De novo formation of familial Alzheimer's disease-relevant Aβ strains occurs exclusively in the human brain.
12 affiliations
- 1Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, Rm. 4KD481, 60 Leonard Ave., Toronto, ON, M5T 0S8, Canada.
- 2Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
- 3Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
- 4Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
- 5Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
- 6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
- 7Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden.
- 8Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
- 9Unit for Hereditary Dementias, Karolinska University Hospital Solna, Stockholm, Sweden.
- 10Department of Medicine, University of Toronto, Toronto, ON, Canada.
- 11Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, Rm. 4KD481, 60 Leonard Ave., Toronto, ON, M5T 0S8, Canada. [email protected].
- 12Department of Biochemistry, University of Toronto, Toronto, ON, Canada. [email protected].
Abstract
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.
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BibTeX
@article{mao2026novo,
title = {{De novo formation of familial Alzheimer's disease-relevant Aβ strains occurs exclusively in the human brain.}},
author = {Alison Mao and Alejandro Ruiz-Riquelme and Marim M Barghash and Nicholas R G Silver and Heather H C Lau and Erica Stuart and Silvia Zampar and Dag Sehlin and Stina Syvänen and Michael S Pollanen and K Peter R Nilsson and Caroline Graff and Martin Ingelsson and Joel C Watts},
journal = {Acta neuropathologica communications},
year = {2026},
month = jul,
doi = {10.1186/s40478-026-02390-z},
url = {https://europepmc.org/article/MED/42897618},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - De novo formation of familial Alzheimer's disease-relevant Aβ strains occurs exclusively in the human brain.
AU - Alison Mao
AU - Alejandro Ruiz-Riquelme
AU - Marim M Barghash
AU - Nicholas R G Silver
AU - Heather H C Lau
AU - Erica Stuart
AU - Silvia Zampar
AU - Dag Sehlin
AU - Stina Syvänen
AU - Michael S Pollanen
AU - K Peter R Nilsson
AU - Caroline Graff
AU - Martin Ingelsson
AU - Joel C Watts
PY - 2026
DA - 2026/07/01
JO - Acta neuropathologica communications
DO - 10.1186/s40478-026-02390-z
UR - https://europepmc.org/article/MED/42897618
AB - 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.
SN - 2051-5960
ER -