Aβ and Tau Toxicities in Alzheimer's Are Linked via Oxidative Stress-Induced P38 Activation: Protective Role of Vitamin E
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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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Aβ-induced oxidative stress leads to activation of p38 MAPK and subsequent tau hyperphosphorylation.
“Importantly, it has been reported that the Aβ-induced oxidative stress leads to the activation of p38 MAPK and subsequent tau hyperphosphorylation (Giraldo et al., 2014).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Giraldo et al., 2014
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Interplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer’s Disease
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Could Alzheimer’s Disease Originate in the Periphery and If So How So?
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Recent insights on astrocyte mechanisms in CNS homeostasis, pathology, and repair
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Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
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NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases
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“Moreover, both in vivo and in vitro studies showed that vitamin E protects against the formation of Aβ-induced tau phosphorylation through the inhibition of the activation of p38-MAPK by reducing oxidative stress (Table 1) [231].”
BackgroundThe Role of Copper in Tau-Related Pathology in Alzheimer’s Disease
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“This finding is also important as it links Aβ and tau pathology (Giraldo et al., 2014).”
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“It is well known that in the tauopathy AD, Ab is capable of inducing oxidative stress, a process which is hypothesized to be upstream of the formation of pathologic tau (Giraldo et al., 2014).”
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“an important role in tau phosphorylation during the course of AD progression (Giraldo et al. 2014).”
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Tau Toxicity in Neurodegeneration
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“be the prestage of the formation of pathological tau [87].”
BackgroundRole of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration
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“It has been observed that tau phosphorylation can be increased by p38 MAPK, that, in turn, is activated by oxidative stress [34].”
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BackgroundFunctional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology
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Ferroptosis mechanism and Alzheimer's disease
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“[99] stated that Aβ-mediated oxidative stress triggers the oxidation of both NADPH oxidase and p38; the aberrant activation of p38, in turn, triggers the hyperphosphorylation of tau proteins.”
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“32 Our results showed that A β 25–35 treatment could significantly enhance oxidative stress response by increasing the concentration of MDA, LDH, and ROS, which indicate that oxidative stress may play an important role in A β -induced toxicity and pathological process of AD.”
Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity
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Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases
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NDP52 associates with phosphorylated tau in brains of an Alzheimer disease mouse model
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Revisiting the Role of Vitamins and Minerals in Alzheimer’s Disease
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“Similar cognition-preserving effects of vitamin E were also demonstrated in APP/PS1 mice [36,37].”
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“Importantly, the activation of MAPK signalling occurs via cellular stress arising from inflammatory cytokines such as TNFα [46] or Aβ plaques [47].”
Background
- Authors
- Giraldo, E., Lloret, A., Fuchsberger, T., & Viña, J.
- Affiliations
- Universitat de València (ES)
- Corresponding author
- Viña, J.
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2014
- Volume
- 2
- Pages
- 873-877
- ISSN
- 2213-2317 (ISSN-L)
- 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 · 2013: 1
- FWCI
- 12.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Biochemistry › 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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