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"Gate, David"
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Dysregulation of brain and choroid plexus cell types in severe COVID-19
Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms
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–
3
. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease
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–
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. Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans
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and linked to cognitive function
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—is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.
Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.
Journal Article
A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration
The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 with Parkinson’s disease (PD), 27 with Alzheimer’s disease (AD), and 15 with both PD and MCI. The dataset is interactively accessible through a freely available website (
https://www.ccb.uni-saarland.de/adrcsc
). In this work, we identify disease-associated changes in blood cell type composition and the gene expression in a sex-specific manner, offering insights into peripheral and solid tissue signatures in AD and PD.
Neurodegenerative diseases are linked to changes in the immune system and inflammation. Here, the authors studied immune cells from healthy individuals and neurodegenerative diseases and identified sex-specific disease-associated changes.
Journal Article
CNS Infiltration of Peripheral Immune Cells: D-Day for Neurodegenerative Disease?
While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as “immune privilege,” it is now clear that immune responses do occur in the CNS—giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.
Journal Article
Applying single-cell and single-nucleus genomics to studies of cellular heterogeneity and cell fate transitions in the nervous system
Single-cell and single-nucleus genomic approaches can provide unbiased and multimodal insights. Here, we discuss what constitutes a molecular cell atlas and how to leverage single-cell omics data to generate hypotheses and gain insights into cell transitions in development and disease of the nervous system. We share points of reflection on what to consider during study design and implementation as well as limitations and pitfalls.
This Review provides insights for construction of molecular cell atlases and outlines key study design considerations. The authors emphasize the power of single-cell and single-nucleus genomics in revealing cellular transitions during nervous system development and disease.
Journal Article
The haunting in Connecticut 2 : ghosts of Georgia
Building on the terror of The Haunting in Connecticut, this horrifying tale traces a young family's nightmarish descent into a centuries-old Southern hell. When Andy Wyrick moves his wife Lisa and daughter Heidi to an historic home in Georgia, they quickly discover they are not the house's only inhabitants. The family soon comes face-to-face with a bone-chilling mystery born of a deranged desire, a haunting secret rising from underground and threatening to bring down anyone in its path.
DVD
Basic Science and Pathogenesis
Much attention has been paid to the role of the perenchymal brain immune response in Alzheimer's disease (AD). Yet, the peripheral immune system in AD has not been thoroughly studied with modern sequencing methods.
Here, we used a combination of single-cell sequencing strategies, including assay for transposase-accessible chromatin and RNA sequencing, to investigate the epigenetic and transcriptional alterations to the AD peripheral immune system.
We reveal a striking amount of open chromatin in peripheral immune cells in AD. In CD8 T cells, we uncover a cis-regulatory DNA element co-accessible with the CXC motif chemokine receptor 3 gene promoter. In monocytes, we identify a novel RELA transcription factor binding site adjacent to an open chromatin region in the nuclear factor kappa B subunit 2 gene. We also demonstrate apolipoprotein E genotype-dependent epigenetic changes that correspond to altered cytokine gene expression in monocytes. Surprisingly, we also identify differentially accessible chromatin regions in genes associated with sporadic AD. Finally, we provide an online data portal resource to explore gene expression in the AD immune system.
Our findings provide novel insights into the complex relationship between epigenetics and genetic risk factors in the AD peripheral immune system.
Journal Article