IU Indianapolis ScholarWorks :: Browsing by Author "Jury, Nur"

Browsing by Author "Jury, Nur"

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Activated endothelial cells induce a distinct type of astrocytic reactivity
(Springer Nature, 2022-03-29) Taylor, Xavier; Cisternas, Pablo; Jury, Nur; Martinez, Pablo; Huang, Xiaoqing; You, Yanwen; Redding-Ochoa, Javier; Vidal, Ruben; Zhang, Jie; Troncoso, Juan; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Reactive astrogliosis is a universal response of astrocytes to abnormal events and injuries. Studies have shown that proinflammatory microglia can polarize astrocytes (designated A1 astrocytes) toward a neurotoxic phenotype characterized by increased Complement Component 3 (C3) expression. It is still unclear if inflammatory stimuli from other cell types may also be capable of inducing a subset of C3+ neurotoxic astrocytes. Here, we show that a subtype of C3+ neurotoxic astrocytes is induced by activated endothelial cells that is distinct from astrocytes activated by microglia. Furthermore, we show that endothelial-induced astrocytes have upregulated expression of A1 astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we demonstrate that endothelial-induced astrocytes are Decorin-positive and are associated with vascular amyloid deposits but not parenchymal amyloid plaques in mouse models and AD/CAA patients. These findings demonstrate the existence of potentially extensive and subtle functional diversity of C3+-reactive astrocytes.
Bassoon contributes to tau-seed propagation and neurotoxicity
(Springer Nature, 2022) Martinez, Pablo; Patel, Henika; You, Yanwen; Jury, Nur; Perkins, Abigail; Lee-Gosselin, Audrey; Taylor, Xavier; You, Yingjian; Di Prisco, Gonzalo Viana; Huang, Xiaoqing; Dutta, Sayan; Wijeratne, Aruna B.; Redding-Ochoa, Javier; Shahid, Syed Salman; Codocedo, Juan F.; Min, Sehong; Landreth, Gary E.; Mosley, Amber L.; Wu, Yu-Chien; McKinzie, David L.; Rochet, Jean-Christophe; Zhang, Jie; Atwood, Brady K.; Troncoso, Juan; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.
Enhanced microglial dynamics in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer’s disease
(Wiley, 2025-01-03) Jury, Nur; Redding, Javier; You, Yanwen; Martinez, Pablo; Karahan, Hande; Juarez, Enrique Chimal; Johnson, Travis S.; Zhang, Jie; Kim, Jungsu; Troncoso, Juan C.; Reeves, Cristian A. Lasagna; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
Background: Asymptomatic Alzheimer’s disease (AsymAD) refers to individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology, including beta‐amyloid (Aβ) deposits, neuritic plaques and neurofibrillary tangles upon autopsy. Unlike AD cases, AsymAD exhibits low neuroinflammation and fewer soluble pathological tau species at synaptic levels. However, the link between these observations and the ability to counteract AD pathology is not fully understood. Evidence from AD mice models suggests that the plaque microenvironment significantly influences Aβ plaque‐associated tau pathogenesis. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Method: We conducted a detailed histological and biochemical analysis using postmortem brain samples from age‐matched controls (N = 13), AD (N = 19), and AsymAD subjects (N = 17). In fixed brain tissue, we performed the GeoMx whole spatial transcriptome atlas to compare the gene expression within the Aβ‐plaque microenvironment in AsymAD versus AD cases. To further explore the mechanisms insights of our findings we used human microglial cells. Result: Our findings showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation with increased surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD versus AD brains, and tau seeding activity was comparable to that in healthy brains. To further characterize the plaque niche, we used spatial transcriptomics, finding an increase in components of the actin‐based motility pathways within the microglia surrounding amyloid plaques in AsymAD brains. Ongoing mechanistic experiments in vitro aim to elucidate the role of this pathway in microglial response to Aβ. Conclusion: Our findings indicate that the amyloid‐plaque microenvironment in AsymAD brains is characterized by microglia with highly efficient actin‐based cell motility mechanisms and decreased tau seeding versus that observed in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.
Interactome Analysis of Tau‐seed Isolated from AD Brains Suggests New Mechanism for Tau Aggregation and Spreading
(Wiley, 2025-01-03) Martinez, Pablo; You, Yanwen; Patel, Henika; Jury, Nur; Min, Yuhao; Redding, Javier; Huang, Xiaoqing; Dutta, Sayan; Mosley, Amber L.; Rochet, Jean-Christophe; Zhang, Jie; Ertekin-Taner, Nilüfer; Troncoso, Juan C.; Lasagna Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Background: Tau aggregates, a hallmark of Alzheimer’s disease (AD) and other tauopathies, spread throughout the brain, contributing to neurodegeneration. How this propagation occurs remains elusive. Previous research suggests that tau‐seed interactors play a crucial role. Based on this, the study aimed to identify novel tau‐seed interactors in AD brains and validate their impact in vivo. Method: AD and control brain extracts were separated in fractions by Size Exclusion Chromatography. Fractions with the highest tau seeding activity, measured using a tai‐biosensor cell line, were analyzed by mass spectrometry to identify interacting proteins. Bioinformatic tools dissected enriched pathways, identifying interactors that were validated in a Drosophila tauopathy model by genetically interfering with their homologs and assessing tau accumulation and eye degeneration. Results: Tau seeding activity was concentrated in high molecular weight fractions containing only a small portion of total tau in the AD brains. Compared to controls, AD brains revealed a distinct interactome for tau‐seeds, enriched in proteins associated with synaptic and mitochondrial pathways. Notably, Drosophila screening confirmed that several novel interactors significantly reduced tau accumulation and eye degeneration, suggesting their potential therapeutic relevance. Conclusion: This study sheds light on tau propagation mechanisms in AD by identifying novel tau‐seed interactors. These interactors, particularly those involved in synaptic and mitochondrial pathways, offer promising targets for therapeutic interventions aimed at decreasing tau spread and potentially preventing neurodegeneration in tauopathies. The findings add to the growing evidence that targeting tau‐seed interactors, like previously identified BSN, could represent a novel strategy for treating these debilitating conditions.
Optimal Transport‐Based Transcriptomic Mapping Revealed Atypical Disease Progression Subtypes in Living Alzheimer’s Disease Patients
(Wiley, 2025-01-09) Huang, Xiaoqing; Zhang, Jie; Huang, Kun; Lasagna Reeves, Cristian A.; Jury, Nur; Medical and Molecular Genetics, School of Medicine
Background: Alzheimer’s disease (AD) exhibits substantial heterogeneity in its disease trajectory. A subset of AD patients with unmatched cognitive decline/tauopathy severity has not been well studied. We identified such atypical subgroups in post‐mortem AD brain studies. However, such atypical subtypes may not be easily identified in living patients, as obtaining brain samples are unfeasible, and NFT measurement is not accurate. In this study, we utilize the matched transcriptomic data from both brain and blood of ROSMAP cohort to identify such atypical AD groups in the blood transcriptomic data of live patients in other cohorts using transfer learning‐based approach, to uncover distinct molecular signatures and biomarkers for earlier and more accurate disease subtyping and prognosis in living AD patients. Method: Three subgroups were defined from ROSMAP cohort with the blood and brain RNA‐seq data based on the clinical information of their tauopathies and disease progression, namely, Asymptomatic AD, Low‐NFT AD, Typical AD, plus normal Control, which serves as our training dataset for a supervised transfer learning. Then, the labels were transferred to the blood RNA‐seq samples from two new cohorts, ADNI and ANMerge using optimal transport. Next, we identify the genes consistently expressed in three independent cohorts for that specific AD subtype. Lastly, the diffusion pseudo‐time analysis infers the temporal order of the gene expression patterns within each subgroups. Dominant genes with a consistent expression pattern across cohorts are considered as the signature for each subgroup, and their relevance to AD pathology is analyzed. Result: We identified distinctive genes with consistent expression patterns across cohorts for each AD subgroup. Remarkably, our analysis also reveals the temporal gene expression dynamics differs for sex, age (late/early onset), and onset pattern (sudden/gradual) across the cohorts. Conclusion: Through a deep transfer learning‐based approach on the blood and brain transcriptomic data, we successfully identified the atypical disease progression subgroups among live AD patient cohorts in ADNI and ANMerge with promising biomarkers/gene signatures. The molecular signatures identified in this study not only enhance our comprehension of the underlying pathophysiological mechanisms but also hold promise for developing early prognosis and effective personalized treatments for AD and related tauopathies.
Pathological tau and reactive astrogliosis are associated with distinct functional deficits in a mouse model of tauopathy
(Elsevier, 2022) Patel, Henika; Martinez, Pablo; Perkins, Abigail; Taylor, Xavier; Jury, Nur; McKinzie, David; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Pathological aggregation of tau and neuroinflammatory changes mark the clinical course of Alzheimer’s disease and related tauopathies. To understand the correlation between these pathological hallmarks and functional deficits, we assessed behavioral and physiological deficits in the PS19 mouse model, a broadly utilized model of tauopathy. At 9 months, PS19 mice have characteristic hyperactive behavior, a decline in motor strength, and deterioration in physiological conditions marked by lower body temperature, reduced body weight, and an increase in measures of frailty. Correlation of these deficits with different pathological hallmarks revealed that pathological tau species, characterized by soluble p-tau species, and tau seeding bioactivity correlated with impairment in grip strength and thermal regulation. On the other hand, astrocyte reactivity showed a positive correlation with the hyperactive behavior of the PS19 mice. These results suggest that a diverse spectrum of soluble pathological tau species could be responsible for different symptoms and that neuroinflammation could contribute to functional deficits independently from tau pathology. These observations enhance the necessity of a multi-targeted approach for the treatment of neurodegenerative tauopathies.
Protein degradation impairment and synapse elimination by microglia in BSN P3866A knock‐in mouse model of tauopathy
(Wiley, 2025-01-03) Patel, Henika; Martinez, Pablo; Lopes, Daniella; Jury, Nur; Vanderbosch, Katie; You, Yanwen; Kouri, Naomi; Rothberg, Darren M.; Yaguchi, Hiroaki; Tanaka, Shinya; Wakabayashi, Koichi; Yabe, Ichiro; Murray, Melissa E.; Lasagna Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Background: Tau aggregation is the major cause of several neurodegenerative tauopathies. Tau interaction with other proteins affects the formation of tau aggregates with seeding activity but less is known about its effects on tau‐seed properties. Our previous study revealed that Bassoon (BSN), a presynaptic protein, interacts with tau‐seed, exacerbating its toxicity in vivo. Bsndownregulation reduced tau spreading and overall pathology. Intriguingly, a parallel study associated missense mutations in BSN with tau aggregation in patients, prompting an investigation into the influence of genetic mutations in BSN on tau pathology for potential therapeutic insights. Method: We generated a knock‐in mouse model (BSNKI) harboring the disease‐associated p.Pro3866Ala mutation in endogenous Bsn. Cognitive and motor abilities were assessed in aged heterozygous and homozygous BSNKI mice, followed by analyses of BSN and tau patterns, gliosis, and gene expression changes in their brains. Additionally, we validated our findings in a human BSN mutation carrier. Result: At 10 months, BSNKI mice displayed motor impairments on the rotarod, and grip strength assays compared to WT mice. Their brains displayed somatic BSN and pathological tau accumulation, with the gene expression changes indicating alterations in microglia activation, protein degradation pathways, complement activation, and synapse pruning. We also observed an accumulation of pathological tau at the synapses and synapse engulfment by microglia. Histopathological analyses revealed robust microglia activation and co‐deposition of proteasomal subunits with BSN. The human BSN mutation carrier displayed inclusions of BSN and tau pathology similar to observations in the BSNKI model. Conclusion: Our BSNKI mouse model, reflecting a disease‐associated BSN mutation, revealed motor impairments and pathological tau and BSN deposits, mirroring observations in BSN mutation carriers. Notably, BSN seems to play a dual role, promoting tau aggregation and sequestering protein degradation molecules, leading to tau and protein accumulation at the soma and synapse, triggering microgliosis and neuroinflammation. These findings propose BSN as a promising therapeutic target for tauopathies, underscoring the need for further exploration to elucidate underlying mechanisms and therapeutic implications.
Tau ablation rescues vascular amyloid‐related deficits in a cerebral amyloid angiopathy model
(Wiley, 2025-01-03) Mardones, Muriel D.; Jury, Nur; Juarez, Enrique Chimal; Patel, Henika; Martinez, Jonathan; Vanderbosch, Katie; Perkins, Abigail; Marambio, Yamil; Vidal, Ruben; Lasagna Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Background: Close to 80 to 90% of subjects with AD also present cerebral amyloid angiopathy (CAA) a disease in which amyloid accumulation damages the vasculature and impairs blood flow. Since current AD therapies are targeting the disease focusing on amyloid, we are interested on determine how to decrease the accumulation of amyloid in the vasculature observed in CAA and our aim is to determine the impact of tau reduction in CAA pathogenesis. Method: We crossed the Tg‐FDD mice CAA model with Mapt‐/‐ mice to decrease tau levels and analyzed the disease pathogenesis in the different genotypes though behavioral tests, histological and morphometric assays and transcriptomic analysis using the nCounter neuroimmflamation panel from Nanostring. Result: We determined that tau ablation improved motor strength in the Tg‐FDD mice model, reduced amyloid deposition in the vasculature, decrease fibrinogen levels in the cortex, reduced astrocyte branching process associated to immunoreactivity. Nanostring analysis revealed that microglia function, oligodendrocyte and cytokine signaling are altered in the Tg‐FDD mice and that in the Tg‐FDD, Mapt ‐/‐ mice there is an increase in this mechanisms restoring the values to the ones observed in wild type mice. Conclusion: We are currently evaluating the pathways observed in the distinct inflammatory profile in microglia and oligodendrocytes. Our results suggest that tau ablation decreased CAA pathology in the Tg‐FDD mice model, which shows the potential therapeutic implications of targeting tau in CAA and related neurodegenerative diseases.
The reduction of astrocytic tau prevents amyloid-β-induced synaptotoxicity
(Oxford University Press, 2022-09-19) Cisternas, Pablo; Taylor, Xavier; Martinez, Pablo; Maldonado, Orlando; Jury, Nur; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Alzheimer’s disease is a neurological disorder characterized by the overproduction and aggregation of amyloid-beta and the phosphorylation and intraneuronal accumulation of tau. These events promote synaptic dysfunction and loss, leading to neurodegeneration and cognitive deficits. Astrocytes are intimately associated with synapses and become activated under pathological conditions, becoming neurotoxic and detrimentally affecting synapses. Although it has been established that reducing neuronal tau expression prevents amyloid-beta-induced toxicity, the role of astrocytic tau in this setting remains understudied. Herein, we performed a series of astrocytic and neuronal primary cultures to evaluate the effects of decreasing astrocytic tau levels on astrocyte-mediated amyloid-beta-induced synaptic degeneration. Our results suggest that the downregulation of tau in astrocytes mitigates the loss of synapses triggered by their exposure to amyloid-beta. Additionally, the absence of tau from astrocytes promotes the upregulation of several synaptoprotective genes, followed by increased production of the neuroprotective factor Pentraxin 3. These results expand our understanding of the contribution of astrocytic tau to the neurodegenerative process induced by amyloid-beta-stimulation and how reducing astrocytic tau could improve astrocyte function by stimulating the expression of synaptoprotective factors. Reducing endogenous astrocytic tau expression could be a potential strategy to prevent synaptic damage in Alzheimer's disease and other neurological conditions.
Therapeutic targeting of immunometabolism in Alzheimer's disease reveals a critical reliance on Hexokinase 2 dosage on microglial activation and disease progression
(bioRxiv, 2023-11-15) Codocedo, Juan F.; Mera-Reina, Claudia; Lin, Peter Bor-Chian; Puntambekar, Shweta S.; Casali, Brad T.; Jury, Nur; Martinez, Pablo; Lasagna-Reeves, Cristian A.; Landreth, Gary E.; Anatomy, Cell Biology and Physiology, School of Medicine
Microgliosis and neuroinflammation are prominent features of Alzheimer's disease (AD). Disease-responsive microglia meet their increased energy demand by reprogramming metabolism, specifically, switching to favor glycolysis over oxidative phosphorylation. Thus, targeting of microglial immunometabolism might be of therapeutic benefit for treating AD, providing novel and often well understood immune pathways and their newly recognized actions in AD. We report that in the brains of 5xFAD mice and postmortem brains of AD patients, we found a significant increase in the levels of Hexokinase 2 (HK2), an enzyme that supports inflammatory responses by rapidly increasing glycolysis. Moreover, binding of HK2 to mitochondria has been reported to regulate inflammation by preventing mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that its inflammatory role extends beyond its glycolytic activity. Here we report, that HK2 antagonism selectively affects microglial phenotypes and disease progression in a gene-dose dependent manner. Paradoxically, complete loss of HK2 fails to improve AD progression by exacerbating inflammasome activity while its haploinsufficiency results in reduced pathology and improved cognition in the 5XFAD mice. We propose that the partial antagonism of HK2, is effective in slowed disease progression and inflammation through a non-metabolic mechanism associated with the modulation of NFKβ signaling, through its cytosolic target IKBα. The complete loss of HK2 affects additional inflammatory mechanisms associated to mitochondrial dysfunction.

Browsing by Author "Jury, Nur"

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