A single cell-based atlas of human microglial states reveals associations with neurological disorders and histopathological features of the aging brain
Marta Olah,Menon,Naomi Habib,Mariko Taga,Christina J. Yung,Maria Cimpean,Khairalla A,Danielle Dionne,Sarah C. Hopp,Matthew P. Frosch,B. T. Hyman,Thomas G. Beach,Rani A. Sarkis,Garth Rees Cosgrove,Jeffrey Helgager,Jeffrey A. Golden,Page B. Pennell,Julie A. Schneider,David A. Bennett,Aviv Regev,Wassim Elyaman,Elizabeth M. Bradshaw,De Jager Pl +22 more
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TLDR
Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies, and several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microGlia.Abstract:
Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.read more
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The multiplex model of the genetics of Alzheimer’s disease
TL;DR: The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.
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CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
John V. Pluvinage,Michael S. Haney,Benjamin A. H. Smith,Jerry Sun,Tal Iram,Liana Bonanno,Lulin Li,Davis P. Lee,David W. Morgens,Andrew C. Yang,Steven R. Shuken,David Gate,Madeleine K D Scott,Purvesh Khatri,Jian Luo,Jian Luo,Carolyn R. Bertozzi,Michael C. Bassik,Tony Wyss-Coray +18 more
TL;DR: CD22 inhibits microglial phagocytosis in the ageing brain, and treatment with a CD22-blocking antibody restores microglia homeostasis and cognitive function in ageing mice.
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Neuropathological correlates and genetic architecture of microglial activation in elderly human brain.
Daniel Felsky,Daniel Felsky,Tina Roostaei,Kwangsik Nho,Shannon L. Risacher,Elizabeth M. Bradshaw,Vlad Petyuk,Julie A. Schneider,Andrew J. Saykin,David A. Bennett,Philip L. De Jager,Philip L. De Jager +11 more
TL;DR: The proportion of morphologically activated microglia in postmortem cortical tissue is strongly associated with β-amyloid, tau-related neuropathology, and the rate of cognitive decline, and mediation models support an upstream role for microglial activation in Alzheimer’s disease via accumulation of tau.
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Transcriptional profiling of microglia; current state of the art and future perspectives
TL;DR: Results show that microglia nuclear RNAs obtained from frozen CNS tissue are a reliable proxy for microglian gene expression and cellular heterogeneity and may prove an effective strategy to study of the role of microglIA in neuropathology.
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Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells.
Vasiliki Panagiotakopoulou,Vasiliki Panagiotakopoulou,Dina Ivanyuk,Dina Ivanyuk,Silvia De Cicco,Silvia De Cicco,Wadood Haq,Aleksandra Arsić,Cong Yu,Cong Yu,Daria Messelodi,Daria Messelodi,Marvin Oldrati,Marvin Oldrati,David C. Schöndorf,David C. Schöndorf,Maria-Jose Perez,Maria-Jose Perez,Ruggiero Pio Cassatella,Ruggiero Pio Cassatella,Meike Jakobi,Nicole Schneiderhan-Marra,Thomas Gasser,Thomas Gasser,Ivana Nikić-Spiegel,Michela Deleidi,Michela Deleidi +26 more
TL;DR: It is proposed that synergistic LRRK2/IFN-γ activation serves as a potential link between inflammation and neurodegeneration in Parkinson’s disease.
References
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The microglial sensome revealed by direct RNA sequencing
Suzanne E. Hickman,Nathan D. Kingery,Toshiro K. Ohsumi,Mark L. Borowsky,Li-chong Wang,Terry K. Means,Joseph El Khoury +6 more
TL;DR: It is found that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that are referred to as the sensome and aging was associated with an overall increase in the expression of microglial genes involved in neuroprotection.
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