Neuronal protein synthesis is critical for synaptic plasticity and long-term memory, yet whether non-neuronal cells instructively shape neuronal translation is not well understood. This study reports that astrocyte-secreted proteins regulate global neuronal translation in a manner that depends on astrocytic state. Astrocyte-conditioned medium (ACM) from resting astrocytes increased neuronal translation under basal conditions. When astrocytes were stimulated with the activity-dependent factor BDNF, their ACM produced an enhanced stimulatory effect on neuronal translation. In contrast, ACM derived from neurotoxic reactive astrocytes, a state linked to neuroinflammation and Alzheimer’s disease, suppressed neuronal translation. Across these conditions, neuronal mTORC1 activity consistently tracked with translational output, whereas the integrated stress response (ISR) acted through distinct state-specific mechanisms and did not always correspond with the measured neuronal translation. The authors identified astrocyte-secreted apolipoprotein E (APOE) and its associated cargo as a negative regulator that contributed to decreased neuronal translation induced by neurotoxic reactive astrocytes. Astrocyte-secreted signals required neuronal endocytosis to influence translation and promoted synaptic remodeling dependent on glutamatergic signaling and neuronal mTORC1 activity. These observations support a model in which astrocytes actively and instructively regulate neuronal translation and synaptic structure, with potential relevance to how astrocyte dysfunction may impair translation-dependent synaptic plasticity and long-term memory in neurodegenerative disease.
The study compares ACM collected from astrocytes in different states and examines effects on neuronal protein synthesis. ACM from unstimulated astrocytes increased neuronal translation under baseline conditions, indicating that even resting astrocytes secrete factors that elevate neuronal translational output. When astrocytes were stimulated with BDNF, an activity-dependent trophic factor, the resulting ACM produced a stronger enhancement of neuronal translation relative to baseline ACM, demonstrating that astrocyte activation can augment their pro-translation influence on neurons.
By contrast, ACM obtained from neurotoxic reactive astrocytes suppressed neuronal translation. The reactive astrocyte state is described as neurotoxic and is associated in the literature with neuroinflammation and Alzheimer’s disease; in this study, reactive-state ACM yielded the opposite effect from resting or BDNF-stimulated ACM, reducing global neuronal protein synthesis.
Across the astrocyte conditions tested, neuronal mTORC1 activity paralleled the changes in translational output: conditions that increased neuronal translation coincided with elevated mTORC1 activity, whereas suppressed translation coincided with lower mTORC1 signaling. This consistent relationship suggests mTORC1 is an important downstream mediator of astrocyte-instructed changes in neuronal translation.
The integrated stress response (ISR) was also engaged but acted through distinct, state-specific mechanisms. ISR activation did not uniformly track with translation changes across conditions, indicating that ISR-related signaling and mTORC1-related signaling can be dissociated in the context of astrocyte-to-neuron communication about translation control.
The authors identified astrocyte-secreted APOE and its associated cargo as a negative regulator of neuronal translation. APOE contributed to the decreased translation observed with neurotoxic reactive astrocyte ACM. The report highlights APOE-containing astrocyte secretions as a mechanistic contributor to translation suppression, linking a well-known astrocytic product to direct modulation of neuronal protein synthesis.
Astrocyte-secreted signals required neuronal endocytosis to exert their influence on translation, indicating that uptake mechanisms in neurons are necessary for astrocyte-derived factors to modify translational machinery or signaling pathways. In addition to regulating protein synthesis, ACM-driven signaling produced changes in synaptic structure: astrocyte signals drove synaptic remodeling, and this structural remodeling depended on glutamatergic signaling and neuronal mTORC1 activity. Thus, astrocyte-to-neuron communication influences both molecular translation processes and synaptic architecture through linked but specific signaling requirements.
These findings position astrocytes as active, instructive regulators of neuronal translation and synaptic structure. The state-dependent nature of astrocyte influence — stimulatory when resting or BDNF-stimulated, suppressive when in a neurotoxic reactive state — suggests a mechanism by which astrocyte dysfunction could perturb the translational mechanisms that underlie synaptic plasticity and long-term memory. The identification of astrocyte-secreted APOE as a negative regulator that contributes to translation suppression is particularly relevant given APOE’s association with neurodegenerative disease. Overall, the reported observations underscore that non-neuronal cells can directly shape neuronal translation and synaptic remodeling, with potential consequences for understanding and potentially targeting astrocyte-mediated contributions to cognitive impairment in disease.