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Cited by 277Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAntioxidant Activity and Oxidative Stress

The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.

Aβ and Tau Toxicities in Alzheimer's Are Linked via Oxidative Stress-Induced P38 Activation: Protective Role of Vitamin E

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Giraldo, E., Lloret, A., Fuchsberger, T., Viña, J.·2014·Redox Biology
DOI 10.1016/j.redox.2014.03.002PMC PMC4099506
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Abstract

Oxidative stress is a hallmark of Alzheimer's disease (AD). We propose that rather than causing damage because of the action of free radicals, oxidative stress deranges signaling pathways leading to tau hyperphosphorylation, a hallmark of the disease. Indeed, incubation of neurons in culture with 5 µM beta-amyloid peptide (Aβ) causes an activation of p38 MAPK (p38) that leads to tau hyperphosphorylation. Inhibition of p38 prevents Aβ-induced tau phosphorylation. Aβ-induced effects are prevented when neurons are co-incubated with trolox (the water-soluble analog of vitamin E). We have confirmed these results in vivo, in APP/PS1 double transgenic mice of AD. We have found that APP/PS1 transgenic mice exhibit a high level of P-p38 in the hippocampus but not in cortex and this is prevented by feeding animals with a diet supplemented with vitamin E. Our results underpin the role of oxidative stress in the altered cell signaling in AD pathology and suggest that antioxidant prevention may be useful in AD therapeutics.

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Crossref · 10.1016/j.redox.2014.03.002

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Figures

Fig. 1 Trolox prevents Aβ dependent p38 activation in neurons in primary culture. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. Data were normalized with tubulin values. **p < 0.01 compared to control values; ++p< 0.01 compared to values obtained with Aβ.
Fig. 1 Trolox prevents Aβ dependent p38 activation in neurons in primary culture. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. Data were normalized with tubulin values. **p < 0.01 compared to control values; ++p< 0.01 compared to values obtained with Aβ.CC BY-NC-ND · PubMed Central
Fig. 2 Vitamin E supplementation prevents activation of p38 in AD mice in vivo. Representative Western blots are shown. In all cases, values are means ± SD of 9 mice (A) or 6 mice (B). Data were normalized with tubulin values, *p < 0.05 compared to values found in wild type mice (WT) or in mice fed with standard diet (TG).
Fig. 2 Vitamin E supplementation prevents activation of p38 in AD mice in vivo. Representative Western blots are shown. In all cases, values are means ± SD of 9 mice (A) or 6 mice (B). Data were normalized with tubulin values, *p < 0.05 compared to values found in wild type mice (WT) or in mice fed with standard diet (TG).CC BY-NC-ND · PubMed Central
Fig. 3 P38 activation leads to an increase in p-tau. Cultured neurons were pre-incubated with a p38 inhibitor (SB203580) for 30 min. Prior to the treatment with 5 µM of Aβ. Results showed that when p38 is inhibited there is a decrease in tau-phosphorylation compared to neurons without p38 inhibitor. Representative Western blots are shown. In all cases, values are means ± SD of 4 experiments. **p < 0.01 compared to control values. +p < 0.05 compared to values obtained with Aβ.
Fig. 3 P38 activation leads to an increase in p-tau. Cultured neurons were pre-incubated with a p38 inhibitor (SB203580) for 30 min. Prior to the treatment with 5 µM of Aβ. Results showed that when p38 is inhibited there is a decrease in tau-phosphorylation compared to neurons without p38 inhibitor. Representative Western blots are shown. In all cases, values are means ± SD of 4 experiments. **p < 0.01 compared to control values. +p < 0.05 compared to values obtained with Aβ.CC BY-NC-ND · PubMed Central
Fig. 4 Effect of Aβ peptide and trolox in the expression of p-tau. Cultured neurons treated with 5 µM of Aβ showed significantly higher expression of p-tau (p < 0.05). Trolox reverted the Aβ-induced effects. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. **p < 0.05 compared to control values. +p < 0.05 compared to values obtained with Aβ.
Fig. 4 Effect of Aβ peptide and trolox in the expression of p-tau. Cultured neurons treated with 5 µM of Aβ showed significantly higher expression of p-tau (p < 0.05). Trolox reverted the Aβ-induced effects. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. **p < 0.05 compared to control values. +p < 0.05 compared to values obtained with Aβ.CC BY-NC-ND · PubMed Central
Fig. 5 P-tau in AD mice model. P-tau was higher in the hippocampus of AD transgenic mice compared to wild type mice. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. *p < 0.05 compared to WT animals.
Fig. 5 P-tau in AD mice model. P-tau was higher in the hippocampus of AD transgenic mice compared to wild type mice. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. *p < 0.05 compared to WT animals.CC BY-NC-ND · PubMed Central
Fig. 6 Schematic representation of the role of oxidative stress linking Aβ and tau toxicities. Numbers near the arrows indicate the pertinent reference in the reference list. Figures refer to those in the paper.
Fig. 6 Schematic representation of the role of oxidative stress linking Aβ and tau toxicities. Numbers near the arrows indicate the pertinent reference in the reference list. Figures refer to those in the paper.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Giraldo, E., Lloret, A., Fuchsberger, T., & Viña, J.
Affiliations
Universitat de València (ES)
Corresponding author
Viña, J.
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2014
Volume
2
Pages
873-877
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2014.03.002
PMC
PMC4099506
OpenAlex
W2039173359
Cited by
268
References
28
Citations by year
2026: 10 · 2025: 18 · 2024: 23 · 2023: 34 · 2022: 27 · 2021: 26 · 2020: 27 · 2019: 24 · 2018: 22 · 2017: 21 · 2016: 12 · 2015: 19 · 2014: 3
FWCI
12.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Spanish Ministry of Education and Science (MEC) (SAF2010-19498)
  • “Red Tematica de investigacion cooperativa en envejecimiento y fragilidad” (RETICEF) (ISCIII2006-RED13-027, ISCIII2012-RED-43-029)
  • “Conselleria d’Educació, Cultura i Esport de la Generalitat Valenciana” (PROMETEO2010/074)
  • “Fundació Gent Per Gent de la Comunitat Valenciana” (35NEURO)
  • INCLIVA (RS2012-609)
  • EU (CM1001, FRAILOMIC-HEALTH.2012.2.1.1-2)
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
  • Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords
Alzheimer's disease, amyloid-beta, tau hyperphosphorylation, oxidative stress, p38 MAPK, vitamin E, Trolox, APP/PS1 mice, hippocampus, antioxidant therapy, neuronal signaling
MeSH terms
Alzheimer Disease, Animals, Cells, Cultured, Disease Models, Animal, Hippocampus, Male, Mice, Transgenic, Neurons, Phosphorylation, Vitamin E, Amyloid beta-Peptides, tau Proteins, Oxidative Stress, Protective Agents, p38 Mitogen-Activated Protein Kinases, Mice, Rats

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