Synaptic dysfunction is an early feature in Alzheimer’s disease and correlates with cognitive decline. Astrocytes are essential regulators of synapses, impacting synapse formation, maturation, elimination and function. To understand if synapse-supporting functions in astrocytes are altered in Alzheimer’s disease, we used the BacTRAP system to generate a comprehensive dataset characterizing the astrocyte translatome in two different mouse models of neurodegeneration (APP/PS1 and Tau P301S). We analyzed the hippocampal astrocyte translatome at 3 different timepoints across disease progression: (4, 6 and 12 months), and in male and female mice independently. Using this dataset we found that astrocytes from both models downregulate genes important for synapse regulation and function, and this signature is shared with human post-mortem Alzheimer’s disease patients. Among the downregulated genes we found Glypican 5, an astrocyte factor important for synapse maturation and stabilization in the adult brain. We showed that in vivo overexpression of Glypican 5 specifically in astrocytes is sufficient to prevent early hippocampal neuronal hyperactivity in APP/PS1 mice. Additionally, overexpression of Glypican 5 improved spatial learning in the Barnes maze and increased levels of GluA2-containing AMPA receptors in hippocampal CA3 neurons. These findings open new avenues to target astrocytic factors to mitigate Alzheimer’s disease synaptic dysfunction.

More information:

• https://www.brightfocus.org/grantee/isabel-salas-phd/