Abstract

Coordinated cell-to-cell communications is crucial for the proper functioning and maintenance of brain activities, and its disruption contributes to neurological disorders, including Alzheimer’s disease (AD). Altered astrocyte-neuron communications have been implicated in AD progression, yet the underlying regulatory networks remain poorly understood. Given that secretory proteins mediate both local and long-range intercellular signaling, we constructed a spatiotemporal profile of the astrocyte-derived secretome using in vivo TurboID proximity labeling in mice of amyloid pathology. Early alterations in the entorhinal cortex secretome were identified and enriched in metabolic pathways, whereas changes in the hippocampus were observed later, correlating with neuronal and synaptic maintenance. These findings suggest that early remodeling of the astrocyte secretome in the entorhinal cortex may be involved in AD pathogenesis, while later changes in the hippocampus contribute to neurodegeneration and cognitive decline. This work provides a systematic map of the dynamic, region-specific remodeling of the astrocyte secretome in AD, identifying novel spatiotemporal vulnerabilities and potential therapeutic targets.