Publications by authors named "Zachary Papadopoulos"

6 Publications

  • Page 1 of 1

Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.

Nature 2021 May 28;593(7858):255-260. Epub 2021 Apr 28.

Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.

Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
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http://dx.doi.org/10.1038/s41586-021-03489-0DOI Listing
May 2021

Functional characterization of the dural sinuses as a neuroimmune interface.

Cell 2021 Feb 27;184(4):1000-1016.e27. Epub 2021 Jan 27.

Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA; Gutenberg Research Fellowship Group of Neuroimmunology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn(2)), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address:

Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of multiple sclerosis.
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http://dx.doi.org/10.1016/j.cell.2020.12.040DOI Listing
February 2021

Meningeal Lymphatics: From Anatomy to Central Nervous System Immune Surveillance.

J Immunol 2020 01;204(2):286-293

Center for Brain Immunology and Glia, Neuroscience Graduate Program, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908

At steady state, the CNS parenchyma has few to no lymphocytes and less potent Ag-presentation capability compared with other organs. However, the meninges surrounding the CNS host diverse populations of immune cells that influence how CNS-related immune responses develop. Interstitial and cerebrospinal fluid produced in the CNS is continuously drained, and recent advances have emphasized that this process is largely taking place through the lymphatic system. To what extent this fluid process mobilizes CNS-derived Ags toward meningeal immune cells and subsequently the peripheral immune system through the lymphatic vessel network is a question of significant clinical importance for autoimmunity, tumor immunology, and infectious disease. Recent advances in understanding the role of meningeal lymphatics as a communicator between the brain and peripheral immunity are discussed in this review.
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http://dx.doi.org/10.4049/jimmunol.1900838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061974PMC
January 2020

Lymphatic Cannulation for Lymph Sampling and Molecular Delivery.

J Immunol 2019 10 13;203(8):2339-2350. Epub 2019 Sep 13.

Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY 10461;

Unlike the blood, the interstitial fluid and the deriving lymph are directly bathing the cellular layer of each organ. As such, composition analysis of the lymphatic fluid can provide more precise biochemical and cellular information on an organ's health and be a valuable resource for biomarker discovery. In this study, we describe a protocol for cannulation of mouse and rat lymphatic collectors that is suitable for the following: the "omic" sampling of pre- and postnodal lymph, collected from different anatomical districts; the phenotyping of immune cells circulating between parenchymal organs and draining lymph nodes; injection of known amounts of molecules for quantitative immunological studies of nodal trafficking and/or clearance; and monitoring an organ's biochemical omic changes in pathological conditions. Our data indicate that probing the lymphatic fluid can provide an accurate snapshot of an organ's physiology/pathology, making it an ideal target for liquid biopsy.
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http://dx.doi.org/10.4049/jimmunol.1900375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783364PMC
October 2019

Chronic Traumatic Encephalopathy: Is Latency in Symptom Onset Explained by Tau Propagation?

Cold Spring Harb Perspect Med 2018 02 1;8(2). Epub 2018 Feb 1.

Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, Massachusetts 02118.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild brain trauma. CTE, previously termed "dementia pugilistica," has been identified in American football, ice hockey, baseball, rugby and soccer players, boxers, wrestlers, and military personnel exposed to blast and other traumatic brain injuries. There is often a long latency period between an individual's exposure to repetitive brain trauma and the clinical symptoms of CTE. The pathology of CTE is characterized by a progression from isolated focal perivascular hyperphosphorylated tau lesions in the cerebral cortex to a widespread tauopathy that involves diffuse cortical and medial temporal lobe regions. We hypothesize that the spread of tau from focal perivascular lesions to a widespread tauopathy occurs as a result of intraneuronal and intrasynaptic prion-like protein templating, as well as tau secretion and propagation along glymphatic and cerebrospinal fluid pathways.
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http://dx.doi.org/10.1101/cshperspect.a024059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793739PMC
February 2018

Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study.

Alzheimers Res Ther 2015 Oct 12;7(1):62. Epub 2015 Oct 12.

Alzheimer's Disease Center, Boston University School of Medicine, 72 East Concord Street, B-7800, Boston, MA, 02118, USA.

Introduction: Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as "at risk" for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE.

Methods: Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE.

Results: We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology.

Conclusions: The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.
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http://dx.doi.org/10.1186/s13195-015-0148-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601147PMC
October 2015