Mild oxidative stress induces redistribution of BACE1 in non-apoptotic conditions and promotes the amyloidogenic processing of Alzheimer's disease amyloid precursor protein
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BACE1 is responsible for β-secretase cleavage of the amyloid precursor protein (APP), which represents the first step in the production of amyloid β (Aβ) peptides. Previous reports, by us and others, have indicated that the levels of BACE1 protein and activity are increased in the brain cortex of patients with Alzheimer's disease (AD). The association between oxidative stress (OS) and AD has prompted investigations that support the potentiation of BACE1 expression and enzymatic activity by OS. Here, we have established conditions to analyse the effects of mild, non-lethal OS on BACE1 in primary neuronal cultures, independently from apoptotic mechanisms that were shown to impair BACE1 turnover. Six-hour treatment of mouse primary cortical cells with 10-40 µM hydrogen peroxide did not significantly compromise cell viability but it did produce mild oxidative stress (mOS), as shown by the increased levels of reactive radical species and activation of p38 stress kinase. The endogenous levels of BACE1 mRNA and protein were not significantly altered in these conditions, whereas a toxic H2O2 concentration (100 µM) caused an increase in BACE1 protein levels. Notably, mOS conditions resulted in increased levels of the BACE1 C-terminal cleavage product of APP, β-CTF. Subcellular fractionation techniques showed that mOS caused a major rearrangement of BACE1 localization from light to denser fractions, resulting in an increased distribution of BACE1 in fractions containing APP and markers for trans-Golgi network and early endosomes. Collectively, these data demonstrate that mOS does not modify BACE1 expression but alters BACE1 subcellular compartmentalization to favour the amyloidogenic processing of APP, and thus offer new insight in the early molecular events of AD pathogenesis.
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Oxidative stress may decrease the activity of α-secretase, promoting β and γ-secretase and increasing Aβ production.
“It has also been postulated that oxidative stress may decrease the activity of α-secretase, which promotes the expression and activity of β and γ-secretase, leading to the increased production of Aβ (Tan et al., 2013).”
From Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial (2016) · cites this paper as Tan et al., 2013
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- [56]Chami L, Checler F (2012) BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and beta-amyloid production in Alzheimer’s disease. Mol Neurodegener 7: 52. 23039869 PMC3507664
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Investigation of BACE1 as a stress-induced regulator of neuronal metabolism
Findlay, J. A. (2014) · Discovery Research Portal (University of Dundee)
- Authors
- Tan, J.-L., Li, Q.-X., Ciccotosto, G. D., Crouch, P. J., Culvenor, J. G., White, A. R., & Evin, G.
- Affiliations
- The University of Melbourne (AU)
- Corresponding author
- Evin, Genevieve
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-04-17
- Volume
- 8
- Issue
- 4
- Pages
- e61246
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3629182
- OpenAlex
- W2084951515
- Cited by
- 66
- References
- 87
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 7 · 2018: 9 · 2017: 4 · 2016: 8 · 2015: 9 · 2014: 11 · 2013: 3
- FWCI
- 7.18
- Type
- journal article
- Language
- en
- Update notices
- correction (2013-10-17)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- BACE1, amyloid precursor protein, oxidative stress, Alzheimer's disease, amyloid-beta, hydrogen peroxide, subcellular redistribution, trans-Golgi network, early endosomes, p38 MAPK, beta-secretase, neuronal culture, cortical neurons
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Cells, Cultured, Centrifugation, Density Gradient, Cerebral Cortex, Enzyme Activation, Fluorescent Antibody Technique, Hydrogen Peroxide, Mice, Inbred C57BL, Protein Processing, Post-Translational, Subcellular Fractions, Immunoblotting, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Apoptosis, Oxidative Stress, Protein Transport, Adaptor Proteins, Vesicular Transport, Mice, Caspase 3, Amyloid Precursor Protein Secretases
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