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Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer’s disease

Chen, Shuo, Chang, Yuzhou, Li, Liangping, Acosta, Diana, Li, Yang, Guo, Qi, Wang, Cankun, Turkes, Emir, Morrison, Cody, Julian, Dominic, Hester, Mark E., Scharre, Douglas W., Santiskulvong, Chintda, Song, Sarah XueYing, Plummer, Jasmine T., Serrano, Geidy E., Beach, Thomas G., Duff, Karen E., Ma, Qin, Fu, Hongjun·2022·Acta Neuropathologica Communications
DOI 10.1186/s40478-022-01494-6PMC PMC9773466

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Abstract

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer’s disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell–cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A , PAQR6 , and SLC1A3 ) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region.

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Metadata

Authors
Chen, S., Chang, Y., Li, L., Acosta, D., Li, Y., Guo, Q., Wang, C., Turkes, E., Morrison, C., Julian, D., Hester, M. E., Scharre, D. W., Santiskulvong, C., Song, S. X., Plummer, J. T., Serrano, G. E., Beach, T. G., Duff, K. E., Ma, Q., & Fu, H.
ORCID
Fu, Hongjun
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2022-12-21
Volume
10
Issue
1
ISSN
2051-5960
DOI
10.1186/s40478-022-01494-6
PMC
PMC9773466
Cited by
144
References
31
Language
en
Licence
Funders
  • National Institute on Aging (R01-AG075092-01, K01-AG056673, R56-AG066782-01)
  • National Institute of General Medical Sciences (R01-GM131399)
  • Alzheimer's Association (AARF-17-505009)
  • U.S. Department of Defense (W81XWH1910309)
  • Foundation for the National Institutes of Health (U24-NS072026, P30-AG19610)

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