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Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta
Open accessAbstract
Familial Alzheimer's disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD.
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“iPSCs were previously obtained or generated, and validated, by CA and SW [18,19].”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [18]
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Metadata
- Authors
- Arber, C., Toombs, J., Lovejoy, C., Ryan, N. S., Paterson, R. W., Willumsen, N., Gkanatsiou, E., Portelius, E., Blennow, K., Heslegrave, A., Schott, J. M., Hardy, J., Lashley, T., Fox, N. C., Zetterberg, H., & Wray, S.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- UK Dementia Research Institute (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- University of Gothenburg (SE)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Zetterberg, Henrik
- Wray, Selina
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2019-04-12
- Volume
- 25
- Issue
- 11
- Pages
- 2919-2931
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC7577860
- OpenAlex
- W2937299859
- Cited by
- 148
- References
- 53
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 25 · 2023: 27 · 2022: 20 · 2021: 26 · 2020: 20 · 2019: 4
- FWCI
- 12.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Alzheimer's Research UK (ARUK-SRF2016B-2)
- RCUK | Medical Research Council (MR/M02492X/1, MC_U12266B)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- familial Alzheimer's disease, amyloid-beta, presenilin 1 mutations, Aβ42/Aβ40 ratio, iPSC-derived neurons, 3D neuronal culture, APP processing, disease modeling
- MeSH terms
- Adult, Aged, Alzheimer Disease, Cells, Cultured, Female, Humans, Male, Middle Aged, Mutation, Neurons, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Presenilin-1, Amyloid Precursor Protein Secretases, Young Adult
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