Investigating a novel astrocytic phenotype in aging and alzheimer's disease

Abstract

The aging brain shows a regional-specific decrease in synaptic number and plasticity. Among the various glial cells in the brain, astrocytes play an important role in regulating the number and function of synapses during development and adulthood, it has been hypothesized that changes in the function of astrocytes during aging may contribute to the increased vulnerability to cognitive impairment and degenerative neurological diseases. In this study, single-cell RNA-sequencing was performed with the hippocampus of 2-year-old mice, and as a result, I identified a new subtype of astrocytes that exhibits defective autophagy and morphology. I named these unique subtype of astrocytes AutoPhagy-Defective Astrocytes (APDAs). In these APDAs, autophagosomes were abnormally accumulated inside the swollen astrocytic processes, and protein trafficking and secretion were impaired. Interestingly, I found that reduced mTOR signaling pathway, proteasome activity, and lysosomal dysfunction in aged hippocampal astrocytes were critical factors for generating APDAs. APDAs exhibited impaired secretion of synaptogenic molecules by astrocytes and synapse elimination by astrocytic phagocytosis, suggesting that APDAs, unlike normal astrocytes, have lost the ability to maintain the number and homeostasis of synapses. Indeed, in the aged mouse hippocampi, excitatory synapses and dendritic spines close to APDAs were significantly reduced. Finally, I found that mouse models of Alzheimer’s disease showed a significantly accelerated increase in the generation of APDAs, suggesting that APDAs may act as a potential factor in synaptic pathology and cognitive impairment associated with aging and dementia.