Browsing by Author "Redding, Javier"

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    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.
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    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.
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    Unraveling Vascular and Parenchymal Microenvironment Changes in Patients with Mixed CAA/AD Pathology: A Spatial Transcriptomic In‐Depth Analysis
    (Wiley, 2025-01-03) Juarez, Enrique Chimal; Garfe, Nur Jury; Redding, Javier; Troncoso, Juan C.; Johnson, Travis S.; Lasagna Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Cerebral amyloid angiopathy (CAA), defined as the accumulation of amyloid in cerebral blood vessels causing alterations in the blood brain barrier (BBB) and the gliovascular unit, occurs in over 85% of Alzheimer’s disease (AD) cases, positioning CAA as one of the strongest vascular contributors to age‐related cognitive decline. However, the specific mechanisms in the microvasculature that become altered due to amyloid deposition and its downstream effects on the brain are complex and incompletely understood. A spatial transcriptomic analysis comparing pathways affected in the gliovascular niche differently in the presence of vascular amyloid could provide critical insight into the mechanisms underlying cerebrovascular changes involved in the deposition of Amyloid in the cerebrovasculature. Method: Using NanoString’s GeoMx Human Whole Transcriptome Atlas, which measures over 18,000 protein‐coding genes at each region of interest (ROI) in tissue sections, we evaluated mixed CAA/AD pathology patients. We evaluated and performed selected pair wise comparisons between 4 types of ROI: 1) Astrocytes surrounding vascular amyloid, 2) astrocytes surrounding amyloid‐free vasculature, 3) astrocytes surrounding parenchymal amyloid, & 4) astrocytes in an amyloid‐free parenchymal zone. Result: Conducting pairwise comparisons among the four types of Regions of Interest (ROIs) unveiled distinctive transcriptomic signatures across ROI categories. Notably, gene expression profiles in regions of vasculature positive for Aβ‐amyloid differed significantly from those in amyloid‐free vasculature, showcasing pronounced gene expression changes. While the signatures corresponding to both Parenchymal amyloid and vascular amyloid have a similar transcriptional signature, they differ in certain pathways. Through meticulous data mining, we identified a co‐expression cluster of genes intricately linked to vascular amyloid deposition. Further analysis involved determining Differentially Expressed Genes (DEGs) based on ROI types, yielding a comprehensive list of potential targets indicative of the perturbations induced by vascular amyloid deposition versus parenchymal amyloid deposition. Conclusion: In summary, the identified differential (parenchymal vs vascular) genes underscore a clear association with alterations in the neurovascular microenvironment, indicating a discernible shift in vasculature dynamics attributed to amyloid presence. This observation emphasizes the significance of comprehending the changes within the vascular unit to address Cerebral Amyloid Angiopathy (CAA) thoroughly to develop comprehensive strategies to tackle CAA‐related challenges.