Browsing by Author "Bissel, Stephanie J."
Now showing 1 - 9 of 9
Results Per Page
Sort Options
Item Age-Related Pathology Associated with H1N1 A/California/07/2009 Influenza Virus Infection(Elsevier, 2019-12) Bissel, Stephanie J.; Carter, Chalise E.; Wang, Guoji; Johnson, Scott K.; Lashua, Lauren P.; Kelvin, Alyson A.; Wiley, Clayton A.; Ghedin, Elodie; Ross, Ted M.; Medical and Molecular Genetics, School of MedicineInfluenza virus infection causes a spectrum of diseases, ranging from mild upper respiratory tract infection to severe lower respiratory tract infection, that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood, but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with a higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia after 2009 H1N1 influenza virus infection in newly weaned, adult, and aged ferrets to better understand age-dependent susceptibility and pathology. Aged ferrets exhibited greater weight loss and higher rates of mortality than adult ferrets, whereas most newly weaned ferrets did not lose weight but had a lack of weight gain. Newly weaned ferrets exhibited minimal pneumonia, whereas adult and aged ferrets had a spectrum of pneumonia severity. Influenza virus-induced pneumonia peaked earliest in adult ferrets, whereas aged ferrets had delayed presentation. Bronchial severity differed among groups, but bronchial pathology was comparable among all cohorts. Alveolar infection was strikingly different among groups. Newly weaned ferrets had little alveolar cell infection. Adult and aged ferrets had alveolar infection, but aged ferrets were unable to clear infection. These different age-related pneumonia and infection patterns suggest therapeutic strategies to treat influenza should be tailored contingent on age.Item Genetic Variants of Phospholipase C-γ2 Alter the Phenotype and Function of Microglia and Confer Differential Risk for Alzheimer’s Disease(Elsevier, 2023) Tsai, Andy P.; Dong, Chuanpeng; Lin, Peter Bor-Chian; Oblak, Adrian L.; Di Prisco, Gonzalo Viana; Wang, Nian; Hajicek, Nicole; Carr, Adam J.; Lendy, Emma K.; Hahn, Oliver; Atkins, Micaiah; Foltz, Aulden G.; Patel, Jheel; Xu, Guixiang; Moutinho, Miguel; Sondek, John; Zhang, Qisheng; Mesecar, Andrew D.; Liu, Yunlong; Atwood, Brady K.; Wyss-Coray, Tony; Nho, Kwangsik; Bissel, Stephanie J.; Lamb, Bruce T.; Landreth, Gary E.; Medical and Molecular Genetics, School of MedicineGenetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.Item Infiltration of inflammatory macrophages and neutrophils and widespread pyroptosis in lung drive influenza lethality in nonhuman primates(Public Library of Science, 2022-03-10) Corry, Jacqueline; Kettenburg, Gwenddolen; Upadhyay, Amit A.; Wallace, Megan; Marti, Michelle M.; Wonderlich, Elizabeth R.; Bissel, Stephanie J.; Goss, Kyndal; Sturgeon, Timothy J.; Watkins, Simon C.; Reed, Douglas S.; Bosinger, Steven E.; Barratt-Boyes, Simon M.; Medical and Molecular Genetics, School of MedicineSevere influenza kills tens of thousands of individuals each year, yet the mechanisms driving lethality in humans are poorly understood. Here we used a unique translational model of lethal H5N1 influenza in cynomolgus macaques that utilizes inhalation of small-particle virus aerosols to define mechanisms driving lethal disease. RNA sequencing of lung tissue revealed an intense interferon response within two days of infection that resulted in widespread expression of interferon-stimulated genes, including inflammatory cytokines and chemokines. Macaques with lethal disease had rapid and profound loss of alveolar macrophages (AMs) and infiltration of activated CCR2+ CX3CR1+ interstitial macrophages (IMs) and neutrophils into lungs. Parallel changes of AMs and neutrophils in bronchoalveolar lavage (BAL) correlated with virus load when compared to macaques with mild influenza. Both AMs and IMs in lethal influenza were M1-type inflammatory macrophages which expressed neutrophil chemotactic factors, while neutrophils expressed genes associated with activation and generation of neutrophil extracellular traps (NETs). NETs were prominent in lung and were found in alveolar spaces as well as lung parenchyma. Genes associated with pyroptosis but not apoptosis were increased in lung, and activated inflammatory caspases, IL-1β and cleaved gasdermin D (GSDMD) were present in bronchoalveolar lavage fluid and lung homogenates. Cleaved GSDMD was expressed by lung macrophages and alveolar epithelial cells which were present in large numbers in alveolar spaces, consistent with loss of epithelial integrity. Cleaved GSDMD colocalized with viral NP-expressing cells in alveoli, reflecting pyroptosis of infected cells. These novel findings reveal that a potent interferon and inflammatory cascade in lung associated with infiltration of inflammatory macrophages and neutrophils, elaboration of NETs and cell death by pyroptosis mediates lethal H5N1 influenza in nonhuman primates, and by extension humans. These innate pathways represent promising therapeutic targets to prevent severe influenza and potentially other primary viral pneumonias in humans.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 PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease(Springer, 2022-02-18) Tsai, Andy P.; Dong, Chuanpeng; Lin, Peter Bor-Chian; Messenger, Evan J.; Casali, Brad T.; Moutinho, Miguel; Liu, Yunlong; Oblak, Adrian L.; Lamb, Bruce T.; Landreth, Gary E.; Bissel, Stephanie J.; Nho, Kwangsik; Medical and Molecular Genetics, School of MedicineBackground Alzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role of PLCG2 in AD is still poorly understood. Methods Using bulk RNA-Seq (N=1249) data from the Accelerating Medicines Partnership-Alzheimer’s Disease Consortium (AMP-AD), we investigated whether PLCG2 expression increased in the brains of LOAD patients. We also evaluated the relationship between PLCG2 expression levels, amyloid plaque density, and expression levels of microglia specific markers (AIF1 and TMEM119). Finally, we investigated the longitudinal changes of PLCG2 expression in the 5xFAD mouse model of AD. To further understand the role of PLCG2 in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivated Plcg2 mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology. Results We observed significant upregulation of PLCG2 expression in three brain regions of LOAD patients and significant positive correlation of PLCG2 expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology. Of note, increased Plcg2 expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low) PLCG2 gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice. PLCG2 co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide. Conclusions Our results provide further evidence that PLCG2 plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.Item The Role of the Lung-Brain Axis in the Ozone-Impaired Amyloid Associated Astrocytic and Vascular Phenotype(2024-06) Ahmed, Chandrama; Oblak, Adrian; Block, Michelle; Baucum, A. J.; Bissel, Stephanie J.; Nass, Richard M.Air pollution has been associated with an increased risk of Alzheimer’s Disease (AD). Studies show ozone (O3), a major component of urban air pollution, can exacerbate amyloid pathology. However, O3 reacts in its entirety with lung epithelial lining after inhalation, hence does not translocate to brain. Studies have implicated the lung−brain axis in O3 induced central nervous system (CNS) pathology. However, the mechanistic underpinnings of its role in amyloid pathology is obscure. Here, we explored the impact of O3 on the astrocytic and vascular response to amyloid plaque in 5xFAD mice and its link to the O3 lung response. O3 exposure increased GFAP positive astrocyte density correlating with increased plaque burden in the cortex. Focusing on the plaque microenvironment, we found O3 qualitatively altered plaque associated astrocytes, evidenced by both proteomic and transcriptomic changes. Along with loss of protein expression, proteomic changes reflected increased cell-cell interaction in plaque microenvironment. Specifically, we found increased astrocyte-microglia contact selectively in periplaque space from O3 exposure. Transcriptional analysis of periplaque astrocytes revealed an accelerated shift towards disease associated astrocyte (DAA) phenotype. Elevated circulating HMGB1 was previously found from O3 exposure. In this study we demonstrate deleting HMGB1 selectively in peripheral myeloid cells and not in CNS microglia ameliorates the lung immune response to O3 as well as downregulates DAA marker in the CNS, providing a potential link between peripheral HMGB1 and O3 induced astrocytic dysregulation. On examining vascular response to O3 we found increased vascular amyloid accumulation associated with an altered vascular proteomic profile. Our analysis indicates O3 potentially disrupts vascular function such as amyloid clearance. Taken together, our study demonstrates that astrocyte and neurovasculature are contributors to O3 lung-brain axis with important implications towards amyloid pathology progression and identifies peripheral myeloid HMGB1 as its potential modulator. Further studies are required to fully understand the consequences of this impact and its role in amyloid pathology.Item TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation(BMC, 2023-02-20) Moutinho, Miguel; Coronel, Israel; Tsai, Andy P.; Di Prisco, Gonzalo Viana; Pennington, Taylor; Atwood, Brady K.; Puntambekar, Shweta S.; Smith, Daniel C.; Martinez, Pablo; Han, Seonggyun; Lee, Younghee; Lasagna‑Reeves, Cristian A.; Lamb, Bruce T.; Bissel, Stephanie J.; Nho, Kwangsik; Landreth, Gary E.; Anatomy, Cell Biology and Physiology, School of MedicineBackground: TREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer's disease (AD) brain. TREM2 is also present in a soluble form (sTREM2), and its CSF levels fluctuate as a function of AD progression. Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor. However, alternatively spliced TREM2 species lacking a transmembrane domain have been postulated to contribute to the pool of sTREM2. Thus, both the source of sTREM2 species and its actions in the brain remain unclear. Methods: The expression of TREM2 isoforms in the AD brain was assessed through the analysis of the Accelerating Medicines Partnership for Alzheimer's Disease Consortium transcriptomics data, as well as qPCR analysis using post-mortem samples of AD patients and of the AD mouse model 5xFAD. TREM2 cleavage and secretion were studied in vitro using HEK-293T and HMC3 cell lines. Synaptic plasticity, as evaluated by induction of LTP in hippocampal brain slices, was employed as a measure of sTREM2 actions. Results: Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2230), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2222) and ENST00000338469 (TREM2219), are moderately increased in specific brain regions of patients with AD. We provide experimental evidence that TREM2 alternatively spliced isoforms are translated and secreted as sTREM2. Furthermore, our functional analysis reveals that all sTREM2 species inhibit LTP induction, and this effect is abolished by the GABAA receptor antagonist picrotoxin. Conclusions: TREM2 transcripts can give rise to a heterogeneous pool of sTREM2 which acts to inhibit LTP. These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease. Given that sTREM2 levels are linked to AD pathogenesis and progression, our finding that sTREM2 species interfere with LTP furthers our understanding about the role of TREM2 in AD.Item Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice(BMC, 2020-10-28) Jadhav, Vaishnavi S.; Lin, Peter B. C.; Pennington, Taylor; Di Prisco, Gonzalo Viana; Jannu, Asha Jacob; Xu, Guixiang; Moutinho, Miguel; Zhang, Jie; Atwood, Brady K.; Puntambekar, Shweta S.; Bissel, Stephanie J.; Oblak, Adrian L.; Landreth, Gary E.; Lamb, Bruce T.; Medical and Molecular Genetics, School of MedicineBackground Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. Supplementary information Supplementary information accompanies this paper at 10.1186/s13024-020-00409-0.Item Trem2-deficiency aggravates and accelerates age-related myelin degeneration(Springer Nature, 2024-09-19) McCray, Tyler J.; Bedford, Logan M.; Bissel, Stephanie J.; Lamb, Bruce T.; Medical and Molecular Genetics, School of MedicineAging is the greatest known risk factor for most neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and a normal part of aging; albeit, to a lesser extent. Despite this, little is known about the contribution of age-related myelin degeneration on neurodegenerative disease. Microglia participate in modulating white matter events from demyelination to remyelination, including regulation of (de)myelination by the microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2). Here, we demonstrate Trem2-deficiency aggravates and accelerates age-related myelin degeneration in the striatum. We show TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. In response to demyelination, TREM2 is required for phagocytosis of large volumes of myelin debris. In addition to lysosomal regulation, we show TREM2 can modify the ER stress response, even prior to overt myelin debris, that prevents lipid accumulation and microglial dysfunction. These data support a role for Trem2-dependent interactions in age-related myelin degeneration and suggest a basis for how early dysfunctional microglia could contribute to disease pathology through insufficent repair, defective phagocytosis, and the ER stress response.