The ER stress factor XBP1s prevents amyloid-β neurotoxicity
Open accessAbstract
Alzheimer's disease (AD) is an incurable neurodegenerative disorder clinically characterized by progressive cognitive impairment. A prominent pathologic hallmark in the AD brain is the abnormal accumulation of the amyloid-β 1-42 peptide (Aβ), but the exact pathways mediating Aβ neurotoxicity remain enigmatic. Endoplasmic reticulum (ER) stress is induced during AD, and has been indirectly implicated as a mediator of Aβ neurotoxicity. We report here that Aβ activates the ER stress response factor X-box binding protein 1 (XBP1) in transgenic flies and in mammalian cultured neurons, yielding its active form, the transcription factor XBP1s. XBP1s shows neuroprotective activity in two different AD models, flies expressing Aβ and mammalian cultured neurons treated with Aβ oligomers. Trying to identify the mechanisms mediating XBP1s neuroprotection, we found that in PC12 cells treated with Aβ oligomers, XBP1s prevents the accumulation of free calcium (Ca(2+)) in the cytosol. This protective activity can be mediated by the downregulation of a specific isoform of the ryanodine Ca(2+) channel, RyR3. In support of this observation, a mutation in the only ryanodine receptor (RyR) in flies also suppresses Aβ neurotoxicity, indicating the conserved mechanisms between the two AD models. These results underscore the functional relevance of XBP1s in Aβ toxicity, and uncover the potential of XBP1 and RyR as targets for AD therapeutics.
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The Aβ42 eye produces a very rough and small eye, with increased roughness and ommatidial fusion toward the posterior.
“The Aβ42 eye produces a very rough and small eye, with increased roughness and ommatidial fusion toward the posterior of the eye (Fig. 8C; 89).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [89]
In “Generation of a new AD model in flies” and the Figure 1 caption (page not provided), the paper describes Aβ42-expressing eyes as small and highly disorganized, supporting the small, rough-eye description. It does not report increasing roughness or ommatidial fusion toward the posterior of the eye. (LLM, conf=0.86)
Experimental — accuracy not yet measuredExpression of Aβ42 and TDP-43Q331K in the fly eye driven by GMR-GAL4 leads to eye phenotypes.
“Similar to tau and to polyglutamine proteins, expression of Aβ42 and TDP-43Q331K in the fly eye driven by GMR-GAL4 leads to eye phenotypes.”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [89]
The “Generation of a new AD model in flies” section reports that Aβ42 expression with gmr-Gal4 produced small, disorganized eyes with necrotic spots. The cited paper does not report an eye phenotype for TDP-43Q331K, so it supports only the Aβ42 part of the claim. No page number is available in our copy. (LLM, conf=0.88)
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- Authors
- Casas-Tinto, S., Zhang, Y., Sanchez-Garcia, J., Gomez-Velazquez, M., Rincon-Limas, D. E., & Fernandez-Funez, P.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- ORCID
- Zhang, Yan
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-03-09
- Volume
- 20
- Issue
- 11
- Pages
- 2144-2160
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3090193
- OpenAlex
- W2103795148
- Cited by
- 275
- References
- 6
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 16 · 2023: 22 · 2022: 22 · 2021: 13 · 2020: 24 · 2019: 13 · 2018: 22 · 2017: 35 · 2016: 16 · 2015: 13 · 2014: 20 · 2013: 20 · 2012: 15
- FWCI
- 12.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DP2OD002721, DP2 OD002721-0)
- 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
- XBP1, endoplasmic reticulum stress, amyloid-beta toxicity, Alzheimer's disease, calcium homeostasis, intracellular calcium, neuroprotection, amyloid-beta oligomers, Drosophila model, PC12 cells, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Calcium, DNA-Binding Proteins, Drosophila, Endoplasmic Reticulum, Eye, Female, Male, Neurons, Peptide Fragments, RNA Splicing, Transfection, Amyloid beta-Peptides, PC12 Cells, Protein Folding, Ryanodine Receptor Calcium Release Channel, Drosophila Proteins, Animals, Genetically Modified, RNA, Small Interfering, Rats
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