Differences in AD astrocyte phenotypes and responses to microglial-derived cytokines

Ferreira, Sofia Gravanita

http://hdl.handle.net/10362/52582

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Autores

Ferreira, Sofia Gravanita

Orientador(es)

Brites, Dora

Borralho, Adelaide

Resumo(s)

Dysregulated cross-talk between activated glia and neurons, mediated by exosomal trafficking, is a key mechanism in the spreading of neuroinflammation and in the exacerbation of the Alzheimer’s disease (AD) pathology. In AD patients, A1 reactive astrocytes are found in brain regions affected by neurodegeneration, and display a neurotoxic profile that is crucial for the disease progression. Despite its pivotal role in AD progression, the astroglial population remains strikingly under-investigated, mainly due to the lack of reliable experimental biological platforms to study glial cell function in a disease context. In this thesis, our goal was to develop a human model able to recapitulate the pathological potential of AD astrocytes, thus surpassing species-specific differences in the study of neurodegenerative mechanisms. For that we differentiated astrocytes from iPSCs generated from the fibroblasts of AD patients and healthy matched controls. After a time-consuming process of differentiation, iPSCs-derived astrocytes from AD patients with PSEN1ΔE9 mutation showed a decrease in cellular HMGB1, S100B and microRNA (miR)-155 expression, together with a reduction in the number of GFAP-positive cells, a finding sustained after A1 induction for 48 h exposure to microglial cytokines (C1q/IL-1α/TNF-α), relatively to matched controls. Such treatment decreased cell arborisation leading to polarization as fibroblast-like and rounded cells, with increased mean surface area, and triggered the release of sAPPβ. A1 stimulation increased miR-155 in cells and exosomes, while diminished the cellular increase in miR-21 and miR-125b by inducing their package in exosomes, thus favouring the dissemination of inflammation to far and near cells. As observed in vivo, our cell population showed astrocyte heterogeneity, mainly for alarmins and miRNAs. In sum, astrocytic atrophy and abnormal distribution of inflammatory-miRNA in iPSCs-derived astrocytes carrying the PSEN1ΔE9 mutation and in their exosomes may provide important tools in targeting discovery, therapeutic development and personalised medicine for AD intervention.