Spatial transcriptomics and snRNA-seq unravel cell-cell interactions and signaling pathways in the entorhinal cortex driving Alzheimer’s disease initiation and progression

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by complex molecular and cellular changes that lead to cognitive decline and dementia. The entorhinal cortex (EC) is one of the earliest cortical regions affected in AD, and the propagation of amyloid-β and tau pathology from the EC is thought to drive disease progression. However, the cellular and molecular mechanisms underlying the selective vulnerability of EC neurons remain poorly understood. Emerging evidence indicates that astrocytes play critical roles in modulating AD pathology and influencing neuronal health, suggesting that glial–neuronal interactions may contribute to early disease onset.

Methods: To elucidate the cellular and molecular landscape of EC degeneration, we applied  spatial transcriptomics at true single-cell level across healthy, early, mid, and late AD stages. We further integrated these data with single-nucleus RNA sequencing (snRNA-seq) to validate and characterize the identified transcriptional changes across distinct glial and neuronal populations in the EC. This approach enabled high-resolution mapping of spatial gene expression and intercellular communication dynamics during AD progression.

Results: Our analysis uncovered distinct transcriptional programs and spatially resolved cell–cell interactions that varied with disease stage. We identified pronounced astrocyte–neuron signaling networks in early AD, suggesting that astrocyte-derived molecular cues may initiate or exacerbate neuronal dysfunction. Multi-omics integration revealed stage-dependent changes in ligand–receptor signaling, highlighting astrocytic pathways that modulate neuronal homeostasis and synaptic integrity. Furthermore, we identified a set of astrocyte-enriched, early stage–specific genes potentially involved in the initiation of AD-related neurodegeneration. These findings suggest that astrocytes may play pivotal roles in shaping the earliest pathological landscape of the EC.

Conclusion: Our findings provide new insights into the molecular mechanisms underlying EC vulnerability in AD. By linking spatially resolved gene expressions to cellular communication networks, our study highlights potential astrocyte-mediated mechanisms driving early neurodegenerative changes and identifies candidate targets for early intervention aimed at slowing or preventing AD progression.

Prof. Jiaqian Wu earned her doctorate from Baylor College of Medicine where she led the NIH Mammalian Gene Collection effort. Her postdoctoral training was at Yale and Stanford University. She joined the University of Texas McGovern Medical School at Houston in 2011. Currently, she holds the UTHealth Houston Distinguished Professorship. Her research focuses on neurodegeneration and regeneration in Neurotrauma and Neurodegenerative Disease, and her publications have been cited more than 25000 times.Dr. Wu’s work has been recognized with prestigious honors, including the NIH Pathway to Independence (PI) Award (K99/R00), and the Senator Lloyd and B.A. Bentsen Investigator Award etc.