Fig. 2

Autophagic and phagocytic degradative functions in normal and reactive astrocytes. (A) In normal astrocytes, lysosomes maintain a sufficiently acidic environment, enabling proper vesicle fusion and optimal autophagic/phagocytic activities, including the clearance of damaged mitochondria and myelin debris, thereby maintaining neuronal health. In addition, astrocytes release regenerative factors which contribute to neuron remyelination. (B) In reactive astrocytes under exposure to pro-inflammatory cytokines, excessive lipids, and toxic protein aggregates, lysosomal acidification is impaired (poorly acidified lysosomes), leading to inhibition of autophagic/phagocytic activities. As a result, there is reduced mitochondrial turnover and increased accumulation of damaged mitochondria, as well as release of neurotoxic factors such as ROS. In addition, damaged astrocytes can release undegraded toxic materials as well as inhibitory factors that further impair neuronal function. Re-acidification of impaired lysosomes by lysosome-targeting small molecules and nanoparticles restores autophagic/phagocytic functions in astrocytes, allowing for effective clearance of neurotoxic factors to maintain neuronal health. The figure was created with BioRender.com