VESICULAR RPS6 RELEASED BY ASTROCYTES IN AN EXPERIMENTAL MODEL OF AD REGULATES LOCAL TRANSLATION AND ENHANCES SYNAPTIC INTEGRITY IN NEURONES

The neuronal soma is considered the primary origin of mRNAs localized to distal compartments and local protein synthesis in neurons is thought to be primarily regulated by the neuron itself. Several evidence indicate the existence of active RNA and ribosomal protein transfer from Schwann cells to regenerating nerves. A few mechanisms have been proposed for RNA and ribosome transfer from glia to axons, but these and other bioactive molecules are likely delivered to axons within EVs. Notably, Schwann cell-derived EVs improve regeneration of injured peripheral nerves. In this context, it has been proposed that glial-EVs induce regeneration by changing the axonal translatome in the peripheral nervous system. However, there is no direct evidence on the regulation of local neuronal translation by glial EVs in the CNS.
Our work shows that astroglial EVs released upon subcronic exposure to Aβ positively regulate intra-axonal protein synthesis. Interestingly, these EVs also enhance the levels of synaptic markers and synaptic integrity. Proteomic analyses of astrocyte-derived EV cargoes revealed that ribosomal protein Rps6 secreted by Aβ-treated glia was responsible for EV-mediated local protein synthesis, and its genetic downregulation led to a decrease in synaptic proteins. Overall, our results suggest that astroglial EVs released in response to Aβ contain ribosomal proteins that regulate local translation in neurons through non-cell-autonomous mechanisms. In turn, locally synthesized proteins enhance synaptic integrity, potentially contributing to synaptic function (Gamarra et al. 2025. J Extracell Vesicles. 2025 Dec;14(12):e70216.doi: 10.1002/jev2.70216)