Spatial transcriptomics Reveals Impact of APOE4 Allele on a-Synuclein Aggregation and Cell-Cell Communication in Lewy Body Dementia

We performed spatial transcriptomics to understand a-synuclein pathology-specific molecular profiles and cell-cell communication in human Lewy Body Dementia (LBD) brains. We included APOE3/3 and APOE3/4 LBD brains to dissect APOE4 impact on a-synuclein pathologies. Our analysis showed the key dysregulated pathways around the pathology comparing LBD brains to control brains, which further exacerbated by APOE4. Overall design: To explore this, we conducted spatial transcriptomics using the 10X Genomics Visium CytAssist platform on Formalin-Fixed Paraffin-Embedded tissue slides from the temporal cortex of human LBD brains (N=4 control and N=6 LBD brains, with an equal ratio of APOE3/3 and APOE3/4 genotypes). We defined the neuronal layers of the gray matter (Layers 1 to 6, L1-6) and white matter (WM), and identified LBs from hematoxylin and eosin (H&E) staining to annotate LB-positive (LB+), LB-surrounding and LB-negative (LB-) spots in each brain. We evaluated gene signatures in each layer and analyzed cell-cell communication using the CellChat tool across the layers.