Lucas, T. A. | bioRxiv Science

bioRxiv2025

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

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/.

neuroscience↗

bioRxiv2023

Translatome analysis reveals microglia and astrocytes to be distinct regulators of inflammation in the hyperacute and acute phases after stroke

Neuroinflammation is a hallmark of ischemic stroke, which is a leading cause of death and long-term disability. Understanding the exact cellular signaling pathways that initiate and propagate neuroinflammation after stroke will be critical for developing immunomodulatory stroke therapies. In particular, the precise mechanisms of inflammatory signaling in the clinically relevant hyperacute period, hours after stroke, have not been elucidated. We used the RiboTag technique to obtain astrocyte and microglia-derived mRNA transcripts in a hyperacute (4 hours) and acute (3 days) period after stroke, as these two cell types are key modulators of acute neuroinflammation. Microglia initiated a rapid response to stroke at 4 hours by adopting an inflammatory profile associated with the recruitment of immune cells. The hyperacute astrocyte profile was marked by stress response genes and transcription factors, such as Fos and Jun, involved in pro-inflammatory pathways such as TNF-. By 3 days, microglia shift to a proliferative state and astrocytes strengthen their inflammatory response. The astrocyte pro-inflammatory response at 3 days is partially driven by the upregulation of the transcription factors C/EBP{beta}, Spi1, and Rel, which comprise 25% of upregulated transcription factor-target interactions. Surprisingly, few sex differences across all groups were observed. Expression and log2 fold data for all sequenced genes are available on a user-friendly website for researchers to examine gene changes and generate hypotheses for stroke targets. Taken together our data comprehensively describe the astrocyte and microglia-specific translatome response in the hyperacute and acute period after stroke and identify pathways critical for initiating neuroinflammation.

neuroscience↗