Gomes, Cláudio Emanuel MoreiraRousseau, FredericRomão, Mariana Amoroso das Neves2023-01-032022-102022-06http://hdl.handle.net/10451/55590Alzheimer’s disease (AD) is the most prominent cause of dementia and is accompanied by chronic neuroinflammation, protein aggregation and formation of amyloids. During inflammation important modulators of inflammatory responses are implicated, including cytokines and chemokines, among which are S100 proteins. Expression levels of S100 proteins are increased in inflammatory diseases and neurodegenerative disorders such as AD, where they are found around amyloid plaques. This was suggestive of a functional link with Aβ aggregation, in agreement with the newly uncovered activity of S100B as a chaperone suppressor of amyloid formation. This PhD thesis aimed at investigating the role and S100 proteins as potential modifiers of proteostasis in pathophysiological states, resorting to different model systems - from brains of animal models to isolated proteins and peptides, combining cellular, molecular, biophysical, and biochemical techniques. First the distribution of S100 proteins in the brains of AD APP23 mice models was investigated. Results showed that in the brain of wild type mice, S100A6 and S100B are mostly expressed in astrocytes, while low expression of S100A8 was found in neurons and glial cells in vitro. Analysis of APP23 mice brains revealed increased expression of S100A8 in neurons and co-localization of S100 proteins with Aβ plaques. In vitro assays showed that S100A6, S100A8, S100A9, S100A8/A9, delay Aβ aggregation, similarly to S100B. This regulatory activity is similar to that of molecular chaperones, which highlights the potential of S100 proteins as regulators of proteostasis in pathophysiological states. Next, the focus was on the S100A9 protein which is abundant in the brain and has been linked with amyloid formation and deposition in neurodegenerative disorders. We investigated the self-assembly of the S100A9 protein and characterized the formation of polymeric structures formed by this protein, combining biophysical spectroscopies and biochemical assays, outlining the steps of a possible mechanism of functional assembly of this protein with relevance in health and disease.engAgregação e Enrolamento de ProteínasBiofísica de ProteínasDoença de AlzheimerProteínas que ligam CálcioChaperões MolecularesProtein Folding and aggregationProtein BiophysicsAlzheimer’s diseaseCalcium proteinsMolecular Chaperonesdoctoral thesis101580533