Browsing by Author "You, Yingjian"

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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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    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.
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    Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy
    (BMC, 2019-02-26) You, Yingjian; Perkins, Abigail; Cisternas, Pablo; Muñoz, Braulio; Taylor, Xavier; You, Yanwen; Garringer, Holly J.; Oblak, Adrian L.; Atwood, Brady K.; Vidal, Ruben; Lasagna-Reeves, Cristian A.; Medicine, School of Medicine
    Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis is accompanied by significant tau pathology. However, the contribution of tau to neurodegeneration associated to CAA remains to be determined. We used a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature, to characterize the contribution of tau to neurodegeneration associated to CAA. We performed histological and biochemical assays to establish tau modifications associated with CAA in conjunction with cell-based and electrophysiological assays to determine the role of tau in the synaptic dysfunction associated with ADan. We demonstrated that ADan aggregates induced hyperphosphorylation and misfolding of tau. Moreover, in a mouse model for CAA, we observed tau oligomers closely associated to astrocytes in the vicinity of vascular amyloid deposits. We finally determined that the absence of tau prevents synaptic dysfunction induced by ADan oligomers. In addition to demonstrating the effect of ADan amyloid on tau misfolding, our results provide compelling evidence of the role of tau in neurodegeneration associated with ADan-CAA and suggest that decreasing tau levels could be a feasible approach for the treatment of CAA.