Poster #95: Chunwan Sun MS

Epigenetically constrained astrocyte states underlie prefrontal cortex vulnerability in Down syndrome–associated Alzheimer’s disease

Chuhanwen Sun1,2*, Raina Thomas3*, Cherie Stringer5*, Kyriakitsa Galani3,4, Li-Lun Ho3,4, Na Sun3,4, Ashley Renfro3,4, Sierra Wright5,6, Rosalind Firenze7, Li-Huei Tsai4,7, Elizabeth Head5,6†, Manolis Kellis3,4†, Jiekun Yang1,2,3,4† 1 Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. 2 Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. 3 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. 4 Broad Institute of MIT and Harvard, Cambridge, MA, USA. 5 Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA. 6 Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, Irvine, CA, USA. 7 Department of Brain and Cognitive Sciences and the Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA. * Equal contributors.

Down syndrome (DS), caused by trisomy 21, carries a lifelong increased risk for Alzheimer’s disease (AD), largely due to triplication of the amyloid precursor protein gene. Although most individuals with DS develop AD neuropathology by mid-adulthood, the timing and severity of cognitive decline vary widely. The cellular mechanisms underlying this divergence remain poorly understood. Here, we present a multiomic atlas of the prefrontal cortex (PFC) and amygdala (AMY), integrating matched single-nucleus RNA-seq and ATAC-seq from 12 age-matched individuals with DS or DSAD. Transcriptomic profiling revealed major neuronal and non-neuronal cell types and identified a region-specific depletion of astrocytes in the PFC of DSAD individuals, a vulnerability not observed in the AMY. Furthermore, astrocyte-focused analysis identified six distinct subtypes spanning basal to reactive states, with subtype markers validated by protein-level staining, and localized the PFC-specific depletion primarily to basal subtypes, accompanied by increased steroid-related signaling and reduced cytokine-, lipid- and macroautophagy associated programs. Integrative gene-regulatory-network analysis bridged the two modalities by linking these transcriptional program changes to extensive chromatin-accessibility remodeling through candidate TF–region–gene circuits involving AP-1, BACH, and STAT which showed reduced inferred activity in DSAD PFC basal astrocytes. Together, these findings suggest that PFC basal astrocytes represent a region- and state-selective locus of vulnerability in DSAD and reveal the coordinated transcriptional and regulatory programs associated with AD in DS.