Beyond Support Cells: Astrocytic Autophagy as a Central Regulator of CNS Homeostasis and Neurodegenerative Diseases

Abstract

Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood-brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy's dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases.

Keywords: astrocyte; autophagy; neurodegenerative disease; therapeutics.

Figure 1

Autophagy in Neurons and Astrocytes: From Physiological Maintenance to Neurodegenerative Dysfunction. Autophagy supports proteostasis and homeostasis in healthy neurons and astrocytes. In disease, autophagy impairment contributes to protein aggregation, neurotoxicity, and inflammatory glial responses. The figure was created in https://BioRender.com.

Figure 2

Astrocytic Autophagy-Mediated Crosstalk with CNS Cell Types. Astrocytic autophagy regulates bidirectional communication with endothelial cells, microglia, and oligodendrocytes, coordinating stress responses, inflammation, and metabolic support essential for CNS homeostasis. The figure was created in https://BioRender.com.