Tau pathology vulnerable neuronal subpopulation in Alzheimer’s disease

Abstract

AbstractBackgroundTau pathology is known as a primary driver of neurodegeneration in Alzheimer’s disease (AD). Understanding its underlying molecular mechanism is critical in expanding our knowledge of AD pathogenesis and developing novel AD therapeutic strategies. However, interrogating tau induced neurotoxicity mechanisms has been difficult due to heterogeneous susceptibility of neurons to tau pathology. Here, we aim to identify the most vulnerable neuronal subpopulation to tau pathology in AD and reveal more clear molecular mechanisms of tau induced neuro‐toxicity/degeneration by analyzing gene expression changes in the vulnerable population.MethodWe performed single nuclei RNA sequencing and tau biochemistry from same tissue blocks of the same AD patients (5 brain regions of 32 AD donors with various Braak stages). About 1.5x106 neurons were enriched in total by NeuN antibody‐based flow cytometry sorting and these cells were clustered into 15 neuronal subpopulations based on their similarity in gene expression. We tested for association between relative neuronal population abundance and tau pathology readouts (phospho‐T231 ELISA, HT7‐HT7 SIMOA and HEK seeding). Based on the strength of correlation, we identified the neuronal subpopulation that reduces relative abundance in association with its tau pathology.ResultWe identified a tau vulnerable neuronal population that showed strong negative correlation between its relative abundance and tau pathology readouts in BA20 and BA46. The population was one of largest excitatory subpopulation distinguished by marker genes, CBLN2 and LINC00507. This outcome was supported by multiple published transcriptomics studies and histologically validated by multiplexed in situ hybridization and immunohistochemistry. Differential gene expression analysis of the vulnerable neuronal population identified a list of genes that potentially links tau pathology and neuronal death.ConclusionThis study with large number of captured neurons for single cell transcriptomics and quantitative tau pathology readout for direct comparison to transcriptomics data enabled the discovery of a vulnerable neuronal subpopulation in more precise manner and revealed genes related to tau associated neurotoxicity more clearly. This result serves as a great starting point to further interrogate fundamental mechanisms of tau‐driven neurodegeneration in AD and accelerate therapeutic target and biomarker discovery.