Integrated Cross-Disease Atlas of Human And Mouse Astrocytes Reveals Heterogeneity and Conservation of Astrocyte Subtypes in Neurodegeneration

Abstract

Astrocytes play a pivotal role in central nervous system homeostasis and neuroinflammation. Despite advancements in single-cell analyses, the heterogeneity of reactive astrocytes in neurodegenerative diseases, particularly across species, remains understudied. Here, we present an integrated atlas of 187,000 astrocytes from mouse models of Alzheimers (AD) and multiple sclerosis (MS) alongside 438,000 astrocytes from AD, MS, and Parkinsons (PD) patients. Our analysis identified four distinct mouse astrocyte clusters, including two disease-associated astrocyte (DAA) clusters, DAA1 and DAA2. DAA1 displayed reactivity resembling responses to acute stimuli, including endotoxemia, while DAA2 expressed well-known AD risk genes. In an AD model, DAA1 and DAA2 exhibited distinct spatial relationships to amyloid plaques. In humans, we identified eight distinct astrocyte clusters, encompassing homeostatic and disease-associated subtypes. Cross-species analysis linked disease-associated clusters while also highlighting divergent expression in others. Our astrocyte atlas is available through a user-friendly, searchable website: http://research-pub.gene.com/AstroAtlas/.