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<p>In familial Alzheimer’s disease (FAD), mutations in the amyloid precursor protein gene (<i>APP</i>) accelerate the aggregation of Aβ peptide, leading to deposition of amyloid plaques within the brain. Conformational variants of Aβ aggregates (“Aβ strains”) possess distinct pathological properties and may contribute to disease heterogeneity. While the Swedish <i>APP</i> mutation produces wild-type (WT) Aβ, the Arctic <i>APP</i> mutation generates E22G-mutant Aβ. To clarify whether different FAD mutations are sufficient to specify the formation of distinct Aβ strains, we performed Aβ seeding studies in <i>App</i><sup>NL−F</sup> knock-in mice. Aβ aggregates purified from Swedish and Arctic FAD human brains induced distinct neuropathological signatures, characterized by differences in the morphology and localization of the seeded Aβ deposits, which were preserved upon serial passage. Neither synthetic E22G-mutant Aβ aggregates nor Aβ aggregates isolated from the brains of transgenic mice producing E22G-mutant Aβ recapitulated the phenotype induced by Arctic FAD brain-derived Aβ aggregates upon injection into <i>App</i><sup>NL−F</sup> mice. Similarly, neither synthetic WT Aβ aggregates nor Aβ aggregates from Swedish <i>APP</i>-mutant transgenic mice reproduced the seeding behavior of Swedish FAD brain-derived Aβ aggregates. This suggests that it is the structure of Aβ aggregates rather than the Aβ sequence that dictates seeding activity. We conclude that de novo formation of FAD-relevant Aβ strains occurs exclusively in the human brain, implying the existence of human brain-specific cofactors that modulate Aβ aggregate structure and seeding activity.</p>

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De novo formation of familial Alzheimer’s disease-relevant Aβ strains occurs exclusively in the human brain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月24日

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  • Alison Mao,
  • Alejandro Ruiz-Riquelme,
  • Marim M. Barghash,
  • Nicholas R. G. Silver,
  • Heather H. C. Lau,
  • Erica Stuart,
  • Silvia Zampar,
  • Dag Sehlin,
  • Stina Syvänen,
  • Michael S. Pollanen,
  • K. Peter R. Nilsson,
  • Caroline Graff,
  • Martin Ingelsson,
  • Joel C. Watts

摘要

In familial Alzheimer’s disease (FAD), mutations in the amyloid precursor protein gene (APP) accelerate the aggregation of Aβ peptide, leading to deposition of amyloid plaques within the brain. Conformational variants of Aβ aggregates (“Aβ strains”) possess distinct pathological properties and may contribute to disease heterogeneity. While the Swedish APP mutation produces wild-type (WT) Aβ, the Arctic APP mutation generates E22G-mutant Aβ. To clarify whether different FAD mutations are sufficient to specify the formation of distinct Aβ strains, we performed Aβ seeding studies in AppNL−F knock-in mice. Aβ aggregates purified from Swedish and Arctic FAD human brains induced distinct neuropathological signatures, characterized by differences in the morphology and localization of the seeded Aβ deposits, which were preserved upon serial passage. Neither synthetic E22G-mutant Aβ aggregates nor Aβ aggregates isolated from the brains of transgenic mice producing E22G-mutant Aβ recapitulated the phenotype induced by Arctic FAD brain-derived Aβ aggregates upon injection into AppNL−F mice. Similarly, neither synthetic WT Aβ aggregates nor Aβ aggregates from Swedish APP-mutant transgenic mice reproduced the seeding behavior of Swedish FAD brain-derived Aβ aggregates. This suggests that it is the structure of Aβ aggregates rather than the Aβ sequence that dictates seeding activity. We conclude that de novo formation of FAD-relevant Aβ strains occurs exclusively in the human brain, implying the existence of human brain-specific cofactors that modulate Aβ aggregate structure and seeding activity.