The Human Microglia Atlas (HuMicA) unravels changes in disease-associated microglia subsets across neurodegenerative conditions

Abstract

Microglia; Neurodegenerative diseases

Microglía; Enfermedades neurodegenerativas

Microglia; Malalties neurodegeneratives

Dysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression. We constructed an atlas of human brain immune cells by integrating nineteen single-nucleus RNA-seq and single-cell RNA-seq datasets from multiple neurodegenerative conditions, comprising 241 samples from patients with Alzheimer’s disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integrated Human Microglia Atlas (HuMicA) included 90,716 nuclei/cells and revealed nine populations distributed across all conditions. We identified four subtypes of disease-associated microglia and disease-inflammatory macrophages, recently described in mice, and shown here to be prevalent in human tissue. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution in shaping pathological phenotypes. A GPNMB-high subpopulation was expanded in AD and MS. In situ hybridization corroborated this increase in AD, opening the question on the relevance of this population in other pathologies.

We would like to acknowledge all the authors that contributed for the development of the studies from which the data used in our HuMicA was collected. The importance of public data access must always be reinforced as a paramount tool for the progression of scientific knowledge, allowing for alternative interpretations of the original data and additional discoveries. We thank the CERCA Programme/Generalitat de Catalunya, the Josep Carreras Foundation and ICBAS-UP for institutional support. E.B. is funded by the Spanish Ministry of Science and Innovation (MICINN) [PID2020117212RB-I00; AEI/10.13039/501100011033] and the Catalan Agency for Management of University and Research Grants (AGAUR, 2021 SGR 01213). R.M.-F. was funded by an FCT (Fundação para a Ciência e Tecnologia) fellowship (SFRH/BD/137900/2018). UMIB is funded by FCT Portugal (UIDB/00215/2020 and UIDP/00215/2020), and ITR (LA/P/006/2020). A.L. is funded by Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (Spain)-FEDER (PI21/01603) and MICINN (Ramón y Cajal [RYC2021-032947-I] financed by MCIN/AEI/10.13039/501100011033 and the European Union-NextGenerationEU/PRTR). EM.‘s work in this publication was supported by the Ramón y Cajal fellowship RYC2021-032359-I, funded by the Spanish Ministry of Science, and by the Catalan Agency for Management of University and Research Grants (AGAUR, 2021 SGR 01586). Our acknowledgments also extent to all members of the Epigenetics and Immune Disease Group at the Josep Carreras Leukaemia Research institute, to Prof. Berta Martins da Silva and the Immunogenetics Laboratory of ICBAS-UP, and to Prof. António Martins da Silva, M.D. and Dr. João Chaves from Hospital de Santo António – Centro Hospitalar e Universitário do Porto (HSA-CHUP) for the continuous collaborations and guidance. We also thank for advice Dr. Marta Martinez-Vicente from the Autophagy and Lysosomal Dysfunction Lab, Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute-CIBERNED, 08035 Barcelona. We are indebted to brain donors and families for the generous donation of brain tissue for diagnostic and research purposes to the Vall d’Hebron Neurological Tissue Bank (PR(AG)200/2013). We want to particularly acknowledge the patients and the Biobank Banco de Tejidos CIEN for their collaboration. We are grateful to Marta Valeri and Cristina de Dios from the Microscopy Core Facility at the High Technology Unit (UAT) from VHIR for support in confocal imaging; Teresa Moline from the Pathology Department at Vall d’Hebron University Hospital for assistance in histological processing.