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In Silico Investigation of miR-30c’s Interactions with Synaptic and Amyloidogenic Pathways in Alzheimer’s Disease via Molecular Network Analysis
Taiebeh Kafshdooz pourpolsangi1 , Rasoul Sharifi2 , Safar Farajnia3 , Safa Najmi4
1- 1Department of genetics, Ah.C., Islamic Azad University, Ahar, Iran
2- Department of Biology, Ah.C., Islamic Azad University, Ahar, Iran , rasoulsharifi@iau.ir
3- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
4- Tabriz Medical University, Tabriz, Iran
Abstract:   (78 Views)

Background:Alzheimer's disease (AD) is the leading type of dementia, impacting millions of individuals across the globe. Recent clinical evidence from three therapeutic anti-Aβ antibodies has shown that clearing Aβ-amyloid plaques in the early stages of Alzheimer’s disease (AD) can slow the progression of the condition. γ-Secretase, together with β-secretase, sequentially cleaves amyloid precursor protein (APP) during its processing.

 The aim of this study was to use computational methods, specifically docking, to find molecules that can activate the gamma-secretase enzyme

Methods: The gamma-secretase enzyme structure was prepared using Chimera software by removing non-standard structures and water molecules and then amino acids adjacent to the cholesterol ligand were mapped using PyMOL software. The 3D structure and SMILES notation of cholesterol were retrieved from the PubChem database. The docking results, stored in a pdbqt file (with atomic charges and atom types), were analyzed using Discovery Studio, LigPlus+, and PDBsum. LigPlus+ specifically evaluated protein subunit interactions.

Result :This study evaluated key drug-like properties (solubility, tumorigenicity, LogP, toxicity) of compounds using predictive tools (Swiss Target Prediction, PASS-Way2drug, SwissADME) in alignment with Lipinski's rule of five. The identified amino acids—Trp227, Leu192, Arg186, Leu199, Leu203, Leu206, Tyr155, Leu215, Phe162, Ser223, and Ile230—were situated on the C subunit of the gamma-secretase enzyme. AutoDock Vina's efficient docking process and Chimera's visualization capabilities were leveraged, with Ligplot providing interaction analysis

Conclusion: Gamma-secretase modulators are projected to play a key therapeutic role in combating Alzheimer's disease.

Keywords: Alzheimer's disease, gamma-secretase enzyme, molecular docking, mir 30c
Full-Text [PDF 893 kb]   (24 Downloads)    
Research Article: Research Article | Subject: Human Genetics
Received: 2025/04/15 | Accepted: 2025/08/10
References
1. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016;537(7618):50-6. [View at Publisher] [DOI] [PMID] [Google Scholar]
2. Ahn JE, Carrieri C, Dela Cruz F, Fullerton T, Hajos‐Korcsok E, He P, et al. Pharmacokinetic and Pharmacodynamic Effects of a γ‐Secretase Modulator, PF‐06648671, on CSF Amyloid‐β Peptides in Randomized Phase I Studies. Clin Pharmacol Ther. 2020;107(1):211-20. [View at Publisher] [DOI] [PMID] [Google Scholar]
3. Kumar M, Li G. Emerging role of MicroRNA-30c in Neurological Disorders. Int J Mol Sci. 2022;24(1):37. [View at Publisher] [DOI] [PMID] [Google Scholar]
4. Escamilla-Ayala AA, Sannerud R, Mondin M, Poersch K, Vermeire W, Paparelli L, et al. Super-resolution microscopy reveals majorly mono-and dimeric presenilin1/γ-secretase at the cell surface. Elife. 2020;9:e56679. [View at Publisher] [DOI] [PMID] [Google Scholar]
5. Mekala S, Nelson G, Li Y-M. Recent developments of small molecule γ-secretase modulators for Alzheimer's disease. RSC Med Chem. 2020;11(9):1003-22. [View at Publisher] [DOI] [PMID] [Google Scholar]
6. Tomita T. Secretase inhibitors and modulators for Alzheimer's disease treatment. Expert Rev Neurother. 2009;9(5):661-79. [View at Publisher] [DOI] [PMID] [Google Scholar]
7. Hur J-Y. γ-Secretase in Alzheimer's disease. Exp Mol Med. 2022;54(4):433-46. [View at Publisher] [DOI] [PMID] [Google Scholar]
8. Brendel M, Jaworska A, Herms J, Trambauer J, Roetzer C, Gildehaus F-J, et al. Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment. Mol Psychiatry. 2015;20(10):1179-87. [View at Publisher] [DOI] [PMID] [Google Scholar]
9. Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, et al. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci U S A. 1999;96(21):11872-7. [View at Publisher] [DOI] [PMID] [Google Scholar]
10. Smolarkiewicz M, Skrzypczak T, Wojtaszek P. The very many faces of presenilins and the γ-secretase complex. Protoplasma. 2013;250(5):997-1011. [View at Publisher] [DOI] [PMID] [Google Scholar]
11. Robertson AS, Iben LG, Wei C, Meredith Jr JE, Drexler DM, Banks M, et al. Synergistic inhibition of Aβ production by combinations of γ-secretase modulators. Eur J Pharmacol. 2017;812:104-12. [View at Publisher] [DOI] [PMID] [Google Scholar]
12. Ratni H, Alker A, Bartels B, Bissantz C, Chen W, Gerlach I, et al. Discovery of RO7185876, a highly potent γ-secretase modulator (GSM) as a potential treatment for Alzheimer's disease. ACS Med Chem Lett. 2020;11(6):1257-68. [View at Publisher] [DOI] [PMID] [Google Scholar]
13. Wolfe MS, Miao Y. Structure and mechanism of the γ-secretase intramembrane protease complex. Curr Opin Struct Biol. 2022;74:102373. [View at Publisher] [DOI] [PMID] [Google Scholar]
14. Miao Y, Wolfe MS. Emerging structures and dynamic mechanisms of γ-secretase for Alzheimer's disease. Neural Regen Res. 2025;20(1):174-80. [View at Publisher] [DOI] [PMID] [Google Scholar]
15. Luo JE, Li Y-M. Turning the tide on Alzheimer's disease: modulation of γ-secretase. Cell Biosci. 2022;12(1):2. [View at Publisher] [DOI] [PMID] [Google Scholar]
16. Busciglio J, Hartmann H, Lorenzo A, Wong C, Baumann K, Sommer B, et al. Neuronal localization of presenilin-1 and association with amyloid plaques and neurofibrillary tangles in Alzheimer's disease. Journal of Neuroscience. 1997;17(13):5101-7. [View at Publisher] [DOI] [PMID] [Google Scholar]
17. Zhang X, Wen J, Zhang Z. Statins use and risk of dementia: A dose-response meta analysis. Medicine. 2018;97(30):e11304. [View at Publisher] [DOI] [PMID] [Google Scholar]
18. Duncan RS, Song B, Koulen P. Presenilins as drug targets for Alzheimer's disease-recent insights from cell biology and electrophysiology as novel opportunities in drug development. Int J Mol Sci. 2018;19(6):1621. [View at Publisher] [DOI] [PMID] [Google Scholar]
19. Mal S, Malik U, Pal D, Mishra A. Insight γ-secretase: Structure, function, and role in Alzheimer's disease. Curr Drug Targets. 2021;22(12):1376-403. [View at Publisher] [DOI] [PMID] [Google Scholar]
20. Essayan-Perez S, Südhof TC. Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease. Neuron. 2023;111(20):3176-94. e7. [View at Publisher] [DOI] [PMID] [Google Scholar]
21. Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Arch Neurol. 2011;68(10):1239-44. [View at Publisher] [DOI] [PMID] [Google Scholar]
22. Iwagami M, Qizilbash N, Gregson J, Douglas I, Johnson M, Pearce N, et al. Blood cholesterol and risk of dementia in more than 1· 8 million people over two decades: a retrospective cohort study. Lancet Healthy Longev. 2021;2(8):e498-e506. [View at Publisher] [DOI] [PMID] [Google Scholar]
23. Ren Q-w, Teng T-HK, Tse Y-K, Tsang CTW, Yu S-Y, Wu M-Z, et al. Statins and risks of dementia among patients with heart failure: a population-based retrospective cohort study in Hong Kong. Lancet Reg Health West Pac. 2024:44:101006. [View at Publisher] [DOI] [PMID] [Google Scholar]
24. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57(10):1439-43. [View at Publisher] [DOI] [PMID] [Google Scholar]
25. Trompet S, van Vliet P, de Craen AJ, Jolles J, Buckley BM, Murphy MB, et al. Pravastatin and cognitive function in the elderly. Results of the PROSPER study. J Neurol. 2010;257(1):85-90. [View at Publisher] [DOI] [PMID] [Google Scholar]
26. Langness VF, Van der Kant R, Das U, Wang L, Chaves RdS, Goldstein LS. Cholesterol-lowering drugs reduce APP processing to Aβ by inducing APP dimerization. Mol Biol Cell. 2021;32(3):247-59. [View at Publisher] [DOI] [PMID] [Google Scholar]
27. Crump CJ, Johnson DS, Li Y-M. Development and mechanism of γ-secretase modulators for Alzheimer's disease. Biochemistry. 2013;52(19):3197-216. [View at Publisher] [DOI] [PMID] [Google Scholar]
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