NORADRENERGIC DYSFUNCTION AND ASTROCYTE HETEROGENEITY ALONG THE LOCUS COERULEUS- HIPPOCAMPUS AXIS IN ALZHEIMER'S DISEASE AND RELATED DEMENTIA

Neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) represent an increasing economic and medical challenge due to the ageing population and a partial understanding of the detrimental mechanisms. These age-related disorders share several pathological hallmarks such as abnormal intra- and extracellular misfolded protein aggregation. Yet, the implication of astrocytes, one of the major glial cell types with key physiological functions (e.g. maintenance of brain homeostasis, neuroprotection, etc.), and their relationship to early noradrenergic system deterioration still need to be further investigated. After decades on the sidelines, recent research has revealed the significant contribution of astrocytes to the progression of neurodegeneration. They are known to change their properties and react to brain insults, with exhibiting a spectrum of reactive responses which may become toxic under certain conditions. Noradrenaline (NA) is a strong modulator of astrocytes and has potent anti-inflammatory and anti-oxidative effects on these cells. Interestingly, it has been shown that an alteration of the noradrenergic system affects glial cells in AD and PD. However, how NA system disruption affects astrocyte function and responses in such disorders is still poorly understood. Furthermore, the astrocytic heterogeneity is increasingly recognised, since astrocytes exhibit notable diversity in morphologies, properties and functionality between and within brain regions. Nevertheless, their heterogeneity is still poorly considered as a factor of regional vulnerability and/or in the progression of NDDs. This PhD thesis addressed two crucial aspects of astrocyte implication in NDDs pathophysiology. The first study provides a detailed characterisation of the heterogeneity of the hippocampal astrocytes and their distribution within the hippocampus of healthy individuals as well as patients with AD and PD with dementia (PDD). Using a high-content neuropathological approach involving chromogenic immunohistochemistry and digital pathology, we discovered specific distribution patterns of astrocyte markers, suggesting the existence of distinct subpopulations with region-specific vulnerabilities and molecular signatures. In addition, we also emphasise the importance of incorporating new markers in order to capture the full astrocytic response to neurodegeneration. The second study provides a comprehensive understanding of the modulatory role of NA on astrocyte physiology and responses. By combining bulk RNA sequencing on primary mouse astrocytes with RT-qPCR, cytokine assays and digital pathology analyses on post-mortem brain samples, we demonstrated that NA influences core astrocyte functions, and that the expression of NA-sensitive genes in hippocampal astrocytes is severely altered in NDDs. Our results suggest that the intimate relationship between the noradrenergic system and the astrocytes affords a significant phenotypic control of the astrocytes by NA and may be drastically impacted in disease. NA deprivation might lead to altered astrocyte roles and impaired neuroprotection, thus enhancing pathology progression.