Hippocampal and cerebellar astrocytes differentially engage protein translation mechanisms following Aβ oligomer exposure

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aβ) peptides, with oligomeric forms implicated in synaptic dysfunction and neuroinflammation. Distinct brain regions exhibit varying vulnerability to both AD pathogenesis and functional alterations associated with normal brain aging. Astrocytes, essential glial cells in the central nervous system, play a pivotal role in maintaining homeostasis and responding to pathological insults. Despite this, region-specific alterations in the astrocytic proteome following exposure to Aβ oligomers (AβO) remain poorly understood. To address this knowledge gap, our study utilized a comprehensive differential proteomics approach to compare the protein expression profiles of cultured astrocytes derived from two distinct brain regions: the hippocampus and the cerebellum, following AβO exposure. We found notable differences in the impact on biological processes related to protein synthesis and ribosome assembly and regulation. Specifically, hippocampal astrocytes displayed upregulated expression of ribosome machinery, while cerebellar astrocytes exhibited a downregulation in the same processes. Moreover, only hippocampal astrocytes showed alterations in biological processes related to vesicle transport in the endoplasmic reticulum, whereas cerebellar astrocytes demonstrated changes in necroptosis and mediators of the citric acid cycle. Our findings were further confirmed by western blotting of the translational machinery regulators p-eEF2a, p-S6 and SUnSET (SUrface SEnsing of Translation) assay.Our results suggest that altered responses in astrocytic protein synthesis regulation may be associated with the diverse susceptibility of brain regions to AD pathogenesis. 

Support: CNPq, FAPERJ, FAPESP, Ministério da Saúde, Instituto Nacional de Neurociência Translacional.