Hücre Ölüm Mekanizması Ferroptozun Alzheimer Patogenezindeki Rolü

Year 2024, Volume: 6 Issue: 2, 82 - 102, 31.12.2024

Hilal Koyuncu , Tuğba Keskin , Sengul Tural

https://doi.org/10.71051/jnlm.1595473

Abstract

Alzheimer hastalığı (AH), demansın en yaygın nedenidir ve tüm vakaların yaklaşık %60-%80'ini oluşturmaktadır. Yıllar içinde büyük çabalar harcanmış olmasına rağmen, AH'nin tam mekanizması henüz tamamen aydınlatılamamıştır. Son zamanlarda, AH patogenezinde demir metabolizması, lipid peroksidasyonu ve oksidatif stresin rolleri büyük ilgi görmeye başlamıştır. Ayrıca, bu patolojik olayların, ferroptoz adı verilen hücre ölümünün önemli düzenleyicileri olduğunu da belirtmek gerekir. Artan kanıtlar, ferroptozun AH’de nörolojik fonksiyon bozukluklarıyla ilişkili olabileceğini göstermektedir. Ancak, altındaki mekanizmalar henüz tam olarak aydınlatılmamıştır. Bu derlemenin amacı, ferroptozun temel mekanizmalarını gözden geçirmek; AH ve ferroptoz arasındaki potansiyel etkileşimi demir metabolizması, lipid peroksidasyonu ve glutatiyon/glutatyon peroksidaz 4 ekseni çerçevesinde kapsamlı bir şekilde ele almaktır.

Keywords

ferroptoz, demir metabolizması, lipid peroksidasyonu, Alzheimer patogenezi, hücre ölüm mekanizması

The Role of the Cell Death Mechanism Ferroptosis in Alzheimer's Pathogenesis

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 60-80% of all cases. Despite significant efforts over the years, the exact mechanisms of AD remain incompletely understood. Recently, the roles of iron metabolism, lipid peroxidation, and oxidative stress in the pathogenesis of AD have garnered considerable attention. Moreover, it should be noted that these pathological events are important regulators of a form of cell death known as ferroptosis. Increasing evidence suggests that ferroptosis may be associated with neurological dysfunction in AD. However, the underlying mechanisms have not yet been fully elucidated. The aim of this review is to examine the basic mechanisms of ferroptosis and to comprehensively discuss the potential interactions between AD and ferroptosis within the framework of iron metabolism, lipid peroxidation, and the glutathione/glutathione peroxidase 4 axis.

Keywords

ferroptosis, iron metabolism, lipid peroxidation, Alzheimer, cell death mechanism

References

• Alim, I., Caulfield, J. T., Chen, Y., Swarup, V., Geschwind, D. H., Ivanova, E., ... & Ratan, R. R. (2019). Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell, 177(5), 1262-1279.
• Allen, M., Zou, F., Chai, H. S., Younkin, C. S., Miles, R., Nair, A. A., ... & Ertekin-Taner, N. (2012). Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications. Molecular neurodegeneration, 7, 1-12.
• Aquilano, K., Baldelli, S., & Ciriolo, M. R. (2014). Glutathione: new roles in redox signaling for an old antioxidant. Frontiers in pharmacology, 5, 196.
• Ayton, S., Janelidze, S., Roberts, B., Palmqvist, S., Kalinowski, P., Diouf, I., ... & Hansson, O. (2021). Acute phase markers in CSF reveal inflammatory changes in Alzheimer’s disease that intersect with pathology, APOE ε4, sex and age. Progress in Neurobiology, 198, 101904.
• Bai, Q., Liu, J., & Wang, G. (2020). Ferroptosis, a regulated neuronal cell death type after intracerebral hemorrhage. Frontiers in Cellular Neuroscience, 14, 591874.
• Bannai, S., & Kitamura, E. (1980). Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. The Journal of biological chemistry, 255(6), 2372-2376.
• Bayır, H., Dixon, S. J., Tyurina, Y. Y., Kellum, J. A., & Kagan, V. E. (2023). Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney. Nature Reviews Nephrology, 19(5), 315-336.
• Bok, E., Leem, E., Lee, B. R., Lee, J. M., Yoo, C. J., Lee, E. M., & Kim, J. (2021). Role of the lipid membrane and membrane proteins in tau pathology. Frontiers in cell and developmental biology, 9, 653815.
• Cao, J. Y., & Dixon, S. J. (2016). Mechanisms of ferroptosis. Cellular and Molecular Life Sciences, 73, 2195-2209.
• Casley, C. S., Land, J. M., Sharpe, M. A., Clark, J. B., Duchen, M. R., & Canevari, L. (2002). β-Amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiology of disease, 10(3), 258-267.
• Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., ... & Stockwell, B. R. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. cell, 149(5), 1060-1072.
• Doll, S., Proneth, B., Tyurina, Y. Y., Panzilius, E., Kobayashi, S., Ingold, I., ... & Conrad, M. (2017). ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nature chemical biology, 13(1), 91-98.
• Dolma, S., Lessnick, S. L., Hahn, W. C., & Stockwell, B. R. (2003). Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer cell, 3(3), 285-296.
• Du, Y., & Guo, Z. (2022). Recent progress in ferroptosis: inducers and inhibitors. Cell death discovery, 8(1), 501.
• Feng, J., Lu, P. Z., Zhu, G. Z., Hooi, S. C., Wu, Y., Huang, X. W., ... & Lu, G. D. (2021). ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma. Acta Pharmacologica Sinica, 42(1), 160-170.
• Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., ... & Conrad, M. (2014). Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature cell biology, 16(12), 1180-1191.
• García-Viñuales, S., Sciacca, M. F., Lanza, V., Santoro, A. M., Grasso, G., Tundo, G. R., ... & Milardi, D. (2021). The interplay between lipid and Aβ amyloid homeostasis in Alzheimer’s Disease: risk factors and therapeutic opportunities. Chemistry and Physics of Lipids, 236, 105072.
• Hambright, W. S., Fonseca, R. S., Chen, L., Na, R., & Ran, Q. (2017). Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox biology, 12, 8-17.
• Huang, L., McClatchy, D. B., Maher, P., Liang, Z., Diedrich, J. K., Soriano-Castell, D., ... & Currais, A. (2020). Intracellular amyloid toxicity induces oxytosis/ferroptosis regulated cell death. Cell death & disease, 11(10), 828.
• Ingold, I., Berndt, C., Schmitt, S., Doll, S., Poschmann, G., Buday, K., ... & Conrad, M. (2018). Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell, 172(3), 409-422.
• Kist, M., & Vucic, D. (2021). Cell death pathways: intricate connections and disease implications. The EMBO Journal, 40(5), e106700.
• Lee, J. Y., Kim, W. K., Bae, K. H., Lee, S. C., & Lee, E. W. (2021). Lipid metabolism and ferroptosis. Biology, 10(3), 184.
• Lei, P., Ayton, S., Finkelstein, D. I., Spoerri, L., Ciccotosto, G. D., Wright, D. K., ... & Bush, A. I. (2012). Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nature medicine, 18(2), 291-295.
• Li, J., Cao, F., Yin, H. L., Huang, Z. J., Lin, Z. T., Mao, N., ... & Wang, G. (2020). Ferroptosis: past, present and future. Cell death & disease, 11(2), 88.
• Li, J., Lama, R., Galster, S. L., Inigo, J. R., Wu, J., Chandra, D., ... & Wang, X. (2022). Small-molecule MMRi62 induces ferroptosis and inhibits metastasis in pancreatic cancer via degradation of ferritin heavy chain and mutant p53. Molecular cancer therapeutics, 21(4), 535-545.
• Liu, D., Liang, C. H., Huang, B., Zhuang, X., Cui, W., Yang, L., ... & Chu, B. (2023). Tryptophan metabolism acts as a new anti‐ferroptotic pathway to mediate tumor growth. Advanced Science, 10(6), 2204006.
• Lovell, M. A., Xie, C., & Markesbery, W. R. (1998). Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer's disease. Neurology, 51(6), 1562-1566.
• Murphy, T. H., Miyamoto, M., Sastre, A., Schnaar, R. L., & Coyle, J. T. (1989). Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron, 2(6), 1547-1558.
• Patterson, C. The state of the art of dementia research: New frontiers, World Alzheimer Report (2018).
• Peña-Bautista, C., Vigor, C., Galano, J. M., Oger, C., Durand, T., Ferrer, I., ... & Cháfer-Pericás, C. (2018). Plasma lipid peroxidation biomarkers for early and non-invasive Alzheimer Disease detection. Free Radical Biology and Medicine, 124, 388-394.
• Plascencia-Villa, G., & Perry, G. (2021). Preventive and therapeutic strategies in Alzheimer's disease: focus on oxidative stress, redox metals, and ferroptosis. Antioxidants & redox signaling, 34(8), 591-610.
• Pope, L. E., & Dixon, S. J. (2023). Regulation of ferroptosis by lipid metabolism. Trends in Cell Biology.
• Radadiya, P. S., Thornton, M. M., Puri, R. V., Yerrathota, S., Dinh-Phan, J., Magenheimer, B., ... & Sharma, M. (2021). Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease. JCI insight, 6(8).
• Schubert, D., Kimura, H., & Maher, P. (1992). Growth factors and vitamin E modify neuronal glutamate toxicity. Proceedings of the National Academy of Sciences, 89(17), 8264-8267.
• Skonieczna, M., Cieslar-Pobuda, A., Saenko, Y., Foksinski, M., Olinski, R., Rzeszowska-Wolny, J., & Wiechec, E. (2017). The impact of DIDS-induced inhibition of voltage-dependent anion channels (VDAC) on cellular response of lymphoblastoid cells to ionizing radiation. Medicinal Chemistry, 13(5), 477-483.
• Skouta, R., Dixon, S. J., Wang, J., Dunn, D. E., Orman, M., Shimada, K., ... & Stockwell, B. R. (2014). Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. Journal of the American Chemical Society, 136(12), 4551-4556.
• Song, Q., Peng, S., Sun, Z., Heng, X., & Zhu, X. (2021). Temozolomide drives ferroptosis via a DMT1-dependent pathway in glioblastoma cells. Yonsei medical journal, 62(9), 843.
• Song, S., Su, Z., Kon, N., Chu, B., Li, H., Jiang, X., ... & Gu, W. (2023). ALOX5-mediated ferroptosis acts as a distinct cell death pathway upon oxidative stress in Huntington's disease. Genes & Development, 37(5-6), 204-217.
• Sun, Z., Zhao, C., Liu, X., Zhang, P., Wang, X., Man, X., ... & Xiang, Y. (2023). Mutation analysis of the ECE1 gene in late-onset Alzheimer’s disease. Neurobiology of Aging, 129, 58-61.
• Tang, D., Chen, X., Kang, R., & Kroemer, G. (2021). Ferroptosis: molecular mechanisms and health implications. Cell research, 31(2), 107-125.
• Tiwari, S., Atluri, V., Kaushik, A., Yndart, A., & Nair, M. (2019). Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. International journal of nanomedicine, 5541-5554.
• Van der Flier PhD, W. M. (2021). Philip Scheltens, Bart De Strooper, Miia Kivipelto, Henne Holstege, Gael Chételat, Charlotte E Teunissen, Jeffrey Cummings, Wiesje M van der Flier. Lancet, 397, 1577-90.
• Verma, A., Waiker, D. K., Bhardwaj, B., Saraf, P., & Shrivastava, S. K. (2022). The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer’s disease. Bioorganic Chemistry, 119, 105562.
• Villalón-García, I., Álvarez-Córdoba, M., Povea-Cabello, S., Talaverón-Rey, M., Villanueva-Paz, M., Luzón-Hidalgo, R., ... & Sánchez-Alcázar, J. A. (2022). Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration. Neurobiology of disease, 165, 105649.
• Villalón-García, I., Povea-Cabello, S., Álvarez-Córdoba, M., Talaverón-Rey, M., Suárez-Rivero, J. M., Suárez-Carrillo, A., ... & Sánchez-Alcázar, J. A. (2023). Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration. Neural Regeneration Research, 18(6), 1196-1202.
• Wang, C., Chen, S., Guo, H., Jiang, H., Liu, H., Fu, H., & Wang, D. (2022). Forsythoside a mitigates alzheimer's-like pathology by inhibiting ferroptosis-mediated neuroinflammation via Nrf2/GPX4 axis activation. International Journal of Biological Sciences, 18(5), 2075.
• Wang, S., Jiang, Y., Liu, Y., Liu, Q., Sun, H., Mei, M., & Liao, X. (2022). Ferroptosis promotes microtubule-associated protein tau aggregation via GSK-3β activation and proteasome inhibition. Molecular Neurobiology, 59(3), 1486-1501.
• Wenz, C., Faust, D., Linz, B., Turmann, C., Nikolova, T., & Dietrich, C. (2019). Cell–cell contacts protect against t-BuOOH-induced cellular damage and ferroptosis in vitro. Archives of toxicology, 93, 1265-1279.
• Wu, L., Xian, X., Tan, Z., Dong, F., Xu, G., Zhang, M., & Zhang, F. (2023). The role of iron metabolism, lipid metabolism, and redox homeostasis in Alzheimer’s disease: from the perspective of ferroptosis. Molecular Neurobiology, 60(5), 2832-2850.
• Xu, H., Perreau, V. M., Dent, K. A., Bush, A. I., Finkelstein, D. I., & Adlard, P. A. (2016). Iron regulates apolipoprotein E expression and secretion in neurons and astrocytes. Journal of Alzheimer's Disease, 51(2), 471-487.
• Yagoda, N., Von Rechenberg, M., Zaganjor, E., Bauer, A. J., Yang, W. S., Fridman, D. J., ... & Stockwell, B. R. (2007). RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature, 447(7146), 865-869.
• Yan, H. F., Zou, T., Tuo, Q. Z., Xu, S., Li, H., Belaidi, A. A., & Lei, P. (2021). Ferroptosis: mechanisms and links with diseases. Signal transduction and targeted therapy, 6(1), 49.
• Yang, W. S., Kim, K. J., Gaschler, M. M., Patel, M., Shchepinov, M. S., & Stockwell, B. R. (2016). Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proceedings of the National Academy of Sciences, 113(34), E4966-E4975.
• Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., ... & Stockwell, B. R. (2014). Regulation of ferroptotic cancer cell death by GPX4. Cell, 156(1), 317-331.
• Yao, H., Jiang, W., Liao, X., Wang, D., & Zhu, H. (2024). Regulatory mechanisms of amino acids in ferroptosis. Life Sciences, 122803.
• Yin, H., Xu, L., & Porter, N. A. (2011). Free radical lipid peroxidation: mechanisms and analysis. Chemical reviews, 111(10), 5944-5972.
• Zhao, D., Yang, K., Guo, H., Zeng, J., Wang, S., Xu, H., ... & Ge, J. (2023). Mechanisms of ferroptosis in Alzheimer's disease and therapeutic effects of natural plant products: a review. Biomedicine & Pharmacotherapy, 164, 114312.
• Zhao, T., Guo, X., & Sun, Y. (2021). Iron accumulation and lipid peroxidation in the aging retina: implication of ferroptosis in age-related macular degeneration. Aging and disease, 12(2), 529.
• Zheng, H., Jiang, J., Xu, S., Liu, W., Xie, Q., Cai, X., ... & Li, R. (2021). Nanoparticle-induced ferroptosis: detection methods, mechanisms and applications. Nanoscale, 13(4), 2266-2285.
• Zou, Y., Henry, W. S., Ricq, E. L., Graham, E. T., Phadnis, V. V., Maretich, P., ... & Schreiber, S. L. (2020). Plasticity of ether lipids promotes ferroptosis susceptibility and evasion