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<p>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 <i>post-mortem</i> brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB<sup>+</sup>FOXP2<sup>+</sup> and L3,5,6 GAD1<sup>+</sup>FOXP2<sup>+</sup> neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3 RORB<sup>+</sup>GPC5<sup>+</sup> 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<sup>+</sup>FOXP2<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月4日

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  • Alessia Caramello,
  • Nurun Fancy,
  • Clotilde Tournerie,
  • Maxine Eklund,
  • Vicky Chau,
  • Emily Adair,
  • Marianna Papageorgopoulou,
  • Nanet Willumsen,
  • Johanna S. Jackson,
  • John Hardy,
  • Paul M. Matthews

摘要

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.