Injury
C. Bromberg1,2,3, S. Ogle1, G. Krishna1,2, and
1University of Arizona- College of Medicine-PHX, Phoenix, AZ, 85004 USA
2Phoenix Children’s Hospital-Department of Child Health, Phoenix, AZ, 85016 USA
3Arizona State University-School of Life Sciences, Tempe, AZ, 85287 USA
4University of South Florida, Tampa, FL, 33612 USA
Traumatic brain injury (TBI) frequently results in persisting post-concussive symptoms (PPCS), which arise, in part, from maladaptive synaptic reorganization. Astrocyte-derived thrombospondins (TSPs) have been implicated as transient mediators of post-injury synaptogenesis through binding to the α2δ-1 subunit. This interaction may be allosterically inhibited by gabapentin (GBP), an FDA-approved drug for neuropathic pain and epilepsy; however, its effects on TBI-induced synaptic remodeling have not been evaluated.
Here, we characterized the temporal profile of post-injury TSP expression and administered GBP during the window of TSP elevation, quantified subacute synaptic changes in thalamocortical relays, evaluated effects on late-onset sensory symptoms, and determined the pharmacokinetic relevance of the dose in male and female sham and injured rats. Young adult Sprague–Dawley rats underwent diffuse axonal injury using midline fluid percussion injury (righting reflex time: 6-11min) and received GBP (30, 100, or 300 mg/kg/day) or vehicle during the first 7–10 days post-injury (DPI). Rats were randomized to sham+vehicle, injury+vehicle, or injury+GBP groups and assessed for whisker hypersensitivity using the whisker nuisance task (WNT) at 28DPI. All GBP doses reduced WNT scores relative to injury+vehicle rats (p<0.05, n=10/group).
Using the 100 mg/kg dose, synaptic colocalization was quantified using synaptic puncta colocalization at 7DPI. Injury+vehicle rats exhibited increased synaptic colocalization in the thalamic relay compared to sham (p<0.05, n=3–6/group), whereas injury+GBP rats showed a 53% reduction, with values comparable to sham. Pharmacokinetic analysis following 48h of GBP (100mg/kg/day) revealed sex- and injury-dependent differences in serum levels and sex differences in brain concentrations (p<0.05, n=8/group), while achieving clinically relevant serum concentrations (6.0±0.4 ng/mL).
Together, these findings demonstrate that early, short-term GBP administration is associated with reduced subacute thalamic synaptic remodeling and attenuation of late-onset sensory hypersensitivity following TBI, providing a pharmacokinetic and mechanistic foundation for further investigation of α2δ-1–targeted strategies as early interventions for PPCS.
Evaluation of Large Familial Intracranial Aneurysm Database
1Canon Stroke and Vascular Research Center, University at Buffalo, Buffalo, NY, USA 14203
2Neurovascular Diagnostics, Buffalo, NY, USA 14203
3Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14203
4Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14203
5Baptist Neurological Institute, Lyerly Neurosurgery; Jacksonville, FL, USA, 32207
Unruptured intracranial aneurysms (UIAs) affect approximately 3.2% of the population, with a higher incidence in females. These vascular abnormalities carry an annual risk of rupture of about 10 cases per 100,000 individuals. Aneurysmal subarachnoid hemorrhage (SAH) accounts for roughly 30,000 cases annually in the US, representing a severe untreated mortality burden of 66.7%. This study aims to conduct a comprehensive analysis of local, retrospective, and prospective data on the diagnosis and treatment of intracranial aneurysms (IAs) in patients. Additionally, it seeks to establish an effective screening protocol for first-degree relatives of IA patients, utilizing non-contrasted magnetic resonance imaging (MRA). Through subsequent blood sample collection and genetic sequencing, the study seeks to identify potential genetic markers, thereby enhancing future screening and treatment strategies. Following approval from the hospital’s ethics committee, a cohort registry was established, which aggregated retrospective and prospective data from individuals diagnosed/treated for IA. Further, it includes screening of first-degree relatives of IA patients via MRA. These relatives also consented to participate in blood sample collection for genetic marker evaluation. Ultimately, the study enrolled 1,523 individuals with females comprising 72.3%. Of these, 585 were clinically diagnosed with IAs, and 938 were first-degree relatives. From the family members enrolled, 90% have one and 10% have two or more first-degree relatives with IAs. Among the screened relatives, 85.6% underwent MRA, revealing a 11.7% positive detection rate for IAs, a higher-than-expected incidence of positive IA screenings among first-degree relatives. Blood samples were collected from 1,354 subjects for genetic sequencing. These blood samples will be used in a subsequent study, the DREAM (