Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood–brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Neuroscience |
| Vol/bind | 25 |
| Udgave nummer | 8 |
| Sider (fra-til) | 1034-1048 |
| Antal sider | 15 |
| ISSN | 1097-6256 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We would like to thank G. Mesander, J. Teunis and T. Bijma from the flow cytometry unit of the University Medical Center Groningen for sorting of the nuclei; L. Hesse and L. Apperloo for use of the 10x Genomics Chromium system; M. Meijer and H. van Weering for microscopy; J. Mulder for the WDR49 antibody; W. Baron and J. Dallinga-de Jonge for materials; the Research Sequencing Facility of the University Medical Center Groningen for sequencing; and the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine high-performance computing cluster. We would like to thank the Netherlands Brain Bank and S. Leclère-Turbant of the Neuro-CEB brain bank for providing brain tissues. We would like to thank D. J. Irwin (University of Pennsylvania) for sharing the digital analysis protocol for pathology quantification using the open-source QuPath software. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project ID 739510). E.G. was funded by the Graduate School of Medical Sciences of the University of Groningen. I.L.B. received funding from the ‘Investissements d’avenir ANR-11INBS-0011’ and the ‘Programme Hospitalier de Recherche Clinique FTLD-exome’ (promotion AP-HP). This study was supported by ZonMw (project no. 733050513), the Bluefield Project to Cure Frontotemporal Dementia and Alzheimer Nederland (WE.03-2019-09). This project was co-financed by the Ministry of Economic Affairs and Climate Policy by means of the PPP allowance made available by the Top Sector Life Sciences & Health to stimulate public–private partnerships. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
Funding Information:
We would like to thank G. Mesander, J. Teunis and T. Bijma from the flow cytometry unit of the University Medical Center Groningen for sorting of the nuclei; L. Hesse and L. Apperloo for use of the 10x Genomics Chromium system; M. Meijer and H. van Weering for microscopy; J. Mulder for the WDR49 antibody; W. Baron and J. Dallinga-de Jonge for materials; the Research Sequencing Facility of the University Medical Center Groningen for sequencing; and the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine high-performance computing cluster. We would like to thank the Netherlands Brain Bank and S. Leclère-Turbant of the Neuro-CEB brain bank for providing brain tissues. We would like to thank D. J. Irwin (University of Pennsylvania) for sharing the digital analysis protocol for pathology quantification using the open-source QuPath software. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project ID 739510). E.G. was funded by the Graduate School of Medical Sciences of the University of Groningen. I.L.B. received funding from the ‘Investissements d’avenir ANR-11INBS-0011’ and the ‘Programme Hospitalier de Recherche Clinique FTLD-exome’ (promotion AP-HP). This study was supported by ZonMw (project no. 733050513), the Bluefield Project to Cure Frontotemporal Dementia and Alzheimer Nederland (WE.03-2019-09). This project was co-financed by the Ministry of Economic Affairs and Climate Policy by means of the PPP allowance made available by the Top Sector Life Sciences & Health to stimulate public–private partnerships. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
ID: 316679435