Browsing by Author "Marambio, Yamil"

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    A1 reactive astrocytes and a loss of TREM2 are associated with an early stage of pathology in a mouse model of cerebral amyloid angiopathy
    (BMC, 2020-07-25) Taylor, Xavier; Cisternas, Pablo; You, Yanwen; You, Yingjian; Xiang, Shunian; Marambio, Yamil; Zhang, Jie; Vidal, Ruben; Lasagna-Reeves, Cristian A.; Anatomy and Cell Biology, School of Medicine
    Background Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not currently understood. Although CAA is highly associated with the accumulation of amyloid beta (Aβ), other amyloids are known to associate with the vasculature. Alzheimer’s disease (AD) is characterized by parenchymal Aβ deposition, intracellular accumulation of tau, and significant neuroinflammation. CAA increases with age and is present in 85–95% of individuals with AD. A substantial amount of research has focused on understanding the connection between parenchymal amyloid and glial activation and neuroinflammation, while associations between vascular amyloid pathology and glial reactivity remain understudied. Methods Here, we dissect the glial and immune responses associated with early-stage CAA with histological, biochemical, and gene expression analyses in a mouse model of familial Danish dementia (FDD), a neurodegenerative disease characterized by the vascular accumulation of Danish amyloid (ADan). Findings observed in this CAA mouse model were complemented with primary culture assays. Results We demonstrate that early-stage CAA is associated with dysregulation in immune response networks and lipid processing, severe astrogliosis with an A1 astrocytic phenotype, and decreased levels of TREM2 with no reactive microgliosis. Our results also indicate how cholesterol accumulation and ApoE are associated with vascular amyloid deposits at the early stages of pathology. We also demonstrate A1 astrocytic mediation of TREM2 and microglia homeostasis. Conclusion The initial glial response associated with early-stage CAA is characterized by the upregulation of A1 astrocytes without significant microglial reactivity. Gene expression analysis revealed that several AD risk factors involved in immune response and lipid processing may also play a preponderant role in CAA. This study contributes to the increasing evidence that brain cholesterol metabolism, ApoE, and TREM2 signaling are major players in the pathogenesis of AD-related dementias, including CAA. Understanding the basis for possible differential effects of glial response, ApoE, and TREM2 signaling on parenchymal plaques versus vascular amyloid deposits provides important insight for developing future therapeutic interventions.
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    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.
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    Vascular amyloid accumulation alters the gabaergic synapse and induces hyperactivity in a model of cerebral amyloid angiopathy
    (Wiley, 2020-09-10) Cisternas, Pablo; Taylor, Xavier; Perkins, Abigail; Maldonado, Orlando; Allman, Elysabeth; Cordova, Ricardo; Marambio, Yamil; Munoz, Braulio; Pennington, Taylor; Xiang, Shunian; Zhang, Jie; Vidal, Ruben; Atwood, Brady; Lasagna-Reeves, Cristian A.; Anatomy and Cell Biology, School of Medicine
    Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not currently understood. Although CAA is highly associated with the accumulation of β‐amyloid (Aβ), other amyloids are known to associate with the vasculature. Alzheimer's disease (AD) is characterized by parenchymal Aβ deposition and intracellular accumulation of tau as neurofibrillary tangles (NFTs), affecting synapses directly, leading to behavioral and physical impairment. CAA increases with age and is present in 70%–97% of individuals with AD. Studies have overwhelmingly focused on the connection between parenchymal amyloid accumulation and synaptotoxicity; thus, the contribution of vascular amyloid is mostly understudied. Here, synaptic alterations induced by vascular amyloid accumulation and their behavioral consequences were characterized using a mouse model of Familial Danish dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature. The mouse model (Tg‐FDD) displays a hyperactive phenotype that potentially arises from impairment in the GABAergic synapses, as determined by electrophysiological analysis. We demonstrated that the disruption of GABAergic synapse organization causes this impairment and provided evidence that GABAergic synapses are impaired in patients with CAA pathology. Understanding the mechanism that CAA contributes to synaptic dysfunction in AD‐related dementias is of critical importance for developing future therapeutic interventions.