Neuronal autophagosomes are transported to astrocytes for degradation

Autophagy is a vital catabolic process responsible for the degradation of cytosolic components, playing a key role in cellular homeostasis and survival. At synapses, autophagy is crucial for regulating neuronal activity and utilizes a specialized machinery. While considerable progress has been made in understanding the initiation of autophagy and autophagosome formation, the mechanisms governing the clearance of autophagosomes from synaptic sites remain poorly understood. Here, we identify a novel pathway in which astrocytes actively participate in the clearance of pre-synaptic autophagosomes. Using neurons derived from human induced pluripotent stem cell (hiPSC) lines expressing fluorescent autophagy markers and chimeric mouse models, we demonstrate that neuronal autophagosomal vesicles are physically transferred to astrocytes, a process that is enhanced when synaptic activity is suppressed. Autophagosome transfer does not require direct physical cellular contact, but it does require Dynamin and cholesterol-dependent endocytosis for the internalized neuronal autophagosomes to ultimately fuse with astrocytic lysosomes. Our findings reveal a previously unrecognized mechanism of neuronal autophagosome clearance that does not require slow axonal retrograde transport but their transfer to nearby astrocytes.