Singel-cell characterisation of ageing and disease

Besson-Girard, Simon (2023): Singel-cell characterisation of ageing and disease. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Over the last decade, emerging single-cell technologies triggered a revolution in our perception of biological systems. While new library generation methods flourished and precipitated a deeper understand- ing of the mechanisms of life, novel computational analyses saw the light, permeabilising even further the boundaries of the field. Systemic approaches, by the large scope and complexity that they aim to cover, particularly benefited from this leap. Unravelling the heterogeneity of cells identities is key to understanding their states dynamic and how they influence each others with regards to the host phenotype. In this cumulative thesis, we present two articles that highlight ageing immune mechanisms as fertile soil for the emergence of neu- rodegeneration. We demonstrated the critical influence of the cell location on the gene expression and cellular state, especially in the white-matter, a lipid-rich region of the parenchyma that is particu- larly susceptible to ageing and neurodegeneration. The first article focuses on a microglial population found in the ageing white matter: the white matter associated microglia (WAM). We show that WAM formation is dependent on TREM2 but not APOE. WAMs present pathways significantly enriched in lipid processing and antigen presentation. They cluster in nodules and are engaged in clearing the myelin degradation accumulating in ageing. The second article complements the WAM study by exploring fur- ther the antigen presentation mechanisms. It also focuses on the ques- tion of white-matter volume loss more directly. We show that CD8 T cells, by crossing the blood-brain barrier, and entering the immuno- logically priviledged central nervous system, play a role in oligoden- drocyte degeneration, notably by secretion of interferon-γ, that we confirm to be detrimental specifically in the aged brain. Overall, we deliver new arguments to enrich the dichotomic de- bate on the good and bad role of microglia in ageing and disease. Fur- thermore, we illustrate the current trajectory of single-cell-enriched research at the interface of the neuroscience and immunology fields. We provide revolutionary insights revealing the importance of the lo- cation, signalling and environmental context of a cell in the shaping of its identity and the functions that it carries. Identifying further the mechanisms of ageing draws an optimistic horizon for the future of medical treatment and life improvement in ageing and disease.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Aging, Dementia, Microglia, Neuron, Brain
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 29. September 2023
• 1. Bericht­erstatter:in: Gökçe, Öszgün