Impairment of astrocyte homeostasis and lysosomal function in Alzheimer's disease pathogenesis

Physiological functions of astrocytes, the most abundant cell type in the brain, are important in maintaining many central nervous system (CNS) functions. In this review, we summarized astrocytes' normal physiological roles. However, under the pathological conditions of Alzheimer's Disease (AD), astrocytes pause their homeostatic roles to address and contain abnormal changes in AD brains in response to Aβ deposits, neuroinflammation, and neurodegeneration. The chronic perturbation in AD brains causes various populations of astrocytes to permanently forgo their physiological roles throughout different regions of the brain to contain disease progression. This transition leads to reactive astrogliosis, in which astrocytes transform into reactive phenotypes that eventually contribute to pathological severity. The transformations in astrocytes can negatively impact their morphology and mobility, inflammatory response, energy metabolism, and their ability to properly degrade Aβ deposits. We reviewed recent literature exploring the underlying mechanisms on how AD induces astrocyte morphological, transcriptional, and functional changes. Together, these findings reveal that loss of astrocyte homeostatic function and transformations into neurotoxic states contribute to AD pathology throughout each stage of disease progression. Thus, aims to restore astrocyte homeostatic functions by developing astrocyte-specific therapeutic targets to attenuate AD pathology and clinical manifestations are warranted.