Browsing by Author "You, Yanwen"
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Item 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 MedicineBackground 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.Item 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 MedicineReactive 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.Item 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 MedicineTau 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.Item Deletion of miR‐33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice(Wiley, 2024) Tate, Mason; Wijeratne, H. R. Sagara; Kim, Byungwook; Philtjens, Stéphanie; You, Yanwen; Lee, Do-Hun; Gutierrez, Daniela A.; Sharify, Daniel; Wells, Megan; Perez-Cardelo, Magdalena; Doud, Emma H.; Fernandez-Hernando, Carlos; Lasagna-Reeves, Cristian; Mosley, Amber L.; Kim, Jungsu; Biochemistry and Molecular Biology, School of MedicineIntroduction: Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). ABCA1 facilitates the lipidation of apolipoprotein E (apoE). This study investigated whether microRNA-33 (miR-33)-mediated regulation of this ABCA1-APOE pathway affects phenotypes of an amyloid mouse model. Methods: We generated mir-33+/+;APP/PS1 and mir-33-/-;APP/PS1 mice to determine changes in amyloid pathology using biochemical and histological analyses. We used RNA sequencing and mass spectrometry to identify the transcriptomic and proteomic changes between our genotypes. We also performed mechanistic experiments by determining the role of miR-33 in microglial migration and amyloid beta (Aβ) phagocytosis. Results: Mir-33 deletion increases ABCA1 levels and reduces Aβ accumulation and glial activation. Multi-omics studies suggested miR-33 regulates the activation and migration of microglia. We confirm that the inhibition of miR-33 significantly increases microglial migration and Aβ phagocytosis. Discussion: These results suggest that miR-33 might be a potential drug target by modulating ABCA1 level, apoE lipidation, Aβ level, and microglial function. Highlights: Loss of microRNA-33 (miR-33) increased ABCA1 protein levels and the lipidation of apolipoprotein E. Loss of miR-33 reduced amyloid beta (Aβ) levels, plaque deposition, and gliosis. mRNAs and proteins dysregulated by miR-33 loss relate to microglia and Alzheimer's disease. Inhibition of miR-33 increased microglial migration and Aβ phagocytosis in vitro.Item Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer's disease(Springer, 2024-08-05) Jury‑Garfe, Nur; Redding‑Ochoa, Javier; You, Yanwen; Martínez, Pablo; Karahan, Hande; Chimal‑Juárez, Enrique; Johnson, Travis S.; Zhang, Jie; Resnick, Susan; Kim, Jungsu; Troncoso, Juan C.; Lasagna‑Reeves, Cristian A.; Medical and Molecular Genetics, School of MedicineAsymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.Item Enhanced microglial dynamics and paucity of tau seeding in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer’s disease(bioRxiv, 2023-07-28) Jury-Garfe, Nur; You, Yanwen; Martínez, Pablo; Redding-Ochoa, Javier; Karahan, Hande; Johnson, Travis S.; Zhan, Jie; Kim, Jungsu; Troncoso, Juan C.; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of MedicineAsymptomatic Alzheimer’s disease (AsymAD) describes the status of subjects with preserved cognition but with identifiable Alzheimer’s disease (AD) brain pathology (i.e. Aβ-amyloid deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the underlying mechanisms of resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation, as well as an increase in microglia surrounding this last type. In AsymAD cases we found less pathological tau aggregation in dystrophic neurites compared to AD and tau seeding activity comparable to healthy control subjects. We used spatial transcriptomics to further characterize the plaque niche and found autophagy, endocytosis, and phagocytosis within the top upregulated pathways in the AsymAD plaque niche, but not in AD. Furthermore, we found ARP2, an actin-based motility protein crucial to initiate the formation of new actin filaments, increased within microglia in the proximity of amyloid plaques in AsymAD. Our findings support that the amyloid-plaque microenvironment in AsymAD cases is characterized by microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared to AD. These two mechanisms can potentially provide protection against the toxic cascade initiated by Aβ that preserves brain health and slows down the progression of AD pathology.Item Network analysis identifies strain-dependent response to tau and tau seeding-associated genes(Rockefeller University Press, 2023) Acri, Dominic J.; You, Yanwen; Tate, Mason D.; Karahan, Hande; Martinez, Pablo; McCord, Brianne; Sharify, A. Daniel; John, Sutha; Kim, Byungwook; Dabin, Luke C.; Philtjens, Stéphanie; Wijeratne, H. R. Sagara; McCray, Tyler J.; Smith, Daniel C.; Bissel, Stephanie J.; Lamb, Bruce T.; Lasagna-Reeves, Cristian A.; Kim, Jungsu; Anatomy, Cell Biology and Physiology, School of MedicinePrevious research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer's disease phenotypes. However, it is unknown what mechanisms underlie these effects of genetic background on modeling tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT. To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n = 64) and determined core transcriptional signature conserved in all genetic backgrounds and signature unique to wild-derived backgrounds. By measuring tau seeding activity using the cortex, we identified 19 key genes associated with tau seeding and amyloid response. Interestingly, microglial pathways were strongly associated with tau seeding activity in CAST/EiJ and PWK/PhJ backgrounds. Collectively, our study demonstrates that mouse genetic context affects tau-mediated alteration of transcriptome and tau seeding. The gene modules associated with tau seeding provide an important resource to better model tauopathy.Item Protocol for the isolation and proteomic analysis of pathological tau-seeds(Elsevier, 2024) Martinez, Pablo; Patel, Henika; You, Yanwen; Doud, Emma H.; Mosley, Amber L.; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of MedicineThe aggregation and spreading of "tau-seeds" are key for the development and progression of tauopathies, including Alzheimer's disease. Here we describe the steps to isolate and analyze biochemically active tau-seeds from human, mouse, and cell origin. We detail the procedure to isolate soluble tau-seeds by size exclusion chromatography and seeding assay. The isolated tau-seed can be further analyzed to determine the interactome by mass spectrometry. This workflow identifies protein-protein interactors of tau-seeds, providing a useful tool for finding new therapeutic targets. For complete details on the use and execution of this protocol, please refer to Martinez et al.1.Item 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 MedicineCerebral 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.Item TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo(MDPI, 2023-06-10) Lee-Gosselin, Audrey; Jury-Garfe, Nur; You, Yanwen; Dabin, Luke; Soni, Disha; Dutta, Sayan; Rochet, Jean-Christophe; Kim, Jungsu; Oblak, Adrian L.; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of MedicineThe role of TREM2 in Alzheimer's disease (AD) is not fully understood. Previous studies investigating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have focused only on tau overexpression models. Herein, we investigated the effects of TREM2 deficiency on tau spreading using a mouse model in which endogenous tau is seeded to produce AD-like tau features. We found that Trem2-/- mice exhibit attenuated tau pathology in multiple brain regions concomitant with a decreased microglial density. The neuroinflammatory profile in TREM2-deficient mice did not induce an activated inflammatory response to tau pathology. These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading. However, caution should be exercised when targeting TREM2 as a therapeutic entry point for AD until its involvement in tau aggregation and propagation is better understood.