Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout.
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Abstract Mutations in presenilin-1 (PSEN1), encoding the catalytic subunit of the amyloid precursor protein-processing enzyme γ-secretase, cause familial Alzheimer’s disease. However, the mechanism of disease is yet to be fully understood and it remains contentious whether mutations exert their effects predominantly through gain or loss of function. To address this question, we generated an isogenic allelic series for the PSEN1 mutation intron 4 deletion; represented by control, heterozygous and homozygous mutant induced pluripotent stem cells in addition to a presenilin-1 knockout line. Induced pluripotent stem cell-derived cortical neurons reveal reduced, yet detectable amyloid-beta levels in the presenilin-1 knockout line, and a mutant gene dosage-dependent defect in amyloid precursor protein processing in PSEN1 intron 4 deletion lines, consistent with reduced processivity of γ-secretase. The different effects of presenilin-1 knockout and the PSEN1 intron 4 deletion mutation on amyloid precursor protein-C99 fragment accumulation, nicastrin maturation and amyloid-beta peptide generation support distinct consequences of familial Alzheimer’s disease-associated mutations and knockout of presenilin-1 on the function of γ-secretase.
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The study used iPSC lines with APP V717I, PSEN1 R278I, PSEN1 int4del, and PSEN1 WT (corrected) mutations.
“The following cell lines were used in this study: APP V717I 1 (APP V717I mutation), PSEN1 R278I (PSEN1 R278I mutation), PSEN1 int4del (intron 4 deletion in PSEN1), PSEN1 WT (PSEN1 int4del line CRISPR edited to correct the mutation [19]).”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [19]
iPSCs were previously obtained or generated, and validated, by CA and SW.
“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 [19]
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- Authors
- Arber, C., Villegas-Llerena, C., Toombs, J., Pocock, J. M., Ryan, N. S., Fox, N. C., Zetterberg, H., Hardy, J., & Wray, S.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- UK Dementia Research Institute (GB)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Wray, Selina
- ORCID
- Venue
- Brain Communications
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-01-01
- Volume
- 1
- Issue
- 1
- Pages
- fcz024-fcz024
- ISSN
- 2632-1297 (ISSN-L)
- PMC
- PMC7212081
- OpenAlex
- W2980711048
- Cited by
- 19
- References
- 38
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 2
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Brain Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Leonard Wolfson Experimental Neurology Centre
- UK Dementia Research Institute
- Alzheimer’s Society
- Alzheimer’s Research UK Senior Research Fellowship
- University of London Chadburn Academic Clinical Lectureship in Medicine
- Dementia Research Institute at UCL
- UK Medical Research Council
- MRC Dementia Platform UK (MR/M02492X/1)
- MRC-UCL LMCB (MC_U12266B)
- Topics
- Health Sciences › Medicine › Physiology › 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
- presenilin 1, gamma-secretase, APP processing, familial Alzheimer's disease, amyloid-beta, nicastrin, gene dosage
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