Streptozotosin İndüklenen Alzheimer Hastalığı Modelinde Nörogenez ve Metabolik Parametreler Arasındaki İlişkinin Araştırılması

Öz

Amaç: Bu çalışmada, STZ kaynaklı Alzheimer hastalığı modelinde nöroplastisite ile ilişkili proteinler (DCX, EGR1, sFRP3) ile metabolik belirteçler (insülin, HbA1c, asprosin) arasındaki etkileşimleri analiz etmeyi ve bu parametrelerdeki değişikliklerin Alzheimer hastalığının (AD) patofizyolojisini nasıl etkilediğini değerlendirmeyi amaçladık. Yöntemler: 8 ila 10 haftalık, 250-300 g ağırlığında 14 erkek Wistar albino sıçan kullanıldı. Hayvanlar iki gruba ayrıldı: kontrol ve Alzheimer modeli. AD modeli, STZ'nin stereotaksik enjeksiyonuyla oluşturuldu ve kontrol grubuna yapay BOS enjekte edildi. Hayvanlar ameliyattan sonra 14 gün boyunca izlendi. Çalışmanın sonunda serum örnekleri toplandı ve DCX, EGR1, sFRP3, insülin, gHbA1c ve asprosin düzeyleri ELISA ile analiz edildi. Değişkenler gruplar arasında karşılaştırıldı ve P değerleri < 0,05 anlamlı kabul edildi. Sonuçlar: DCX ve EGR1 düzeyleri istatistiksel anlamlılık olmaksızın sınırda değişiklikler gösterdi (sırasıyla p = 0,056 ve p = 0,080), sFRP3 düzeyleri ise AD grubunda anlamlı olarak daha yüksekti (p = 0,012). İnsülin düzeyleri farklılık göstermedi (p = 0,829), ancak asprosin ve gHbA1c düzeyleri anlamlı olarak daha yüksekti (sırasıyla p = 0,046 ve p = 0,000), bu da metabolik düzensizliği gösteriyordu. Korelasyon analizi asprosin ve gHbA1c (r = 0,807, p < 0,01) ve sFRP3 ve EGR1 (r = 0,780, p < 0,01) arasında güçlü pozitif korelasyonlar gösterdi, bu da AD patofizyolojisinde birbirine bağlı roller olduğunu düşündürmektedir. Sonuç: Bu çalışma AD'de nörogenez ve metabolik parametreler arasındaki ilişkiyi göstermektedir.

Anahtar Kelimeler

• Alzheimer Hastalığı
• Streptozotosin
• Nörogenez
• Metabolik Parametreler
• İnsülin Direnci

Investigation of the Relationship Between Neurogenesis and Metabolic Parameters in the Streptozotocin-Induced Alzheimer’s Disease Model

Öz

Aim: In this study, we aimed to analyze the interactions between neuroplasticity-related proteins (DCX, EGR1, sFRP3) and metabolic markers (insulin, HbA1c, asprosin) in an STZ-induced Alzheimer's disease model, as well as to evaluate how changes in these parameters affect the pathophysiology of Alzheimer's disease (AD). Material and Methods: 14 male Wistar albino rats, aged 8 to 10 weeks, weighing 250–300 g, were used. The animals were divided into two groups: control and Alzheimer's model. The AD model was created by stereotaxic injection of STZ, and the control group was injected with artificial CSF. The animals were monitored for 14 days after surgery. At the end of the study, serum samples were collected and DCX, EGR1, sFRP3, insulin, gHbA1c, and asprosin levels were analyzed by ELISA. The variables were compared between the groups, and P-values < 0.05 were considered significant. Results: DCX and EGR1 levels showed borderline changes without statistical significance (p = 0.056 and p = 0.080, respectively), while sFRP3 levels were significantly higher in the AD group (p = 0.012). Insulin levels did not differ (p = 0.829), but asprosin and gHbA1c levels were significantly higher (p = 0.046 and p = 0.000, respectively), indicating metabolic derangement. Correlation analysis showed strong positive correlations between asprosin and gHbA1c (r = 0.807, p < 0.01) and sFRP3 and EGR1 (r = 0.780, p < 0.01), suggesting interconnected roles in AD pathophysiology. Conclusion: This study shows the relationship between neurogenesis and metabolic parameters in AD.

Anahtar Kelimeler

• Alzheimer
• Streptozotocin
• Neurogenesis
• Metabolic Parameters
• Insulin Resistance

Kaynakça

1. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules. 2020 Dec 8;25(24):5789. doi: 10.3390/molecules25245789.
2. Wijesekara N, Ahrens R, Sabale M, Wu L, Ha K, Verdile G, Fraser PE. Amyloid-β and islet amyloid pathologies link Alzheimer’s disease and type 2 diabetes in a transgenic model. FASEB J. 2017 Dec;31(12):5409-5418. doi: 10.1096/fj.201700431R.
3. Ezkurdia A, Ramírez MJ, Solas M. Metabolic Syndrome as a Risk Factor for Alzheimer’s Disease: A Focus on Insulin Resistance. Int J Mol Sci. 2023 Feb 22;24(5):4354. doi: 10.3390/ijms24054354.
4. Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Arch Neurol. 2007 Jan;64(1):93-6. doi: 10.1001/archneur.64.1.93.
5. Arendt T. Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the, dr.jekyll and mr. Hyde concept of Alzheimer’s disease or the yin and yang of neurolasticity. Prog Neurobiol 2003;71(2-3):83-248
6. Turrigiano GG, Nelson SB. Hebb and homeostasis in neuronal plasticity. Curr Opin Neurobiol 2000;10 (3):358-364
7. Manohar S, Paolone NA, Bleichfeld M, Hayes SH, Salvi RJ, Baizer JS. Expression of doublecortin, a neuronal migration protein, in unipolar brush cells of the vestibulocerebellum and dorsal cochlear nucleus of the adult rat. Neuroscience. 2012;202:169-183. doi:10.1016/j.neuroscience.2011.12.013
8. Duclot F, Kabbaj M. The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders. Front Behav Neurosci. 2017 Mar 6;11:35. doi: 10.3389/fnbeh.2017.

9. Hu YT, Chen XL, Huang SH, Zhu QB, Yu SY, Shen Y, Sluiter A, Verhaagen J, Zhao J, Swaab D, Bao AM. Early growth response-1 regulates acetylcholinesterase and its relation with the course of Alzheimer’s disease. Brain Pathol. 2019 Jul;29(4):502-512. doi: 10.1111/bpa.12688.
10. Alkailani MI, Aittaleb M, Tissir F. WNT signaling at the intersection between neurogenesis and brain tumori- genesis. Front Mol Neurosci. 2022 Oct 4;15:1017568. doi: 10.3389/fnmol.2022.1017568.
11. Sędzikowska A, Szablewski L. Insulin and Insulin Resistance in Alzheimer’s Disease. Int J Mol Sci. 2021 Sep 15;22(18):9987. doi: 10.3390/ijms22189987.
12. Milstein JL, Ferris HA. The brain as an insulin-sensitive metabolic organ. Mol Metab. 2021 Oct;52:101234. doi: 10.1016/j.molmet.2021.101234.
13. Ramirez A, Wolfsgruber S, Lange C, Kaduszkiewicz H, Weyerer S, Werle J, Pentzek M, Fuchs A, Riedel-Heller SG, Luck T, Mösch E, Bickel H, Wiese B, Prokein J, König HH, Brettschneider C, Breteler MM, Maier W, Jessen F, Scherer M; AgeCoDe Study Group. Elevated HbA1c is associated with increased risk of incident dementia in primary care patients. J Alzheimers Dis. 2015;44(4):1203-12. doi: 10.3233/JAD-141521.
14. Yuan M, Li W, Zhu Y, Yu B, Wu J. Asprosin: A Novel Player in Metabolic Diseases. Front Endocrinol (Lausanne). 2020 Feb 19;11:64. doi: 10.3389/fendo.2020.00064.
15. Gokdemir GS, Gokdemir MT, Tasdemir E, Yokus B, Baylan M. Importance of curcumin effect and asprosin level on glucose metabolism in diabetic rats. Med Science. 2023;12:167-74.
16. Denis R. Palatability can drive feeding independent of AgRP neurons. Cell Metab 2015, 22: 646-657.
17. Silva SSL, Tureck LV, Souza LC, Mello-Hortega JV, Piumbini AL, Teixeira MD, Furtado-Alle L, Vital MABF, Souza RLR. Animal model of Alzheimer’s disease induced by streptozotocin: New insights about cholinergic pathway. Brain Res. 2023 Jan 15;1799:148175. doi: 10.1016/j.brainres.2022.148175.
18. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego: Academic Press; 1997. http:// mikrokirurgi.se/wp-content/uploads/2013/10/ Paxinos-The-rat-brain-in-stereotaxic-coordinates.pdf
19. Agrawal R, Tyagi E, Shukla R, Nath C. Insulin receptor signaling in rat hippocampus: A study in STZ (ICV) induced memory deficit model. Eur Neuropsychopharmacol. 2011;21(3):261–273.
20. Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner N, Bogdahn U, Winkler J, Kuhn HG, Aigner L. Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci. 2005 Jan;21(1):1-14. doi: 10.1111/j.1460-9568.2004.03813.x.
21. Saaltink DJ, van Zwet EW, Vreugdenhil E. Doublecortin-Like Is Implicated in Adult Hippocampal Neurogenesis and in Motivational Aspects to Escape from an Aversive Environment in Male Mice. eNeuro. 2020 Oct 15;7(5):ENEU- RO.0324-19.2020. doi: 10.1523/ENEURO.0324-19.2020.
22. Sorrells SF, Paredes MF, Velmeshev D, Herranz-Pérez V, Sandoval K, Mayer S, Chang EF, Insausti R, Kriegstein AR, Rubenstein JL, Manuel Garcia-Verdugo J, Huang EJ, Alvarez-Buylla A. Immature excitatory neurons develop during adolescence in the human amygdala. Nat Commun. 2019 Jun 21;10(1):2748. doi: 10.1038/s41467-019-10765-1.
23. Mauffrey P, Tchitchek N, Barroca V, Bemelmans A-P, Firlej V, Allory Y, Roméo P-H, Magnon C (2019) Progenitors from the central nervous system drive neurogenesis in cancer. Nature 569:672–678. doi:10.1038/ s41586-019-1219-y pmid:31092925
24. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7. doi: 10.1073/pnas.2634794100.
25. Hollands C, Tobin MK, Hsu M, Musaraca K, Yu TS, Mishra R, Kernie SG, Lazarov O. Depletion of adult neurogenesis exacerbates cognitive deficits in Alzheimer’s disease by compromising hippocampal inhibition. Mol Neurodegener. 2017 Sep 8;12(1):64. doi: 10.1186/s13024-017-0207-7.
26. Bahrami S, Drabløs F. Gene regulation in the immediate-early response process. Adv Biol Regul. 2016;62:37-49. doi:10.1016/j.jbior.2016.05.001
27. Rahmi U, Goenawan H, Sylviana N, Setiawan S, Murtiani F. The Impact of Early Growth Response 1 (Egr1) on Hippocampal Synaptic Plasticity and Cognitive Function: Narrative Review. Biomed Pharmacol J 2024;17(2). Available from: https://bit.ly/4a19HFA
28. Qin X, Wang Y, Paudel HK. Inhibition of Early Growth Response 1 in the Hippocampus Alleviates Neuropathol- ogy and Improves Cognition in an Alzheimer Model with Plaques and Tangles. Am J Pathol. 2017 Aug;187(8):1828-1847. doi: 10.1016/j.ajpath.2017.04.018.
29. Zhao X, Wang X, Su G, Sun Q, Fu J, Zhang H, Teng J. The effect of early growth response 1 on levels of Amy- loid-β 40 peptide in U87MG cells. J Cell Biochem. 2019 Mar;120(3):3514-3519. doi: 10.1002/jcb.27627.
30. Hu YT, Chen XL, Huang SH, Zhu QB, Yu SY, Shen Y, Sluiter A, Verhaagen J, Zhao J, Swaab D, Bao AM. Early growth response-1 regulates acetylcholinesterase and its relation with the course of Alzheimer’s disease. Brain Pathol. 2019 Jul;29(4):502-512. doi: 10.1111/bpa.12688.
31. Warrier S, Marimuthu R, Sekhar S, Bhuvanalakshmi G, Arfuso F, Das AK, Bhonde R, Martins R, Dharmarajan A. sFRP-mediated Wnt sequestration as a potential therapeutic target for Alzheimer’s disease. Int J Biochem Cell Biol. 2016 Jun;75:104-11. doi: 10.1016/j.biocel.2016.04.002.
32. Jang MH, Bonaguidi MA, Kitabatake Y, Sun J, Song J, Kang E, Jun H, Zhong C, Su Y, Guo JU, Wang MX, Sailor KA, Kim JY, Gao Y, Christian KM, Ming GL, Song H. Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis. Cell Stem Cell. 2013 Feb 7;12(2):215-23. doi: 10.1016/j.stem.2012.11.021.