EXPLORING THE CHANGES IN PROTEINS AND GLYCOSAMINOGLYCANS SECRETED BY ASTROCYTES IN ALZHEIMER’S DISEASE: IMPLICATIONS FOR THE BRAIN MICROENVIRONMENT

Global changes to the brain microenvironment, including extracellular matrix (ECM) remodelling and immune signalling, occur in Alzheimer’s disease (AD); however, what drives these changes remains unclear. Astrocytes, non-neuronal cells of the brain that support function and survival of neurons, are key architects of the brain microenvironment. They secrete proteins and glycosaminoglycans that underpin shaping the biochemical, structural and immune landscape of the brain. We hypothesised that the set of proteins and glycosaminoglycans secreted by astrocytes are altered in AD and contribute to changes observed in the brain microenvironment. As a model system, we used induced pluripotent stem cells-derived astrocytes (iPSC-astrocytes), either controls or carrying AD-associated mutations in the Presenilin 1 gene. To determine their secreted protein and glycosaminoglycan profiles, we applied liquid chromatography-mass spectrometry (LC-MS/MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) to the conditioned medium of control and AD iPSC-astrocytes in culture. We identified significant changes in the identity and levels of proteins and glycosaminoglycans secreted by AD iPSC-astrocytes as compared to controls. Pathway analyses on the significantly dysregulated proteins revealed global changes to the ECM, glycosaminoglycans-regulating proteins and integrin signalling. Given the importance of astrocytes in establishing and maintaining the brain microenvironment, our findings suggest that astrocytes are involved with changes in the brain microenvironment observed in AD.