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Aβ and Tau Toxicities in Alzheimer's Are Linked via Oxidative Stress-Induced P38 Activation: Protective Role of Vitamin E
Open accessAbstract
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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“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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Solfrizzi, V., Agosti, P., Lozupone, M., Custodero, C., Schilardi, A., Valiani, V., Sardone, R., Dibello, V., Lena, L. D., Lamanna, A., et al. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179940 · Cited by 63
Arrozi, A. P., Shukri, S. N. S., Ngah, W. Z. W., Yusof, Y. A. M., Damanhuri, H. A., Jaafar, F., & Makpol, S. (2020) · Scientific Reports · doi:10.1038/s41598-020-65570-4 · Cited by 59
Tau Toxicity in Neurodegeneration
Liang, S., Wang, Z.-T., Tan, L., & Yu, J. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02809-3 · Cited by 61
“be the prestage of the formation of pathological tau [87].”
BackgroundRole of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration
Angeloni, C., Gatti, M., Prata, C., Hrelia, S., & Maraldi, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093299 · Cited by 62
“It has been observed that tau phosphorylation can be increased by p38 MAPK, that, in turn, is activated by oxidative stress [34].”
BackgroundEndogenous recovery after brain damage: molecular mechanisms that balance neuronal life/death fate
Tovar‐y‐Romo, L. B., Penagos‐Puig, A., & Ramírez‐Jarquín, J. O. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13362 · Cited by 60
Fidélis, E. M., Savall, A. S. P., Abreu, E. D. L., de Carvalho, F. B., Teixeira, F. E. G., Haas, S. E., Sampaio, T. B., & Pinton, S. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.09.032 · Cited by 59
Zhang, X., Gou, Y., Zhang, Y., Li, J., Han, K., Xu, Y. X., Li, H., You, L., Yu, P., Chang, Y., et al. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-00346-3 · Cited by 54
Verma, A., Azhar, G., Zhang, X., Patyal, P., Grishma, K. C., Sharma, S., Che, Y., & Wei, J. Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24020950 · Cited by 55
“gingivalis-mediated inflammasome activity and neuroinflammation have been shown to be activated in AD brains [42,43].”
BackgroundFunctional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology
Guo, J., Cheng, J., North, B. J., & Wei, W. (2017) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2017.07.001 · Cited by 55
Oxidative Stress in Tauopathies: From Cause to Therapy
Bartolomé, F. B., Carro, E., & Alquézar, C. (2022) · Antioxidants · doi:10.3390/antiox11081421 · Cited by 59
“It was demonstrated that OS caused the activation of p38, leading to tau hyperphosphorylation in vivo [101].”
BackgroundYagami, T., Yamamoto, Y., & Koma, H. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1277-4 · Cited by 56
Ferroptosis mechanism and Alzheimer's disease
Feng, L., Sun, J. J., Xia, L., Shi, Q., Hou, Y., Zhang, L., Li, M., Fan, C., & Sun, B. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.389362 · Cited by 56
Redox Homeostasis and Prospects for Therapeutic Targeting in Neurodegenerative Disorders
Akanji, M. A., Rotimi, D. E., Elebiyo, T. C., Awakan, O. J., & Adeyemı, O. S. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9971885 · Cited by 55
“[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.”
BackgroundMelone, M. A. B., Dato, C., Paladino, S., Coppola, C., Trebini, C., Giordana, M. T., & Perrone, L. (2018) · Pharmaceutical Research · doi:10.1007/s11095-017-2276-2 · Cited by 52
RetractedYao, K., Zhao, Y., & Zu, H. (2019) · Drug Design Development and Therapy · doi:10.2147/dddt.s182684 · Cited by 52
“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
Fan, Y., Pang, Z., Wu, T.-Y., Zhang, Y., Xuan, W.-Q., Wang, Z., Yu, X., Li, Y., Guo, C., & Wang, Z. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.10.007 · Cited by 55
Nasoohi, S., Parveen, K., & Ishrat, T. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180735 · Cited by 51
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Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases
Chong, Z. Z., & Souayah, N. (2025) · Antioxidants · doi:10.3390/antiox14060696 · Cited by 50
NDP52 associates with phosphorylated tau in brains of an Alzheimer disease mouse model
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Walia, V., Kaushik, D., Mittal, V., Kumar, K., Verma, R., Parashar, J., Akter, R., Rahman, M. H., Bhatia, S., Al-Harrasi, A., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-021-02617-1 · Cited by 47
Revisiting the Role of Vitamins and Minerals in Alzheimer’s Disease
Shah, H., Dehghani, F., Ramezan, M., Gannaban, R. B., Haque, Z. F., Rahimi, F. C., Abbasi, S., & Shin, A. C. (2023) · Antioxidants · doi:10.3390/antiox12020415 · Cited by 48
“Similar cognition-preserving effects of vitamin E were also demonstrated in APP/PS1 mice [36,37].”
BackgroundMolecular Targets in Alzheimer’s Disease
Bjørklund, G., Aaseth, J., Dadar, M., & Chirumbolo, S. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1563-9 · Cited by 48
Kempf, S. J., Metaxas, A., Ibáñez-Vea, M., Darvesh, S., Finsen, B. R., & Larsen, M. R. (2016) · Oncotarget · doi:10.18632/oncotarget.9092 · Cited by 44
“Importantly, the activation of MAPK signalling occurs via cellular stress arising from inflammatory cytokines such as TNFα [46] or Aβ plaques [47].”
Background
Metadata
- 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
- 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
- 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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