Talk abstracts
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Wednesday 09:15-09:30am: A simulated calcium imaging dataset and analysis pipeline for hippocampal place cells
Meretta A. Hanson (Neuroscience Graduate Program), Jason C. Wester (Department of Neuroscience)
Abstract:
Calcium imaging is a powerful technique that allows researchers to visualize neural activity in hundreds of neurons simultaneously. This technique is especially valuable for studying hippocampal place cells, which fire selectively at specific locations as an animal navigates its environment. Despite its widespread use, calcium imaging analysis currently lacks standardization across labs, with each group often developing custom processing pipelines that employ differing methods for place field identification and analysis. This creates challenges for reproducibility and cross-study comparisons.
I created an application that addresses these challenges by 1) generating realistic simulated calcium imaging datasets from hippocampal place cells during navigation and 2) creating a standardized analysis pipeline validated against ground truth data (i.e. when neurons actually fire an action potential). This simulation accurately models diverse subtypes of place cells (spatial-modulated, reward-modulated, speed-modulated, and more) with realistic calcium indicator kinetics across multiple experimental trials. Environmental changes between trials affect specific place cell subtypes differently. For example, moving reward locations primarily impacts reward-modulated place cells, while sensory context changes affect spatial-modulated cells. Users can easily customize parameters including subtype-specific cell numbers, environment dimensions, reward locations, experimental manipulations, and more.
For labs beginning calcium imaging experiments, this application provides an educational resource with known ground truth for validating analyses. For established groups, I hope it will facilitate cross-lab reproducibility via standardized place cell analysis techniques. Thus, this application not only addresses current technical challenges but also paves the way for more collaborative and reproducible research into the neural basis of spatial navigation and memory.
Keywords: calcium imaging, computational neuroscience, spatial navigation
Wednesday 09:30-09:45am: Arvcf recruits Ankyrin-B and stabilizes the Cadherin-Catenin complex in the functional Aging Lens
Electra Coffman (Molecular, Cellular, and Developmental Biology Graduate Program), Jessica Martin (The Ohio State University, College of Optometry), Tiffani Thalacker (The Ohio State University, College of Optometry), Kenneth Herman (The Ohio State University, College of Optometry), Timothy F. Plageman Jr. (The Ohio State University, College of Optometry)
Abstract:
The eye lens is a unique transparent tissue responsible for focusing light onto the retina to produce a clear image. However, disruptions in lens cell structure can lead to cataracts, a disease marked by lens opacification. Although age is the highest global risk factor for cataract development, how cell architectural changes may contribute to its progression remains poorly characterized. We previously established that mice lacking a cell adhesion gene, Arvcf, develop disrupted adherens junctions (AJs) as soon as 1 month with premature cortical cataracts by 5 months of age. In a proteomic screening of mouse lens tissue, AJ protein N-Cadherin associates with cytoskeletal protein Ankyrin-B (AnkB). As mouse lenses lacking AnkB also possess cell adhesive disruptions, we hypothesize that Arvcf and AnkB function in a similar pathway to maintain lens fiber cell N-Cadherin and lens transparency over age. To test this, mouse lenses lacking one or both Arvcf or AnkB alleles were compared to a wild type control. Arvcf+/-; AnkB+/- mice were also produced to analyze synergistic effects. Lens lysates were analyzed by fractionation, immunoprecipitation, western blot, and/ or mass spectroscopy. This revealed that N-cadherin associates with both Arvcf and AnkB. Gene ontology analysis further identified novel Arvcf associations with neuronal and vesicular cellular components. Western blot reveals that the loss of Arvcf induces a dramatic decrease in N-Cadherin as well as its catenin binding partners. In-vitro and in-vivo immunofluorescent methods further reveal that Arvcf facilitates the recruitment of N-Cadherin and Ankyrin-B to the membrane. Immunofluorescent staining indicates that N-cadherin and AnkB may be reduced in the absence of Arvcf as early as one month. Lastly, fresh lenses were imaged with a stereomicroscope and analyzed with histological immunofluorescent staining followed by confocal microscopy. By 7 months of age, AnkB+/- or Arvcf+/-; AnkB+/- mouse lenses do not develop cataracts. Together, these data suggest that Arvcf may function in part to facilitate the association of Ankyrin-B to the cadherin-catenin complex. These findings further suggest a shared role for Arvcf and AnkB in stabilizing lens fiber AJs and architecture which may provide clues into future cortical cataract prevention.
Keywords: Cytoskeleton, Adherens junction, Cataract
Wednesday 09:45-10:00am: Antibody fusion proteins containing domains from the tripartite motif family protein 72 (TRIM72) increase plasma membrane repair to treat muscle diseases
Gianni Giarrano (Ohio State Biochemistry Program ), Miguel Lopez Perez (Department of Physiology and Cell Biology, The Ohio State University ), Noah Weisleder (Department of Molecular and Cellular Biochemistry, University of Kentucky), Christoph Lepper (Department of Physiology and Cell Biology, The Ohio State University)
Abstract:
Plasma membrane repair is a highly conserved process that muscle cells use to maintain health under mechanical stress from contraction (1). Defective repair mechanisms exacerbate muscle diseases, including Duchenne/Becker muscular dystrophy and limb-girdle muscular dystrophy (2,3). The tripartite motif family protein 72 (TRIM72) is a required component of plasma membrane repair that facilitates vesicle fusion at injury sites by binding to the phospholipid phosphatidylserine (PS) (1). Our laboratory and others have shown that exogenous treatment with TRIM72 ameliorates the pathology of muscle diseases in preclinical models (3,4). However, the therapeutic potential of full-length TRIM72 in muscle diseases is limited by off-target effects, poor pharmacokinetic properties, and manufacturing difficulties (4). Here, we fused the fragment crystallizable (Fc) domain from the human IgG1 protein to a panel of TRIM72 truncations. This approach aims to increase protein half-life through endogenous antibody recycling machinery, simplify manufacturing through standard antibody purification, and decrease off-target effects using truncated versions of TRIM72. We expressed and purified multiple Fc-fusion proteins using antibody purification methods and found that they maintain PS biding activity. Laser ablation and dye exclusion assays in mouse myoblast cells revealed that Fc-fusion proteins significantly improved membrane repair upon intracellular overexpression or exogenous application. Exogenous treatment with Fc-fusion proteins also improved membrane repair in live muscle tissue isolated from a Duchenne muscular dystrophy mouse model. Additionally, subcutaneous injection experiments show that Fc-fusion proteins likely exhibit extended half-lives in vivo. Together, these results suggest that our novel Fc-fusion proteins address critical barriers impeding the clinical development of the full-length TRIM72 protein and represent a possible therapeutic approach for muscle diseases.
References:
1.Blazek, A.D., Paleo, B.J., & Weisleder, N. Plasma Membrane Repair: A Central Process for Maintaining Cellular Homeostasis. Physiology (Bethesda) 30, 438-448 (2015).
2.Paleo BJ, McElhanon KE, Bulgart HR, et al. Reduced Sarcolemmal Membrane Repair Exacerbates Striated Muscle Pathology in a Mouse Model of Duchenne Muscular Dystrophy. Cells. 11(9), 1417 (2022).
3.Gushchina, L. V. et al. Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. Molecular Therapy 25, 2360–2371 (2017).
4.Weisleder N, et al. Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. Sci Transl Med. 4, 139ra85 (2012).
Keywords: Plasma Membrane Repair, Muscular Dystrophy, Fc-fusion proteins
Wednesday 10:00-10:15am: Troponin Enhanceropathies
Jenna Thuma (Biophysics Graduate Program), Yvette Wang (Physiology and Cell Biology), Madhoolika Bisht (Physiology and Cell Biology)
Abstract:
Striated muscle contraction is regulated by the troponin complex which consists of three proteins: troponin C (TnC), troponin I (TnI), and troponin T (TnT). Cardiac troponin’s protein role in the heart is well known and documented; however, we propose a novel role for all three cardiac troponins at the DNA level. DNA regulatory elements are important regions that control cell and time specific gene expression. These types of elements are generally found intergenically or intronically, however, roughly 5-10% are exonic. Shockingly, we found evidence that all three cardiac troponin genes contain exonic DNA regulatory elements. Thus, any nucleotide mutation in their exonic DNA regulatory element could not only change protein structure and function, but also the function of the regulatory element resulting in altered expression of nearby genes. For example, the regulatory element within cardiac TnC is predicted to regulate several genes important for early development and, consistent with this, when we mutate this region we lose all homozygous embryos in both mice and rats. Additionally, the regulatory element within cardiac TnI appears to interact with two genes, slow skeletal TnT and Dnaaf3. TnI knockout mice have diaphragm weakness (1) consistent with TnT misregulation and we have observed internal organ abnormalities consistent with Dnaaf3 misregulation. Furthermore, we have confirmed the misregulation of these genes by qPCR in several non-cardiac tissues where TnI is not expressed. Excitingly, our qPCR data also shows differential gene expression in knock-in animals, which mutate only 4 nucleotides within the putative DNA regulatory region of TnI. Finally, we probed the activity of these sequences with a luciferase assay and in skeletal muscle-like cells, they enhance luciferase expression. Thus, we are proposing a novel DNA regulatory role for the cardiac troponins, independent of their protein function, that, when mutated, may cause non-cardiac disease.
References:
1. Feng, H.Z., Wei, B, Jin, J.P. Deletion of a Genomic Segment Containing the Cardiac Troponin I Gene Knocks Down Expression of the Slow Troponin T Gene and Impairs Fatigue Tolerance of Diaphragm Muscle. J Biol Chem. 284(46). (Sept. 2009)
Keywords: DNA regulation, enhancer, cardiac
Wednesday 10:35-10:55am: Adult mammalian neural stem cell interaction with the hippocampal niche
Elizabeth Kirby (Neuroscience Graduate Program, Department of Psychology)
Abstract:
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Wednesday 10:55-11:15am: Development of Genetic Therapies for Inherited Pediatric Neurological Diseases
Allison Bradbury (Molecular, Cellular, and Developmental Biology Graduate Program, Department of Pediatrics)
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Wednesday 11:15-11:35am: tRNA processing and modification: Adventures with non-canonical pathways and enzymes
Jane Jackman (Ohio State Biochemistry Graduate Program, Department of Chemistry and Biochemistry)
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Wednesday 11:35-11:50am: Biophysical regulation of epithelial tissue development and homeostasis
Daniel Conway (Biophysics Graduate Program, Department of Biomedical Engineering)
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Wednesday 03:00-03:15pm: Hepatocyte Growth Factor Is Overexpressed in AML and Remodels the Mesenchymal Stromal Cell Niche
Annika Chura (Molecular, Cellular, and Developmental Biology Graduate Program), Wantong Li (Molecular, Cellular, and Developmental Biology Graduate Program), Konur Oyman (Molecular, Cellular, and Developmental Biology Graduate Program), Victoria Wang (Division of Hematology/Oncology, University of California, San Francisco), Bradley Blaser (Division of Hematology, The Ohio State University Wexner Medical Center)
Abstract not available online - please check the booklet.
Wednesday 03:00-03:15pm: Title not available online - please see the booklet.
Vlad Bogdanov (The Ohio State University), Bennett Yunker (The Ohio State University), Anastasiia Pokrass (The Ohio State University), Jenna Thuma (The Ohio State University), Ali Ulker (The Ohio State University), Jonathan P Davis (The Ohio State University)
Abstract not available online - please check the booklet.
Wednesday 03:15-03:30pm: PRMT5 targets the HTLV-1 accessory protein p30 and regulates its function
Kyle J Ernzen (MCDB Program), Cameron Phelps (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University), Stefan Niewiesk (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University), Patrick L. Green (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University), Amanda R. Panfil (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University)
Abstract not available online - please check the booklet.
Wednesday 03:15-03:30pm: Functionalized engineered extracellular vesicles for targeted delivery to intervertebral disc cells
Mia Kordowski (Biophysics Graduate Program), Justin Richards (Biomedical Engineering, The Ohio State University), Khady Diop (Biomedical Engineering, The Ohio State University), Juan Jose Gallardo (Biomedical Engineering, The Ohio State University), Elizabeth Yu (Department of Orthopaedics Division of Spine Surgery The Ohio State University Wexner Medical Center ), Devina Purmessur (Biomedical Engineering, The Ohio State University)
Abstract not available online - please check the booklet.
Wednesday 03:30-03:45pm: Two years of efficacy: astrocyte-targeted gene replacement for vanishing white matter disease exposes uncorrected disease mechanisms
Jessica A. Herstine (Molecular, Cellular, and Developmental Biology Graduate Program), Tamara J. Stevenson, Julia Wentz (Department of Pediatrics, University of Utah), Sergiy Chornyy, Nettie Pyne, Abigail Biddle, Tatyana Vetter, Kevin Flanigan (Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Childrens Hospital), Joshua L. Bonkowsky (Department of Pediatrics, University of Utah), Allison M. Bradbury (Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Childrens Hospital)
Abstract:
Vanishing White Matter Disease (VWM) is a progressive childhood leukodystrophy presenting with ataxia, neurological decline, and seizures which lead to death.1,2 There are no approved treatments. Prior studies revealed that astrocytes are a critical therapeutic target.3,4 Caused by mutations in the subunits of eukaryotic initiation factor 2B (eIF2B), VWM most commonly originates from pathologic variants in EIF2B5.5 Due to VWM’s monogenic nature, it is a promising candidate for adeno-associated virus (AAV)-mediated gene replacement therapy. Baseline measurements in the Eif2b5 I98M murine model indicates significant mobility loss and demyelination all within a shortened life span. The integrated stress response—a pathway regulated by eIF2B—is also dysregulated, further supporting that these mice display severe VWM phenotypes.6 To provide targeted disease correction, we designed AAV-mediated gene replacement constructs to drive therapeutic EIF2B5 expression in astrocytes. Ongoing efficacy studies in two Eif2b5 VWM models—R191H and I98M—indicate that gene therapy delays disease progression and partially rescues motor function. Treated I98M survival is significantly extended (2-fold) with our longest extension exceeding 2 years of age. Even with this, our treated animals are still experiencing life-limiting seizures. By targeting astrocytes, we have a unique tool to assess uncorrected mechanisms such as the role of other cell types (microglia, oligodendrocytes, etc.) and pathways which we are now uncovering through single-cell RNA sequencing and spatial proteomics. Elucidating these mechanisms will allow us to adjust our therapeutic design to generate a more comprehensive and durable therapy. Overall, we anticipate the emergence of a lead gene therapy strengthened through the evaluation of molecular, cellular, and clinically relevant measures, allowing for translation to the clinic.
References:
1. Van Der Knaap, M. S. et al. A new leukoencephalopathy with vanishing white matter. Neurology 48, 845–855 (1997).
2. Hamilton, E. M. C. et al. Natural History of Vanishing White Matter. Ann. Neurol. 84, 274–288 (2018).
3. Bugiani, M., Vuong, C., Breur, M. & van der Knaap, M. S. Vanishing white matter: a leukodystrophy due to astrocytic dysfunction. Brain Pathol. 28, 408–421 (2018).
4. Dooves, S. et al. Astrocytes are central in the pathomechanisms of vanishing white matter. J. Clin. Invest. 126, 1512–1524 (2016).
5. Fogli, A. et al. The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology 62, 1509–1517 (2004).
6. Herstine, JA. et al. Evaluation of safety and early efficacy of AAV gene therapy in mouse models of vanishing white matter disease. Mol Ther. 32(6):1701-1720 (2024).
Keywords: Gene Therapy, Vanishing White Matter Disease, Astrocytes
Wednesday 03:30-03:45pm: Autoinhibition Enhances DNA Scanning Rates in Cre Recombinase
Jonathan S. Montgomery (Ohio State Biochemistry Program), Ehsan Akbari (Department of Physics, The Ohio State University), Michael G. Poirier (Department of Physics, The Ohio State University), Mark P. Foster (Department of Chemistry and Biochemistry, The Ohio State University)
Abstract:
Site-specific DNA recombinases are promising gene editing tools with the ability to manipulate DNA without producing double-strand DNA breaks, as do nuclease-based methods (e.g., Cas9)1. The enzyme Cre (Causes Recombination) has been one of the most widely used DNA recombinases in the study of human health and disease. It selects and recombines DNA at 34 base-pair loxP sequences with high specificity. Its versatility is demonstrated through production of conditional knockout mouse models and targeted insertion of genes through recombinase mediated cassette exchange technologies (RMCE)2. While mutant Cre enzymes have been iteratively engineered to recombine DNA at non-canonical sites, its potential as a therapeutic in human health is hindered by a lack of understanding of the site-selection process.
We have observed that in the absence of DNA, Cre adopts an unexpected autoinhibited conformation in which the C-terminus of the protein docks in cis over the DNA binding interface3. Thermodynamic measurements indicate that this property reduces affinity towards both cognate and noncognate DNA, possibly enhancing the rate of DNA scanning by weakening interactions with DNA4. Using single-molecule fluorescence microscopy in combination with optical trapping, we have measured the rates at which Cre undergoes one-dimensional translocation on long DNA substrates. We found that autoinhibition enhances the rates of DNA scanning by enabling a fast-scanning conformation on noncognate DNA. These findings further our understanding of how Cre locates target sequences in a genomic context and highlights the role of the C-terminus in that process.
References:
1.Foster, M. P., Benedek, M. J., Billings, T. D. & Montgomery, J. S. Dynamics in Cre-loxP site-specific recombination. Current Opinion in Structural Biology 88, 102878 (2024).
2.Meinke, G., Bohm, A., Hauber, J., Pisabarro, M. T. & Buchholz, F. Cre Recombinase and Other Tyrosine Recombinases. Chem. Rev. 116, 12785–12820 (2016).
3.Unnikrishnan, A. et al. DNA binding induces a cis -to- trans switch in Cre recombinase to enable intasome assembly. Proc Natl Acad Sci USA 117, 24849–24858 (2020).
4.Montgomery, J. S., Judson, M. E. & Foster, M. P. Protein and DNA Conformational Changes Contribute to Specificity of Cre Recombinase. Biochemistry (2025)
Keywords: Single-Molecule, Protein-DNA Interactions, Protein Dynamics
Wednesday 03:45-04:00pm: A neurodevelopmental disorder-relevant mutation in Argonaute1 cannot efficiently form the RNA-induced silencing complex (RISC)
Andrew Savidge (Ohio State Biochemistry Program), Huaqun Zhang (Ohio State University, Chemistry and Biochemistry), Audrey Kehling (Ohio State University, Chemistry and Biochemistry)
Abstract not available online - please check the booklet.
Wednesday 03:45-04:00pm: In vitro medulloblastoma leptomeningeal metastasis models reveal adhesion signaling as a therapeutic vulnerability
Leyre Jimenez Garcia, MS (Molecular, Cellular, and Developmental Biology Graduate Program.), Amy C. Gross, MS (Center for Childhood Cancer Research, Nationwide Childrens Hospital.), James B. Reinecke, MD, PhD (Center for Childhood Cancer Research, Nationwide Childrens Hospital.)
Abstract not available online - please check the booklet.
Wednesday 04:15-04:30pm: CD200-CD200R signaling axis enhances the immunosuppressive function of myeloid cells in PDAC
Jessica Wedig (MCDB), Morgan Kaiser, Priya Matreja, Shrina Jasani, Debasmita Mukherjee, Ayushi Das, Hannah Lathrop, Maria Schmidt, Timothy Pfau, Liliana DAlesio, Abigail Guenther, Jake McGue, Gina Sizemore, Anne Noonan, Mary Dillhoff, Bradley Blaser, Timothy Frankel, Stacey Culp, Phil Hart, Andrew Gunderson, Zobeida Cruz-Monserrate, and Thomas Mace
Abstract not available online - please check the booklet.
Wednesday 04:15-04:30pm: Bile Neutralizes Bacterial Toxins by Promoting Structural Imbalance, Aggregation, Proteolysis, and Oxidation
Jaylen E. Taylor (Ohio State Biochemistry Program, The Ohio State University, Columbus, OH), David Heisler (Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA), Eshan Choudhary (Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH), Elena Kudryashova (Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH), Dmitri Kudryashov (Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH)
Abstract not available online - please check the booklet.
Wednesday 04:30-04:45pm: Neuronal Interleukin-1 Receptor Signaling Propagates Neuronal Dysfunction, Neuroinflammation, and Cognitive Decline after Diffuse Traumatic Brain Injury
Amara Davis (Ohio State Department of Neuroscience), Lynde Wangler (Ohio State Department of Neuroscience), Razeen Thammachack (Ohio State Department of Neuroscience), Fangli Zhao, Jonathan Packer, Candance Askwith (Ohio State Department of Neuroscience), Ning Quan (Florida Atlantic University), Jonathan Godbout (Ohio State Department of Neuroscience, Chronic Brain Injury Program)
Abstract not available online - please check the booklet.
Wednesday 04:30-04:45pm: Mechanisms of dysferlin-mediated membrane repair in health and disease
Hsiang-Ling Huang (Molecular, Cellular, and Developmental Biology Graduate Program), Giovanna Grandinetti (Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, Center for Electron Microscopy and Analysis, The Ohio State University), Sarah M. Heissler (Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine), Krishna Chinthalapudi (Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine)
Abstract:
Plasma membrane repair in response to damage is essential for cell viability. Dysferlin plays a key role in the Ca2+-dependent membrane repair mechanism in striated muscles by mediating the fusion of intracellular vesicles with the plasma membrane. Defects in dysferlin-mediated membrane repair caused by missense mutations are associated with a wide spectrum of muscle diseases known as dysferlinopathies. However, the lack of a structure of dysferlin or any member of the ferlin family of vesicle fusion and membrane trafficking proteins has impeded a mechanistic understanding of membrane repair in health and disease and the development of effective therapeutic strategies for dysferlinopathies. Here, we present cryo-electron microscopy structures of the full-length human dysferlin monomer and homodimer at 2.96 Ã… and 4.65 Ã… resolution, respectively. The structures define the general architecture of the dysferlin monomer, ferlin family-specific domains, and homodimerization mechanisms essential to function. Finally, the structures, biophysical, and cell biological experiments reveal how clinically relevant missense mutations in dysferlin contribute to disease mechanisms in dysferlinopathies. In summary, our findings provide a framework for the molecular mechanisms of dysferlin and the broader structural context within the ferlin family as a whole and deepen our understanding of membrane repair mechanisms in health and muscle disorders. These structural insights hold the potential to accelerate targeted structure-guided therapeutics aimed at ameliorating dysferlinopathies.
Keywords: Dysferlin, membrane repair, cryo-EM
Wednesday 04:45-05:00pm: Hypercholesterolemia Exacerbates Pathology of Alzheimer’s Disease by Disrupting Microglial Function and Lipid Metabolism
Sarah Kaye (Neuroscience Graduate Program), Andrew Gold (Department of Human Sciences), Da Lin (Neuroscience), Min Chen (Neuroscience), Jiangjiang Zhu (Department of Human Sciences)
Abstract:
Hypercholesterolemia is a recognized comorbidity of Alzheimer’s disease (AD), yet its mechanistic connection to AD pathology, particularly its impact on microglial function and amyloid-beta (Aβ) dynamics remains unclear. To investigate this, we utilized the APPNL-G-F (AK) mouse model, which develops robust Aβ pathology, and the APPNL-G-F;LDLR-/- (ALKO) model, which combines Aβ pathology with LDL receptor deficiency to induce hypercholesterolemia under a Western diet (WD). These models were designed to study the combined effects of genetic predisposition and dietary factors on AD progression. At six months of age, mice were maintained on a chow diet or switched to a WD for two months to induce hypercholesterolemia. Our findings demonstrate that hypercholesterolemia suppresses microglial responses to Aβ plaques, evidenced by reduced clustering and activation of microglia around plaques. The combination of WD and LDLR deficiency synergistically diminished the expression of disease-associated microglia markers, resulting in reduced Aβ plaque compactness. Mechanistically, RNA sequencing revealed hypercholesterolemia impaired microglial mitochondrial function, reduced protein synthesis, and heightened neuroinflammation. Lipidomic profiling revealed significant changes in the microglial lipidome, including elevated ceramides, hexosylceramides, and lysophosphatidylcholine, along with reduced N-acylethanolamines, reflecting a pro-inflammatory and metabolically stressed microglial state. Behavioral analyses further revealed that both WD and LDLR deficiency independently and synergistically impaired cognitive performance and increased anxiety-like behaviors in AD mice. Together, this study highlights the role of hypercholesterolemia in exacerbating AD pathology by disrupting microglial function, altering lipid metabolism, and impairing cognitive function, and suggests that pharmacological management of hypercholesterolemia could slow AD progression.
Keywords: Alzheimers, Hypercholesterolemia, Microglia
Wednesday 04:45-05:00pm: Transient pan-RAF inhibitor treatment for melanoma prevention
Rachel E. Lew (Molecular, Cellular, and Developmental Biology Graduate Program), Harsha S. Sanaka (Department of Molecular Genetics, The Ohio State University ), Venkat R. Chirasani (Department of Biochemistry and Biophysics, University of North Carolina - Chapel Hill), Sharon L. Campbell (Department of Biochemistry and Biophysics, University of North Carolina - Chapel Hill), Christin E. Burd (Department of Cancer Biology and Genetics/Molecular Genetics, The Ohio State University)
Abstract not available online - please check the booklet.
Wednesday 05:00-05:15pm: Title not available online - please see the booklet.
Jake W. Willows (The Ohio State University), Lindsey M. Lazor (The Ohio State University), Kristy L. Townsend (The Ohio State University)
Abstract not available online - please check the booklet.
Wednesday 05:00-05:15pm: Acid Sensing Ion Channel 1a and Mitochondrial Function
Cameron Ford (Neuroscience Graduate Program), Candice Askwith (Neuroscience Graduate Program), Harpreet Singh (Department of Physiology and Cell Biology), Shridhar Sanghvi (Department of Physiology and Cell Biology), Liyah Varghese (Department of Physiology and Cell Biology), Luke Bauer (Neuroscience Graduate Program)
Abstract:
The acid-sensing ion channels (ASICs) contribute to normal brain function and promote neuronal death in mouse models of stroke, traumatic brain injury, and multiple sclerosis. In these models, interventions targeting ASIC1a have prolonged time windows of neuroprotection. To fully capitalize on the therapeutic potential of ASIC1a, the molecular mechanisms mediating ASIC-dependent neuroprotection must be uncovered. The most established model of ASIC1a-dependent death involves acidosis-dependent activation of ASIC1a on the plasma membrane and induction of abnormal signaling cascades. Others, however, have shown the importance of ASIC1a in the regulation of mitochondrial function and have proposed ASIC1a is a mitochondrial ion channel. To investigate this, we tested the role of ASIC1a in mitochondrial activity in cultured neurons and neuron-derived cells. We found that ASIC1a expression impacts H2O2-mediated cell death (which is acidosis-independent). A direct link to mitochondrial function was observed with seahorse metabolic analysis showing that ASIC1a overexpression decreased ATP production, basal respiration, and maximal respiration. These effects were dependent on the N-terminal intracellular region of ASIC1a. We also investigated the effect of ASIC1a on isolated mitochondrial function. In isolated preparations of brain mitochondria, mice with disruption of ASIC1a showed enhanced sensitivity to mitochondrial Ca2+ overload and increased production of reactive oxygen species. These results indicate that ASIC1a can control mitochondrial function. To investigate how this is occurring, we performed subcellular fractionation followed by western blot analysis. We found little ASIC1a signal detected in ultra-pure mitochondrial fractions, however, we found abundant ASIC1a signal in the mitochondria-associated endoplasmic reticulum membrane (MAM). This is a unique localization for ASIC1a and suggests ASIC1a is controlling mitochondrial function through the MAM. Dysregulation of the MAM is a feature of many of the pathological models involving ASIC1a thus uncovering how MAM localized ASIC1a controls mitochondrial function represents a novel therapeutic avenue.
Keywords: ASIC, Mitochondria , MAM