The E693Δ Mutation in Amyloid Precursor Protein Increases Intracellular Accumulation of Amyloid β Oligomers and Causes Endoplasmic Reticulum Stress-Induced Apoptosis in Cultured Cells
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The E693Delta mutation within the amyloid precursor protein (APP) has been suggested to cause dementia via the enhanced formation of synaptotoxic amyloid beta (Abeta) oligomers. However, this mutation markedly decreases Abeta secretion, implying the existence of an additional mechanism of neuronal dysfunction that is independent of extracellular Abeta. We therefore examined the effects of this mutation on both APP processing to produce Abeta as well as subcellular localization and accumulation of Abeta in transfected HEK293 and COS-7 cells. Both beta- and gamma-cleavage of mutant APP increased, indicating a lack of inhibition in Abeta production. Instead, this mutation promoted Abeta accumulation within cells, including the endoplasmic reticulum (ER), Golgi apparatus, early and late endosomes, lysosomes, and autophagosomes, all of which have been proposed as intracellular sites of Abeta generation and/or degradation, suggesting impairment of APP/Abeta trafficking. Notably, the intracellular mutant Abeta was found to predominantly form oligomers. Concomitant with this accumulation, the ER stress markers Grp78 and phosphorylated eIF2alpha were both strongly induced. Furthermore, the activation of caspase-4 and -3 as well as DNA fragmentation were detected in these cells. These results suggest that mutant Abeta induces alteration of Abeta trafficking and subsequent ER stress-induced apoptosis via enhancement of its intracellular oligomerization. Our findings suggest that Abeta oligomers exhibit toxicity in the extracellular space and within the cells themselves.
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In the E693Delta APP mutation discovered in a Japanese kindred, the presence of intracellular oligomers is essentially identical in patients and in the transgenic mouse model.
“In the E693Delta APP mutation discovered in a Japanese kindred (Nishitsuji et al., 2009), the presence of intracellular oligomers is essentially identical in patients and in the transgenic mouse model (Tomiyama et al., 2010).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Nishitsuji et al., 2009
FAD mutations can even decrease secretion of the most abundantly released Aβ isoform, Aβ40, while still increasing the Aβ42 to Aβ40 ratio.
“FAD mutations can even decrease secretion of the most abundantly released Aβ isoform, Aβ40, while still increasing the Aβ42 to Aβ40 ratio [90, 134, 173].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [134]
A recent E693Delta mutation in APP is associated with an AD clinical phenotype in the absence of plaques; cells harboring this mutation have reduced Aβ secretion and increased intracellular Aβ accumulation and oligomerization.
“a recent E693Delta mutation in APP was reported to be associated with an AD clinical phenotype in the absence of plaques; cells harboring this mutation were shown to have reduced Aβ secretion and increased intracellular Aβ accumulation and oligomerization [134].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [134]
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“In transfected human embryonic kidney (HEK)293 cells, the introduction of the APPE693∆ (“Osaka”) mutation resulted in increased β- and γ-secretase cleavage of mutant APP and promoted intracellular Aβ accumulation via decreased total Aβ secretion [89].”
Background
- Authors
- Nishitsuji, K., Tomiyama, T., Ishibashi, K., Ito, K., Teraoka, R., Lambert, M. P., Klein, W. L., & Mori, H.
- Affiliations
- Osaka City University (JP)
- Northwestern University (US)
- Corresponding author
- Tomiyama, Takami
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 174
- Issue
- 3
- Pages
- 957-969
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2665755
- OpenAlex
- W2073593094
- Cited by
- 127
- References
- 64
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 10 · 2019: 4 · 2018: 9 · 2017: 7 · 2016: 4 · 2015: 12 · 2014: 8 · 2013: 13 · 2012: 7
- FWCI
- 7.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (17300114, 18023033, 20023026)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid precursor protein, amyloid-beta oligomers, endoplasmic reticulum stress, ER stress-induced apoptosis, APP processing, APP trafficking, Golgi apparatus, endosomes, lysosomes, autophagosomes, GRP78, eIF2α phosphorylation, caspase-3, caspase-4, DNA fragmentation, Alzheimer's disease
- MeSH terms
- Endoplasmic Reticulum Chaperone BiP, Serum Amyloid A Protein, Animals, Cell Line, Cells, Cultured, Chlorocebus aethiops, Dementia, Endoplasmic Reticulum, Humans, Kidney, Oligopeptides, Transfection, Apoptosis, Sequence Deletion, COS Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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