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Trabalho de Doutoramento realizado em cotutela: Doutoramento em Envelhecimento e Doenças Crónicas e École Doctorale Cerveau, Cognition, Comportement (Paris, no 158), Chronic stress and high levels of the stress hormone, glucocorticoid (GC), are implicated in susceptibility to brain pathologies such as depression or Alzheimer’s disease (AD), as they promote neural plasticity damage and glial reactivity, which can lead to dendritic/synaptic loss, reduced neurogenesis, mood deficits, and impaired cognition. Growing clinical evidence supports a pathological link between depression and AD and shared neurobiological underpinnings with chronic stress being a potential link between them. Exposure of AD animal models to chronic stress triggers Tau pathology (e.g. Tau hyperphosphorylation and accumulation); the latter is causally related to neuronal malfunction and atrophy. Despite the well-known role of Tau in regulating cytoskeletal dynamics, the involvement of Tau in neurostructural remodeling and neuroplastic damage caused by chronic stress in the adult brain remains poorly explored. In the first objective of my thesis, we demonstrated the crucial role of Tau and its malfunction in stress-driven neurogenic, but not astrogliogenic or oligodendrogenic, damage in the cytogenic niches of the adult brain of wild-type animals (hippocampus and subventricular zone-olfactory bulb system) as mice lacking Tau were protected against stress-driven neurogenic suppression. Also, we showed that chronic stress impacts differentially the distinct phases of maturation of newborn immature neurons in the adult hippocampus. The second objective of my thesis focused on the cell-specific actions of the glucocorticoid receptor, GR, in stress-induced Tau pathology. To examine the role of GR specifically in neurons or microglia under stress conditions, we generated P301LTau mice in which GR gene is conditionally inactivated either in forebrain neurons or in microglia. Our findings show that GR was required in both cell types for chronic stress to induce cognitive deficits. Further analyses (which are ongoing) showed that neuronal GR is important in precipitating Tau neuropathology, and apical spine loss in CA1 hippocampal area. Microglial GR was found to affect microglial reactivity both in response to P301LTau as well as chronic stress-induced Tau pathology. Deletion of microglial GR results in spine loss whereas, it promotes spinogenesis under stress. However, it does not appear to impact Tau aggregation/accumulation. In conclusion, our data point to an important role of neuronal GR in mediating stress-driven Tau neuropathology and also identifies the essential role of microglial GR in stress-induced cognitive deficits. Given that the modern lifestyle increasingly exposes individuals to high stress loads, it is clear that understanding the mechanistic link(s) between chronic stress and AD pathogenesis may facilitate the treatment of AD and other related disorders., O stress crónico e as hormonas do stress, glucocorticoides, são sugeridos como causadores de suscetibilidade neuronal, estando associados a danos na plasticidade cerebral (ex. perda dendrítica/sináptica, neurogénese reduzida), inflamação, bem como a distúrbios neurológicos, como depressão e a doença de Alzheimer (DA); onde o dano da neuroplasticidade é um processo muito importante. Evidências clínicas apoiam uma ligação patológica entre a depressão e a DA, e fundamentos neurobiológicos observados no stress crónico indicam que este pode ser um fator de ligação entre elas. A exposição de modelos animais da DA a stress crónico desencadeiam patologia da proteína Tau, que parece estar relacionada com atrofia e o mau funcionamento neuronal. Tendo como função a regulação do citoesqueleto, a proteína Tau tem um papel importante e inexplorado na remodelação neuroestrutural e nos danos neuroplásticos provocados pelo stress crónico. No primeiro objetivo desta Tese, demonstramos a importância da proteína Tau e o impacto do seu mau funcionamento, causado pelo stress, nos nichos citogénicos do cérebro adulto, com impacto na neurogénese, mas não na astrogliogénese ou oligodendrogénese; pois animais sem a proteína Tau são protegidos contra a supressão neurogénica induzida pelo stress crónico. No segundo objetivo, focamo-nos nas ações do receptor de glucocorticoides (GR) na patologia Tau induzida pelo stress, em tipos celulares específicos. Para isso, geramos murganhos P301LTau com deleção condicional de GR em neurónios ou em microglia. Os resultados mostram que o GR é necessário para a indução de danos cognitivos derivados do stress crónico. O GR neuronal é importante para a precipitação da neuropatologia da Tau bem como para a perda de espinhas apicais na zona CA1 do hipocampo. A deleção de GR na microglia levou à sua reatividade, bem como à perda de espinhas, mas com o stress crónico promoveu a sua génese. A mesma não afetou a agregação/acumulação da proteína Tau. Desta forma, concluímos que os nossos dados apontam para o importante papel do GR neuronal na meadiação da neuropatologia da Tau e identificamos o papel essencial do GR na microglia para a indução de danos cognitivos. Dado que o estilo de vida moderno expõe cada vez mais os indivíduos a altas cargas de stress, é clara a necessidade de compreender melhor a ligação entre o stress crónico e a patogénese da DA, facilitando o tratamento da DA e de outros distúrbios., The work presented in this thesis was performed in the Life and Health Sciences Research Institute (ICVS), University of Minho, Portugal and in the Institute of Biology Paris Seine (IBPS), Sorbonne University, France. Financial Support was provided by a Ph.D. fellowship (PD/BD/127825/2016) from the FCT – Foundation for Science and Technology. This Ph.D. has also been funded by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020; and by the projects, NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, the Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298; POCI-01-0145-FEDER-007038) supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). We acknowledge support from PAULIF, a bilateral “Luso-France Integrated Actions” program and to “France Alzheimer et Maladies Apparentées” program.