Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation

Kolabas, Zeynep Ilgin; Kuemmerle, Louis B.; Perneczky, Robert; Foerstera, Benjamin; Büttner, Maren; Çalışkan, Özüm Şehnaz; Ali, Mayar; Rong, Zhouyi; Mai, Hongcheng; Hummel, Selina; Bartos, Laura M.; Biechele, Gloria; Zatcepin, Artem; Albert, Natalie L.; Gnoerich, Johannes; Zhao, S. J.; Khalin, Igor; Rauchmann, Boris‐Stephan; Molbay, Muge; Sterr, Michael; Kunze, Ines; Stanic, Karen; Besson-Girard, Simon; Kopczak, Anna; Katzdobler, Sabrina; Palleis, Carla; Gökçe, Özgün; Lickert, Heiko; Steinke, Hanno; Bechmann, Ingo; Büerger, Katharina; Levin, Johannes; Haass, Christian; Dichgans, Martin; Havla, Joachim; Kümpfel, Tania; Kerschensteiner, Martin; Simons, Mikael; Plesnila, Nikolaus; Krahmer, Natalie; Bhatia, Harsharan S.; Erener, Süheda; Hellal, Farida; Theis, Fabian J.; Ertürk, Ali

doi:10.1101/2021.12.24.473988

Cited by 13 publications

(19 citation statements)

References 74 publications

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“…In particular, in the skull, recent data demonstrate that the BM niches are different from those in other bones and house a highly heterogeneous set of immune cells displaying unique transcriptional signatures, which are also manifested in specific disease-associated patterns in the human skull, including in patients with stroke. 110 Cranial hematopoiesis and subsequent cellular transcriptional signatures may be modulated by dural cerebrospinal fluid efflux, 111 which may be important as a therapeutic target in neuroinflammatory conditions.…”

Section: Innate Inflammation After Strokementioning

confidence: 99%

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Endres

Moro

Nolte

et al. 2022

Circulation Research

146

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Inflammation and immune mechanisms are crucially involved in the pathophysiology of the development, acute damage cascades, and chronic course after ischemic stroke. Atherosclerosis is an inflammatory disease, and, in addition to classical risk factors, maladaptive immune mechanisms lead to an increased risk of stroke. Accordingly, individuals with signs of inflammation or corresponding biomarkers have an increased risk of stroke. Anti-inflammatory drugs, such as IL (interleukin)-1β blockers, methotrexate, or colchicine, represent attractive treatment strategies to prevent vascular events and stroke. Lately, the COVID-19 pandemic shows a clear association between SARS-CoV2 infections and increased risk of cerebrovascular events. Furthermore, mechanisms of both innate and adaptive immune systems influence cerebral damage cascades after ischemic stroke. Neutrophils, monocytes, and microglia, as well as T and B lymphocytes each play complex interdependent roles that synergize to remove dead tissue but also can cause bystander injury to intact brain cells and generate maladaptive chronic inflammation. Chronic systemic inflammation and comorbid infections may unfavorably influence both outcome after stroke and recurrence risk for further stroke. In addition, stroke triggers specific immune depression, which in turn can promote infections. Recent research is now increasingly addressing the question of the extent to which immune mechanisms may influence long-term outcome after stroke and, in particular, cause specific complications such as poststroke dementia or even poststroke depression.

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Section: Innate Inflammation After Strokementioning

confidence: 99%

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Endres

Moro

Nolte

et al. 2022

Circulation Research

146

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show abstract

“…The skull bone marrow was characterized as myeloid cell reservoirs for the meninges and CNS parenchyma through the channels between skull marrow and meninges [35][36][37]47 . The lymphopoietic niche is also identified in the CNS border meninges [38][39][40] , suggesting the involvement of the skull and meninges in neurological diseases.…”

Section: Sars-cov-2 Infection In the Human Skull Meninges And Brainmentioning

confidence: 99%

SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19

Rong

Mai

Kapoor

et al. 2023

Preprint

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Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the virus's acute and potential chronic impact on the central nervous system. In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis. Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spike's persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway. Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities.

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“…Using the Brainnetome atlas (40), the brain was parcellated into 210 cortical and 36 subcortical volume-of-interests (VOIs) and standardized-uptake-value-ratios (SUVr) were calculated for all four PET read-outs. Per subject, the standardized regional deviation of SUVr (z-score) was calculated versus previously established age- and sex-matched normal cohorts for [ 18 F]flutemetamol (number of controls: n c =13, (33)), [ 18 F]GE-180 (n c =13, (41)), early [ 18 F]PI-2620 (n c =14, (42)) and late [ 18 F]PI-2620 (n c =14, (4)).…”

Section: Methodsmentioning

confidence: 99%

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

Finze

Biechele

Rauchmann

et al. 2022

Preprint

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β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1) and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT= 0.412 ± 0.196 vs. βA= 0.142 ± 0.123, p < 0.001; AD-CBS: βT= 0.385 ± 0.176 vs. βA= 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT= 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. An index of tau- and Aβ-associated microglia activation accounts for regional heterogeneity and allows for clinical and biomarker correlations with ATN-specific neuroinflammation.

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Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation

Cited by 13 publications

References 74 publications

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

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