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bioRxiv · 10.1101/2025.07.31.667719

Multi-region spatial transcriptomics reveals region specific differences in response to amyloid beta (Aβ) plaque induced changes in Alzheimer's Disease (AD)

Bayaraa, O.·Aksu, M.·DeBose-Scarlett, E.·Hocke, E.·Jain, V.·Wang, S.-H. J.·Cruz, D.·Gregory, S. G.
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Abstract

Alzheimers disease (AD) is the leading cause of dementia affecting 55 million people worldwide. The pathological hallmarks of AD, beta-amyloid (A{beta}) plaques and neurofibrillary tangles (NFT), follow distinct stereotypical patterns of progression across brain regions and trigger a multicellular response that ultimately leads to neuronal loss and cognitive decline. Despite the uniform spread of A{beta} plaque across the cortex during AD progression, different regions demonstrate varying levels of vulnerability and resilience to temporal A{beta} plaque induced changes, such as NFT accumulation. There is a critical gap in our understanding of the cell types and molecular mechanisms that underlie these region-specific differences in resilience to A{beta} plaque induced changes. In this study, we hypothesized that brain region and cell type specific transcriptional responses within the A{beta} microenvironment, and more broadly within the grey matter, may contribute to this variation. We carried out matched multi-region spatial transcriptomics and A{beta} immunofluorescence staining from the entorhinal, occipito-temporal, dorsolateral prefrontal and striate cortices from two individuals with Braak III and Thal 4 AD. Spatiotemporal comparisons of cell type proportions, gene expression, and cell-cell communication revealed differences in the vulnerability of somatostatin and somatostatin chondrolectin inhibitory neurons and the expression of endosomal and lysosomal trafficking and metallothionein genes within the A{beta} plaque microenvironment. We also observed variations in blood-brain-barrier dysfunction, fibroblast growth factor signaling, and vascular impairment and repair related cell-cell communication networks within the grey matter. Our results demonstrate the value of simultaneously profiling AD-omic and spatial modalities in multiple regions to elucidate how cortical region-specific differences contribute to selective vulnerability and resilience during neurodegeneration.

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Bayaraa, O., Aksu, M., DeBose-Scarlett, E., Hocke, E., Jain, V., Wang, S.-H. J., Cruz, D., Gregory, S. G.. 2025-08-02. Multi-region spatial transcriptomics reveals region specific differences in response to amyloid beta (Aβ) plaque induced changes in Alzheimer's Disease (AD). https://doi.org/10.1101/2025.07.31.667719

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