Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics

Avey, D. R.; Ng, B.; Vialle, R. A.; Kearns, N. A.; Lopes, K. d. P.; Iatrou, A.; Tissera, S. D.; Vyas, H.; Saunders, D. M.; Flood, D. J.; Xu, J.; Tasaki, S.; Gaiteri, C.; Bennett, D. A.; Wang, Y.

doi:10.1101/2024.09.05.611566

bioRxiv · 10.1101/2024.09.05.611566

Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics

Avey, D. R.·Ng, B.·Vialle, R. A.·Kearns, N. A.·Lopes, K. d. P.·Iatrou, A.·Tissera, S. D.·Vyas, H.·Saunders, D. M.·Flood, D. J.·Xu, J.·Tasaki, S.·Gaiteri, C.·Bennett, D. A.·Wang, Y.

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Abstract

Amyloid-beta (A{beta}) plaques and surrounding glial activation are prominent histopathological hallmarks of Alzheimers Disease (AD). However, it is unclear how A{beta} plaques interact with surrounding glial cells in the human brain. Here, we applied spatial transcriptomics (ST) and immunohistochemistry (IHC) for A{beta}, GFAP, and IBA1 to acquire data from 258,987 ST spots within 78 postmortem brain sections of 21 individuals. By coupling ST and adjacent-section IHC, we showed that low A{beta} spots exhibit transcriptomic profiles indicative of greater neuronal loss than high A{beta} spots, and high-glia spots present transcriptomic changes indicative of more significant inflammation and neurodegeneration. Furthermore, we observed that this ST glial response bears signatures of reported mouse gene modules of plaque-induced genes (PIG), oligodendrocyte (OLIG) response, disease-associated microglia (DAM), and disease-associated astrocytes (DAA), as well as different microglia (MG) states identified in human AD brains, indicating that multiple glial cell states arise around plaques and contribute to local immune response. We then validated the observed effects of A{beta} on cell apoptosis and plaque-surrounding glia on inflammation and synaptic loss using IHC. In addition, transcriptomic changes of iPSC-derived microglia-like cells upon short-interval A{beta} treatment mimic the ST glial response and mirror the reported activated MG states. Our results demonstrate an exacerbation of synaptic and neuronal loss in low-A{beta} or high-glia areas, indicating that microglia response to A{beta}-oligomers likely initiates glial activation in plaque-glia niches. Our study lays the groundwork for future pathology genomics studies, opening the door for investigating pathological heterogeneity and causal effects in neurodegenerative diseases.

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Avey, D. R., Ng, B., Vialle, R. A., Kearns, N. A., Lopes, K. d. P., Iatrou, A., Tissera, S. D., Vyas, H., Saunders, D. M., Flood, D. J., Xu, J., Tasaki, S., Gaiteri, C., Bennett, D. A., Wang, Y.. 2024-09-10. Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics. https://doi.org/10.1101/2024.09.05.611566

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