Comparative mapping of single-cell transcriptomic landscapes in neurodegenerative diseases.

INTRODUCTION: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease (PD) represent a spectrum of neurodegenerative diseases (NDDs). Here, we performed the first direct comparison of their transcriptomic landscapes. METHODS: We profiled whole transcriptomes of NDD cortical tissue by single-nucleus RNA sequencing, using computational analyses to identify common and distinct differentially expressed genes (DEGs), pathways, vulnerable and disease-driver cell subtypes, and altered cell-to-cell interactions. RESULTS: The same inhibitory neuron subtype was depleted in both AD and DLB. Potentially disease-driving neuronal cell subtypes were identified in both PD and DLB. Cell-cell communication was predicted to be increased in AD but decreased in DLB and PD. DEGs were most commonly shared across NDDs within inhibitory neuron subtypes. Overall, AD and PD showed greatest transcriptomic divergence, while DLB exhibited an intermediate signature. DISCUSSION: These results may help explain the clinicopathological spectrum of these NDDs and provide unique insights into shared and distinct molecular mechanisms underlying pathogenesis. HIGHLIGHTS: The same vulnerable inhibitory neuron subtype population was depleted in both Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Potentially disease-driving neuronal cell subtypes were discovered in both Parkinson's disease (PD) and DLB. Cell-cell communication was predicted to be increased in AD but decreased in DLB and PD. Differentially expressed genes were most commonly shared across neurodegenerative diseases in inhibitory neuron types. AD and PD had the greatest transcriptomic divergence, with DLB showing an intermediate signature.

Duke Scholars

Author Ornit Chiba-Falek Neurology, Translational Brain Sciences

Author Gregory E. Crawford Pediatrics, Medical Genetics

Author Allison Elizabeth Ashley-Koch Medicine, Nephrology