Distinct Transcriptomic Responses to A beta plaques, Neurofibrillary Tangles, and APOE in Alzheimer's Disease

Das, S.; Li, Z.; Wachter, A.; Alla, S.; Noori, A.; Abdourahman, A.; Tamm, J. A.; Woodbury, M.; Talanian, R. V.; Biber, K.; Karran, E. H.; Hyman, B. T.; Serrano-Pozo, A.

doi:10.1101/2023.03.20.533303

bioRxiv · 10.1101/2023.03.20.533303

Distinct Transcriptomic Responses to A beta plaques, Neurofibrillary Tangles, and APOE in Alzheimer's Disease

Das, S.·Li, Z.·Wachter, A.·Alla, S.·Noori, A.·Abdourahman, A.·Tamm, J. A.·Woodbury, M.·Talanian, R. V.·Biber, K.·Karran, E. H.·Hyman, B. T.·Serrano-Pozo, A.

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Abstract

INTRODUCTIONOmics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimers disease (AD) but the spatial relationships with plaques and tangles and APOE-linked differences remain unclear. METHODSWe performed laser capture microdissection of A{beta} plaques, the 50m halo around them, tangles with the 50m halo around them, and areas distant (>50m) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing. RESULTSA{beta} plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. A{beta} plaques had more differentially expressed genes than tangles. We identified a gradient A{beta} plaque>peri-plaque>tangle>distant for these changes. AD APOE{varepsilon}4 homozygotes had greater changes than APOE{varepsilon}3 across locations, especially within A{beta} plaques. DISCUSSIONTranscriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with A{beta} plaques, and are exacerbated by the APOE{varepsilon}4 allele.

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Das, S., Li, Z., Wachter, A., Alla, S., Noori, A., Abdourahman, A., Tamm, J. A., Woodbury, M., Talanian, R. V., Biber, K., Karran, E. H., Hyman, B. T., Serrano-Pozo, A.. 2023-03-21. Distinct Transcriptomic Responses to A beta plaques, Neurofibrillary Tangles, and APOE in Alzheimer's Disease. https://doi.org/10.1101/2023.03.20.533303

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