Amyloid beta-activated alpha-1-syntrophin has ramifications on Rac1 activation, ROS production and neuronal cell death.

Publisher: Wiley-Blackwell Country of Publication: France NLM ID: 8918110 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-9568 (Electronic) Linking ISSN: 0953816X NLM ISO Abbreviation: Eur J Neurosci Subsets: MEDLINE

Publication: : Oxford : Wiley-Blackwell
Original Publication: Oxford, UK : Published on behalf of the European Neuroscience Association by Oxford University Press, c1989-

Reactive Oxygen Species*/metabolism ; rac1 GTP-Binding Protein*/metabolism ; Amyloid beta-Peptides*/metabolism ; Neurons*/metabolism ; Alzheimer Disease*/metabolism ; Cell Death*/drug effects; Humans ; Cell Line, Tumor ; Membrane Proteins/metabolism ; Membrane Proteins/genetics ; Phosphorylation ; Calcium-Binding Proteins ; Muscle Proteins

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of β-amyloid (Aβ)-containing extracellular neuritic plaques and phosphorylated tau-containing intracellular neurofibrillary tangles. It remains the primary neuropathological criteria for the diagnosis of AD. Additionally, several other processes are currently being recognized as significant risk factors for AD development, including the brain's susceptibility to reactive oxygen species (ROS). The ROS production is among the early signs in the progression of AD. However, the underlying mechanisms behind increased ROS production in AD remain poorly understood. We have observed SNTA1 plays critical role in regulating ROS levels in different pathological conditions. Here, we wanted to gain further insight into the role of SNTA1 in the development of AD by using IMR32 cell line. Our results show that the accumulation of Aβ plaques in Alzheimer's model neuroblastoma cells significantly increases the expression and activation of SNTA1 and MKK6 kinase. The activation of MKK6 results in the phosphorylation of SNTA1, creating a binding site for Rac1, leading to its activation and subsequent production of ROS. Excessive ROS production leads to cell cycle arrest in the G2/M phase, a hallmark of AD. Our study provides new insight into the mechanism of Aβ-mediated cell death in AD and suggests that MKK6-mediated activation of alpha-1-syntrophin promotes ROS production in neuronal cells, resulting in cell death. This study presents a mechanistic insight into Aβ-mediated cell death and could serve as a paradigm for reducing neuronal cell death in AD.
(© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Abdelhamid, R. F., & Nagano, S. (2023). Crosstalk between oxidative stress and aging in neurodegeneration disorders. Cells, 12, 753. https://doi.org/10.3390/cells12050753.
Ahn, A. H., Freener, C. A., Gussoni, E., Yoshida, M., Ozawa, E., & Kunkel, L. M. (1996). The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives. The Journal of Biological Chemistry, 271, 2724–2730. https://doi.org/10.1074/jbc.271.5.2724.
2023 Alzheimer's disease facts and figures. (2023). Alzheimer's & Dementia, 19, 1598–1695. https://doi.org/10.1002/alz.13016.
Araki, W., & Kametani, F. (2022). Protection against amyloid‐β oligomer neurotoxicity by small molecules with antioxidative properties: Potential for the prevention of Alzheimer's disease dementia. Antioxidants, 11, 132. https://doi.org/10.3390/antiox11010132.
Bashir, M., Parray, A. A., Baba, R. A., Bhat, H. F., Bhat, S. S., Mushtaq, U., Andrabi, K. I., & Khanday, F. A. (2014). β‐Amyloid‐evoked apoptotic cell death is mediated through MKK6‐p66shc pathway. Neuromolecular Medicine, 16, 137–149. https://doi.org/10.1007/s12017-013-8268-4.
Bhat, H., Baba, R., Adams, M., & Khanday, F. (2014a). Role of SNTA1 in Rac1 activation, modulation of ROS generation, and migratory potential of human breast cancer cells. British Journal of Cancer, 110, 706–714. https://doi.org/10.1038/bjc.2013.723.
Bhat, S. S., Parray, A. A., Mushtaq, U., Fazili, K. M., & Khanday, F. A. (2016). Actin depolymerization mediated loss of SNTA1 phosphorylation and Rac1 activity has implications on ROS production, cell migration and apoptosis. Apoptosis, 21, 737–748. https://doi.org/10.1007/s10495-016-1241-6.
Bianca, V. D., Dusi, S., Bianchini, E., Dal Prà, I., & Rossi, F. (1999). Beta‐amyloid activates the O‐2 forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer's disease. The Journal of Biological Chemistry, 274, 15493–15499. https://doi.org/10.1074/jbc.274.22.15493.
Birnbaum, J. H., Wanner, D., Gietl, A. F., Saake, A., Kündig, T. M., Hock, C., Nitsch, R. M., & Tackenberg, C. (2018). Oxidative stress and altered mitochondrial protein expression in the absence of amyloid‐β and tau pathology in iPSC‐derived neurons from sporadic Alzheimer's disease patients. Stem Cell Research, 27, 121–130. https://doi.org/10.1016/j.scr.2018.01.019.
Bondy, S. C., Guo‐Ross, S. X., & Truong, A. T. (1998). Promotion of transition metal‐induced reactive oxygen species formation by beta‐amyloid. Brain Research, 799, 91–96. https://doi.org/10.1016/S0006-8993(98)00461-2.
Briyal, S., Ranjan, A. K., & Gulati, A. (2023). Oxidative stress: A target to treat Alzheimer's disease and stroke. Neurochemistry International, 165, 105509. https://doi.org/10.1016/j.neuint.2023.105509.
Butterfield, D. A. (2003). Amyloid beta‐peptide [1‐42]‐associated free radical‐induced oxidative stress and neurodegeneration in Alzheimer's disease brain: Mechanisms and consequences. Current Medicinal Chemistry, 10, 2651–2659. https://doi.org/10.2174/0929867033456422.
Condello, C., Merz, G. E., Aoyagi, A., DeGrado, W. F., & Prusiner, S. B. (2023). Aβ and tau prions causing Alzheimer's disease. Methods in Molecular Biology, 2561, 293–337. https://doi.org/10.1007/978-1-0716-2655-9_16.
Connors, N. C., Adams, M. E., Froehner, S. C., & Kofuji, P. (2004). The potassium channel Kir4.1 associates with the dystrophin‐glycoprotein complex via alpha‐syntrophin in glia. The Journal of Biological Chemistry, 279, 28387–28392. https://doi.org/10.1074/jbc.M402604200.
Ganguly, U., Kaur, U., Chakrabarti, S. S., Sharma, P., Agrawal, B. K., Saso, L., & Chakrabarti, S. (2021). Oxidative stress, neuroinflammation, and NADPH oxidase: Implications in the pathogenesis and treatment of Alzheimer's disease. Oxidative Medicine and Cellular Longevity, 2021, 7086512. https://doi.org/10.1155/2021/7086512.
Gee, S. H., Madhavan, R., Levinson, S. R., Caldwell, J. H., Sealock, R., & Froehner, S. C. (1998). Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin‐associated proteins. The Journal of Neuroscience, 18, 128–137. https://doi.org/10.1523/JNEUROSCI.18-01-00128.1998.
Ghosh, P., Fontanella, R. A., Scisciola, L., Pesapane, A., Taktaz, F., Franzese, M., Puocci, A., Ceriello, A., Prattichizzo, F., Rizzo, M. R., Paolisso, G., & Barbieri, M. (2023). Targeting redox imbalance in neurodegeneration: Characterizing the role of GLP‐1 receptor agonists. Theranostics, 13, 4872–4884. https://doi.org/10.7150/thno.86831.
Goshtasbi, H., Pakchin, P. S., Movafeghi, A., Barar, J., Castejon, A. M., Omidian, H., & Omidi, Y. (2022). Impacts of oxidants and antioxidants on the emergence and progression of Alzheimer's disease. Neurochemistry International, 153, 105268. https://doi.org/10.1016/j.neuint.2021.105268.
Hafner, A., Obermajer, N., & Kos, J. (2010). γ‐1‐syntrophin mediates trafficking of γ‐enolase towards the plasma membrane and enhances its neurotrophic activity. Neurosignals, 18, 246–258. https://doi.org/10.1159/000324292.
Hogan, A., Shepherd, L., Chabot, J., Quenneville, S., Prescott, S. M., Topham, M. K., & Gee, S. H. (2001). Interaction of gamma 1‐syntrophin with diacylglycerol kinase‐zeta. Regulation of nuclear localization by PDZ interactions. The Journal of Biological Chemistry, 276, 26526–26533. https://doi.org/10.1074/jbc.M104156200.
Hugon, J., & Paquet, C. (2021). The PKR/P38/RIPK1 signaling pathway as a therapeutic target in Alzheimer's disease. International Journal of Molecular Sciences, 22, 3136. https://doi.org/10.3390/ijms22063136.
Iversen, L. L., Mortishire‐Smith, R. J., Pollack, S. J., & Shearman, M. S. (1995). The toxicity in vitro of beta‐amyloid protein. The Biochemical Journal, 311, 1–16. https://doi.org/10.1042/bj3110001.
Johnstone, M., Gearing, A. J., & Miller, K. M. (1999). A central role for astrocytes in the inflammatory response to Beta‐amyloid; chemokines, cytokines and reactive oxygen species are produced. Journal of Neuroimmunology, 93, 182–193. https://doi.org/10.1016/S0165-5728(98)00226-4.
Khanday, F. A., Santhanam, L., Kasuno, K., Yamamori, T., Naqvi, A., Dericco, J., Bugayenko, A., Mattagajasingh, I., Disanza, A., Scita, G., & Irani, K. (2006). Sos‐mediated activation of rac1 by p66shc. The Journal of Cell Biology, 172, 817–822. https://doi.org/10.1083/jcb.200506001.
Khanday, F. A., Yamamori, T., Mattagajasingh, I., Zhang, Z., Bugayenko, A., Naqvi, A., Santhanam, L., Nabi, N., Kasuno, K., Day, B. W., & Irani, K. (2006). Rac1 leads to phosphorylation‐dependent increase in stability of the p66shc adaptor protein: Role in Rac1‐induced oxidative stress. Molecular Biology of the Cell, 17, 122–129. https://doi.org/10.1091/mbc.e05-06-0570.
Leonoudakis, D., Conti, L. R., Anderson, S., Radeke, C. M., McGuire, L. M., Adams, M. E., Froehner, S. C., Yates, J. R. 3rd, & Vandenberg, C. A. (2004). Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x)‐associated proteins. The Journal of Biological Chemistry, 279, 22331–22346. https://doi.org/10.1074/jbc.M400285200.
Liu, T., Sun, L., Zhang, Y., Wang, Y., & Zheng, J. (2022). Imbalanced GSH/ROS and sequential cell death. Journal of Biochemical and Molecular Toxicology, 36, 2. https://doi.org/10.1002/jbt.22942.
Manterola, L., Hernando‐Rodríguez, M., Ruiz, A., Apraiz, A., Arrizabalaga, O., Vellón, L., Alberdi, E., Cavaliere, F., Lacerda, H. M., Jimenez, S., Parada, L. A., Matute, C., & Zugaza, J. L. (2013). 1‐42 β‐amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. Translational Psychiatry, 3, 147. https://doi.org/10.1038/tp.2012.147.
Markesbery, W. R. (1997). Oxidative stress hypothesis in Alzheimer's disease. Free Radical Biology & Medicine, 23, 134–147. https://doi.org/10.1016/S0891-5849(96)00629-6.
Mattson, M. P., Barger, S. W., Cheng, B., Lieberburg, I., Smith‐Swintosky, V. L., & Rydel, R. E. (1993). Beta‐amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease. Trends in Neurosciences, 16, 409–414. https://doi.org/10.1016/0166-2236(93)90009-B.
Muraleva, N. A., Kolosova, N. G., & Stefanova, N. A. (2021). MEK1/2‐ERK pathway alterations as a therapeutic target in sporadic Alzheimer's disease: A study in senescence‐accelerated OXYS rats. Antioxidants, 10, 1058. https://doi.org/10.3390/antiox10071058.
Mushtaq, U., Baba, R., Parray, A. A., Bhat, H. F., Saleem, S., Manzoor, U., Kuchay, S., Wani, L., & Khanday, F. A. (2014). Mitogen activated protein kinase kinase‐4 upregulation is a frequent event in human stomach and colon cancers. Journal of Enzymology and Metabolism, 1(1), 103.
Oak, S. A., Zhou, Y. W., & Jarrett, H. W. (2003a). Skeletal muscle signaling pathway through the dystrophin glycoprotein complex and Rac1. Journal of Biological Chemistry., 278, 39287–39295. https://doi.org/10.1074/jbc.M305551200.
Oliver, D. M. A., & Reddy, P. H. (2019). Molecular basis of Alzheimer's disease: Focus on mitochondria. Journal of Alzheimer's Disease, 72, S95–S116. https://doi.org/10.3233/JAD-190048.
Olufunmilayo, E. O., Gerke‐Duncan, M. B., & Holsinger, R. M. D. (2023). Oxidative stress and antioxidants in neurodegenerative disorders. Antioxidants, 12, 517. https://doi.org/10.3390/antiox12020517.
Qin, P., Ran, Y., Liu, Y., Wei, C., Luan, X., Niu, H., Peng, J., Sun, J., & Wu, J. (2022). Recent advances of small molecule JNK3 inhibitors for Alzheimer's disease. Bioorganic Chemistry, 128, 106090. https://doi.org/10.1016/j.bioorg.2022.106090.
Rao, S. B., Skauli, N., Jovanovic, N., Katoozi, S., Frigeri, A., Froehner, S. C., Adams, M. E., Ottersen, O. P., & Amiry‐Moghaddam, M. (2021). Orchestrating Aquaporin‐4 and Connexin‐43 expression in brain: Differential roles of α1‐ and β1‐syntrophin. Biochimica et Biophysica Acta ‐ Biomembranes, 1, 183616. https://doi.org/10.1016/j.bbamem.2021.183616.
Saha, P., Guha, S., & Biswas, S. C. (2020). P38K and JNK pathways are induced by amyloid‐β in astrocyte: Implication of MAPK pathways in Astrogliosis in Alzheimer's disease. Molecular and Cellular Neurosciences, 108, 103551. https://doi.org/10.1016/j.mcn.2020.103551.
Sandberg, A., Berenjeno‐Correa, E., Rodriguez, R. C., Axenhus, M., Weiss, S. S., Batenburg, K., Hoozemans, J. J. M., Tjernberg, L. O., & Scheper, W. (2022). Aβ42 oligomer‐specific antibody ALZ‐201 reduces the neurotoxicity of Alzheimer's disease brain extracts. Alzheimer's Research & Therapy, 14, 196. https://doi.org/10.1186/s13195-022-01141-1.
Simon, M., Wang, M. X., Ismail, O., Braun, M., Schindler, A. G., Reemmer, J., Wang, Z., Haveliwala, M. A., O'Boyle, R. P., Han, W. Y., Roese, N., Grafe, M., Woltjer, R., Boison, D., & Iliff, J. J. (2022). Loss of perivascular Aquaporin‐4 localization impairs Glymphatic exchange and promotes amyloid β plaque formation in mice. Alzheimer's Research & Therapy, 14, 59. https://doi.org/10.1186/s13195-022-00999-5.
Simon, M. J., Wang, M. X., Murchison, C. F., Roese, N. E., Boespflug, E. L., Woltjer, R. L., & Iliff, J. J. (2018). Transcriptional network analysis of human astrocytic endfoot genes reveals region‐specific associations with dementia status and tau pathology. Scientific Reports, 8, 12389. https://doi.org/10.1038/s41598-018-30779-x.
Simonyi, A., He, Y., Sheng, W., Sun, A. Y., Wood, W. G., Weisman, G. A., & Sun, G. Y. (2010). Targeting NADPH oxidase and phospholipases A2 in Alzheimer's disease. Molecular Neurobiology, 41, 73–86. https://doi.org/10.1007/s12035-010-8107-7.
Surguchov, A. (2020). Caveolin: A new link between diabetes and AD. Cellular and Molecular Neurobiology, 40, 1059–1066. https://doi.org/10.1007/s10571-020-00796-4.
Tu, D., Velagapudi, R., Gao, Y., Hong, J. S., Zhou, H., & Gao, H. M. (2023). Activation of neuronal NADPH oxidase NOX2 promotes inflammatory neurodegeneration. Free Radical Biology & Medicine, 200, 47–58. https://doi.org/10.1016/j.freeradbiomed.2023.03.001.
Wang, F. X., Xu, C. L., Su, C., Li, J., & Lin, J. Y. (2022). β‐Hydroxybutyrate attenuates painful diabetic neuropathy via restoration of the Aquaporin‐4 polarity in the spinal Glymphatic system. Frontiers in Neuroscience, 16, 926128. https://doi.org/10.3389/fnins.2022.926128.
Yan, J., Xu, W., Lenahan, C., Huang, L., Ocak, U., Wen, J., Li, G., He, W., Le, C., Zhang, J. H., Mo, L., & Tang, J. (2022). Met‐RANTES preserves the blood‐brain barrier through inhibiting CCR1/SRC/Rac1 pathway after intracerebral hemorrhage in mice. Fluids and Barriers of the CNS, 19, 7. https://doi.org/10.1186/s12987-022-00305-3.

F.09/251(0060)/2015-EMR-I CSIR-University Grants Commission; BT/PR19153/MED/122/20/2016 Department of Biotechnology (DBT), New Delhi

Keywords: Alzheimer's; IMR32; MKK6; ROS; SNTA1; syntrophins

0 (Reactive Oxygen Species)
EC 3.6.5.2 (rac1 GTP-Binding Protein)
0 (Amyloid beta-Peptides)
0 (syntrophin alpha1)
0 (Membrane Proteins)
0 (RAC1 protein, human)
0 (Calcium-Binding Proteins)
0 (Muscle Proteins)

Date Created: 20241115 Date Completed: 20241203 Latest Revision: 20241203

20241204

10.1111/ejn.16609

39543939