Single-soma transcriptomics of tangle-bearing neurons in Alzheimer's disease reveals the signatures of tau-associated synaptic dysfunction

Otero-Garcia, M.; Xue, Y.-Q.; Shakouri, T.; Deng, Y.; Morabito, S.; Allison, T.; Lowry, W. E.; Kawaguchi, R.; Swarup, V.; Cobos, I.

doi:10.1101/2020.05.11.088591

bioRxiv · 10.1101/2020.05.11.088591

Single-soma transcriptomics of tangle-bearing neurons in Alzheimer's disease reveals the signatures of tau-associated synaptic dysfunction

Otero-Garcia, M.·Xue, Y.-Q.·Shakouri, T.·Deng, Y.·Morabito, S.·Allison, T.·Lowry, W. E.·Kawaguchi, R.·Swarup, V.·Cobos, I.

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Abstract

Aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is closely associated with neuronal death and cognitive decline in Alzheimers disease (AD). To define the signatures that distinguish between aggregation-prone and resistant cell states in AD, we developed a FACS-based method for the high-throughput isolation and transcriptome profiling of individual cells with cytoplasmic aggregates and profiled 63,110 somas from human AD brains. By comparing NFT-bearing and NFT-free somas within and across neuronal subtypes, we identified the cell-type-specific and shared states. NFT-bearing neurons shared a marked upregulation of genes associated with synaptic transmission, including a core set of 63 genes enriched for synaptic vesicle cycle and transsynaptic signaling, whereas glucose metabolism and oxidative phosphorylation changes were highly neuronal-subtype-specific. Apoptosis was modestly enriched in NFT-bearing neurons despite the strong link between tau and cell death. Our datasets provide a resource for investigating tau-mediated neurodegeneration and a platform for biomarker and drug target discovery.

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Otero-Garcia, M., Xue, Y.-Q., Shakouri, T., Deng, Y., Morabito, S., Allison, T., Lowry, W. E., Kawaguchi, R., Swarup, V., Cobos, I.. 2020-05-13. Single-soma transcriptomics of tangle-bearing neurons in Alzheimer's disease reveals the signatures of tau-associated synaptic dysfunction. https://doi.org/10.1101/2020.05.11.088591

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