Intracellular accumulation of amyloid-ß is a marker of selective neuronal vulnerability in Alzheimer’s disease

Alessia Caramello, Nurun Fancy, Clotilde Tournerie, Maxine Eklund, Vicky Chau, Emily Adair, Marianna Papageorgopoulou, Nanet Willumsen, Johanna S. Jackson, John Hardy and Paul M. Matthews ()
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Alessia Caramello: 86 Wood Ln
Nurun Fancy: 86 Wood Ln
Clotilde Tournerie: 86 Wood Ln
Maxine Eklund: 86 Wood Ln
Vicky Chau: 86 Wood Ln
Emily Adair: 86 Wood Ln
Marianna Papageorgopoulou: 86 Wood Ln
Nanet Willumsen: 86 Wood Ln
Johanna S. Jackson: 86 Wood Ln
John Hardy: Wing 1.2 Cruciform Building
Paul M. Matthews: 86 Wood Ln

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Defining how amyloid-β and pTau together lead to neurodegeneration is fundamental to understanding Alzheimer’s disease (AD). We used imaging mass cytometry to identify neocortical neuronal subtypes lost with AD in post-mortem brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB+FOXP2+ and L3,5,6 GAD1+FOXP2+ neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3 RORB+GPC5+ neurons, which accumulate pTau but not amyloid-β, are not lost even at late Braak stages. We discovered spatial associations between activated microglia and these vulnerable neurons and found that vulnerable RORB+FOXP2+ neuronal transcriptomes are enriched selectively for pathways involved in inflammation and glycosylation and, with progression to AD, also protein degradation. Our results suggest that the accumulation of intraneuronal amyloid-β, which is associated with glial inflammatory pathology, may contribute to the initiation of degeneration of these vulnerable neurons.

Date: 2025
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DOI: 10.1038/s41467-025-60328-w

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