Alzheimer Hastalığı’nda In Vivo ve In Vitro Modeller

Year 2023, , 54 - 77, 29.04.2023

Başak Aru , Ahmet Develioğlu , Gizem Gürel , Gülderen Yanıkkaya Demirel

https://doi.org/10.54537/tusebdergisi.1213712

Abstract

Alzheimer Hastalığı (AH), amiloid beta plaklarının ve hücre içinde hiper-fosforile mikrotübül ilişkili proteinin birikimi sonucu meydana gelen nörofibriler yumaklar ile karakterize olan geri dönüşsüz bir nörodejeneratif hastalıktır. AH, demansın temel sebebi olup 21. yüzyılda sağlık sistemine ilişkin en büyük problemlerinden biridir. Hastalık patogenezinde çevresel ve genetik faktörlerin rol oynadığı bilinmekte olup bilinen bir tedavisi yoktur. AH patolojisinin anlaşılması ve yeni terapötik yöntemlerin geliştirilmesi hususlarında deneysel AH modelleri kritik önem taşırlar. Ancak çalışmalar, temel araştırmalar sonucu elde edilen verilerin klinik çalışmalarda oldukça düşük oranda başarı gösterdiğini ifade etmektedir; dolayısıyla literatürde bulunan modellerin güçlü ve zayıf yanlarının değerlendirilmesi ve çalışmaların, hastalığın farklı yönlerini kapsayıcı modellerle gerçekleştirilmesinin potansiyel tedavilerin başarılarını artıracağı öngörülmektedir. Bu derleme makalede, farklı in vivo ve in vitro AH modellerinin patolojik ve moleküler özellikleri ele alınmış; bu bağlamda, geleneksel olarak kullanımda olan transgenik hayvan modelleri ile kanser hücrelerinin nöral farklılaştırmalarına dayalı yöntemlere ek olarak güncel hücre kültürü çalışmalarının odak noktaları olan indüklenebilir kök hücre kökenli organoid yapıları ve nöral progenitör hücre kaynaklı AH modelleri karşılaştırılmıştır. Ayrıca farklı in vivo ve in vitro AH modellerinin kullanımlarının dönüşümsel özelliklerini kısıtlayıcı etmenler, organizma bazında özetlenmiştir.

Keywords

Alzheimer Hastalığı, Hayvan Modelleri, Hücre Kültürü Modelleri

In vivo and in vitro Models of Alzheimer’s Disease

Abstract

Alzheimer's Disease (AD) is an irreversible neurodegenerative disease characterized by neurofibrillary tangles resulting from the accumulation of amyloid beta plaques and hyper-phosphorylated microtubule-associated protein in the cell. It is the main cause of dementia and is one of the biggest health care problems in the 21st century. It is known that environmental and genetic factors contribute to the pathogenesis of the disease, and no known cure is available. Experimental models of AD are critical to understand the AD pathology and the development of new therapeutic modalities. However, studies indicate that the data obtained from the basic research contribute to the clinical studies with a very low success rate. Therefore, it is predicted that evaluating the strengths and weaknesses of the models in the literature and carrying out studies with models that cover different aspects of the disease will increase the success of potential treatments. In this review article, pathological and molecular features of different in vivo and in vitro AD models are discussed. In this context, in addition to traditionally used transgenic animal models and methods based on neural differentiation of cancer cells, induced stem cell-derived organoid structures and neural progenitor cell-derived AD models, which are the focus of current cell culture studies, were compared. In addition, the factors limiting the translational properties of the use of different in vivo and in vitro AD models are summarized based on organism.

Keywords

Alzheimer's Disease, Animal Models, Cell Culture Models

References

• Agholme, L., Lindström, T., Kågedal, K., Marcusson, J., & Hallbeck, M. (2010). An in vitro model for neuroscience: differentiation of SH-SY5Y cells into cells with morphological and biochemical characteristics of mature neurons. J Alzheimers Dis, 20(4), 1069-1082. doi:10.3233/jad-2010-091363
• Anand, P., & Singh, B. (2013). A review on cholinesterase inhibitors for Alzheimer's disease. Arch Pharm Res, 36(4), 375-399. doi:10.1007/s12272-013-0036-3
• Arber, C., Toombs, J., Lovejoy, C., Ryan, N. S., Paterson, R. W., Willumsen, N., . . . Wray, S. (2020). Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry, 25(11), 2919-2931. doi:10.1038/s41380-019-0410-8
• Association, A. s. (2021). 2021 Alzheimer's disease facts and figures. Alzheimers Dement, 17(3), 327-406. doi:10.1002/alz.12328
• Barak, M., Fedorova, V., Pospisilova, V., Raska, J., Vochyanova, S., Sedmik, J., . . . Bohaciakova, D. (2022). Human iPSC-Derived Neural Models for Studying Alzheimer's Disease: from Neural Stem Cells to Cerebral Organoids. Stem Cell Rev Rep, 18(2), 792-820. doi:10.1007/s12015-021-10254-3
• Bekris, L. M., Yu, C. E., Bird, T. D., & Tsuang, D. W. (2010). Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol, 23(4), 213-227. doi:10.1177/0891988710383571
• Bertram, L., & Tanzi, R. E. (2004). Alzheimer's disease: one disorder, too many genes? Hum Mol Genet, 13 Spec No 1, R135-141. doi:10.1093/hmg/ddh077
• Brandt, R., Gergou, A., Wacker, I., Fath, T., & Hutter, H. (2009). A Caenorhabditis elegans model of tau hyperphosphorylation: induction of developmental defects by transgenic overexpression of Alzheimer's disease-like modified tau. Neurobiol Aging, 30(1), 22-33. doi:10.1016/j.neurobiolaging.2007.05.011
• Breijyeh, Z., & Karaman, R. (2020). Comprehensive Review on Alzheimer's Disease: Causes and Treatment. Molecules, 25(24). doi:10.3390/molecules25245789
• Brenner, S. (1974). The genetics of Caenorhabditis elegans. Genetics, 77(1), 71-94. doi:10.1093/genetics/77.1.71 Cakir, B., Xiang, Y., Tanaka, Y., Kural, M. H., Parent, M., Kang, Y. J., . . . Park, I. H. (2019). Engineering of human brain organoids with a functional vascular-like system. Nat Methods, 16(11), 1169-1175. doi:10.1038/s41592-019-0586-5
• Carmine-Simmen, K., Proctor, T., Tschäpe, J., Poeck, B., Triphan, T., Strauss, R., & Kretzschmar, D. (2009). Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function. Neurobiol Dis, 33(2), 274-281. doi:10.1016/j.nbd.2008.10.014
• Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D'Avanzo, C., . . . Kim, D. Y. (2014). A three-dimensional human neural cell culture model of Alzheimer's disease. Nature, 515(7526), 274-278. doi:10.1038/nature13800
• Cohen, R. M., Rezai-Zadeh, K., Weitz, T. M., Rentsendorj, A., Gate, D., Spivak, I., . . . Town, T. (2013). A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci, 33(15), 6245-6256. doi:10.1523/jneurosci.3672-12.2013
• Cook, S. J., Jarrell, T. A., Brittin, C. A., Wang, Y., Bloniarz, A. E., Yakovlev, M. A., . . . Emmons, S. W. (2019). Whole-animal connectomes of both Caenorhabditis elegans sexes. Nature, 571(7763), 63-71. doi:10.1038/s41586-019-1352-7
• Corsi, A. K. (2006). A biochemist's guide to Caenorhabditis elegans. Anal Biochem, 359(1), 1-17. doi:10.1016/j.ab.2006.07.033
• Cummings, J. (2018). Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes. Clin Transl Sci, 11(2), 147-152. doi:10.1111/cts.12491
• Cummings, J. L., Morstorf, T., & Zhong, K. (2014). Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther, 6(4), 37. doi:10.1186/alzrt269
• D'Aiuto, L., Zhi, Y., Kumar Das, D., Wilcox, M. R., Johnson, J. W., McClain, L., . . . Nimgaonkar, V. L. (2014). Large-scale generation of human iPSC-derived neural stem cells/early neural progenitor cells and their neuronal differentiation. Organogenesis, 10(4), 365-377. doi:10.1080/15476278.2015.1011921
• Dickinson, D. J., Ward, J. D., Reiner, D. J., & Goldstein, B. (2013). Engineering the Caenorhabditis elegans genome using Cas9-triggered homologous recombination. Nat Methods, 10(10), 1028-1034. doi:10.1038/nmeth.2641
• Do Carmo, S., & Cuello, A. C. (2013). Modeling Alzheimer's disease in transgenic rats. Mol Neurodegener, 8, 37. doi:10.1186/1750-1326-8-37
• Donato, R., Miljan, E. A., Hines, S. J., Aouabdi, S., Pollock, K., Patel, S., . . . Sinden, J. D. (2007). Differential development of neuronal physiological responsiveness in two human neural stem cell lines. BMC Neurosci, 8, 36. doi:10.1186/1471-2202-8-36
• Drummond, E., & Wisniewski, T. (2017). Alzheimer's disease: experimental models and reality. Acta Neuropathol, 133(2), 155-175. doi:10.1007/s00401-016-1662-x
• Du, X., Wang, X., & Geng, M. (2018). Alzheimer's disease hypothesis and related therapies. Transl Neurodegener, 7, 2. doi:10.1186/s40035-018-0107-y
• Ferreira-Vieira, T. H., Guimaraes, I. M., Silva, F. R., & Ribeiro, F. M. (2016). Alzheimer's disease: Targeting the Cholinergic System. Curr Neuropharmacol, 14(1), 101-115. doi:10.2174/1570159x13666150716165726
• Fire, A., Xu, S., Montgomery, M. K., Kostas, S. A., Driver, S. E., & Mello, C. C. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 391(6669), 806-811. doi:10.1038/35888
• Fortini, M. E., Skupski, M. P., Boguski, M. S., & Hariharan, I. K. (2000). A survey of human disease gene counterparts in the Drosophila genome. J Cell Biol, 150(2), F23-30. doi:10.1083/jcb.150.2.f23
• Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., . . . et al. (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature, 373(6514), 523-527. doi:10.1038/373523a0
• Geula, C., Nagykery, N., & Wu, C. K. (2002). Amyloid-beta deposits in the cerebral cortex of the aged common marmoset (Callithrix jacchus): incidence and chemical composition. Acta Neuropathol, 103(1), 48-58. doi:10.1007/s004010100429
• Greeve, I., Kretzschmar, D., Tschäpe, J. A., Beyn, A., Brellinger, C., Schweizer, M., . . . Reifegerste, R. (2004). Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J Neurosci, 24(16), 3899-3906. doi:10.1523/jneurosci.0283-04.2004
• Guo, S. (2009). Using zebrafish to assess the impact of drugs on neural development and function. Expert Opin Drug Discov, 4(7), 715-726. doi:10.1517/17460440902988464
• Hampel, H., Mesulam, M. M., Cuello, A. C., Farlow, M. R., Giacobini, E., Grossberg, G. T., . . . Khachaturian, Z. S. (2018). The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain, 141(7), 1917-1933. doi:10.1093/brain/awy132
• Harris, J. R. (2012). Protein aggregation and fibrillogenesis in cerebral and systemic amyloid disease (Vol. 65): Springer Science & Business Media.
• Henstridge, C. M., & Spires-Jones, T. L. (2018). Modeling Alzheimer's disease brains in vitro. Nat Neurosci, 21(7), 899-900. doi:10.1038/s41593-018-0177-2
• Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol, 15(10), 565-581. doi:10.1038/s41582-019-0244-7
• Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., . . . Goldstein, L. S. (2012). Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature, 482(7384), 216-220. doi:10.1038/nature10821
• Jones, V. C., Atkinson-Dell, R., Verkhratsky, A., & Mohamet, L. (2017). Aberrant iPSC-derived human astrocytes in Alzheimer's disease. Cell Death Dis, 8(3), e2696. doi:10.1038/cddis.2017.89
• Kametani, F., & Hasegawa, M. (2018). Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease. Front Neurosci, 12, 25. doi:10.3389/fnins.2018.00025
• Karadakovan, A. (2005). YAŞLILARDA SAĞLIK SORUNLARI. Ege Üniversitesi Hemşirelik Fakültesi Dergisi, 21(2), 169-179.
• Kelava, I., & Lancaster, M. A. (2016a). Dishing out mini-brains: Current progress and future prospects in brain organoid research. Dev Biol, 420(2), 199-209. doi:10.1016/j.ydbio.2016.06.037
• Kelava, I., & Lancaster, M. A. (2016b). Stem Cell Models of Human Brain Development. Cell Stem Cell, 18(6), 736-748. doi:10.1016/j.stem.2016.05.022
• Kim, C. (2015). iPSC technology--Powerful hand for disease modeling and therapeutic screen. BMB Rep, 48(5), 256-265. doi:10.5483/bmbrep.2015.48.5.100
• Koch, P., Tamboli, I. Y., Mertens, J., Wunderlich, P., Ladewig, J., Stüber, K., . . . Walter, J. (2012). Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation. Am J Pathol, 180(6), 2404-2416. doi:10.1016/j.ajpath.2012.02.012
• Kovalevich, J., Santerre, M., & Langford, D. (2021). Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology. Methods Mol Biol, 2311, 9-23. doi:10.1007/978-1-0716-1437-2_2
• Kraemer, B. C., Zhang, B., Leverenz, J. B., Thomas, J. H., Trojanowski, J. Q., & Schellenberg, G. D. (2003). Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci U S A, 100(17), 9980-9985. doi:10.1073/pnas.1533448100
• Kumar, A., Sidhu, J., Goyal, A., & Tsao, J. W. (2022). Alzheimer Disease. In StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.
• LaFerla, F. M., & Green, K. N. (2012). Animal models of Alzheimer disease. Cold Spring Harb Perspect Med, 2(11). doi:10.1101/cshperspect.a006320
• Lancaster, M. A., & Knoblich, J. A. (2014). Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc, 9(10), 2329-2340. doi:10.1038/nprot.2014.158
• Lancaster, M. A., Renner, M., Martin, C. A., Wenzel, D., Bicknell, L. S., Hurles, M. E., . . . Knoblich, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373-379. doi:10.1038/nature12517
• Leon, W. C., Canneva, F., Partridge, V., Allard, S., Ferretti, M. T., DeWilde, A., . . . Cuello, A. C. (2010). A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis, 20(1), 113-126. doi:10.3233/jad-2010-1349
• Lewis, J., McGowan, E., Rockwood, J., Melrose, H., Nacharaju, P., Van Slegtenhorst, M., . . . Hutton, M. (2000). Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet, 25(4), 402-405. doi:10.1038/78078
• Li, C., & Götz, J. (2017). Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov, 16(12), 863-883. doi:10.1038/nrd.2017.155
• Li, X., Bao, X., & Wang, R. (2016). Experimental models of Alzheimer's disease for deciphering the pathogenesis and therapeutic screening (Review). Int J Mol Med, 37(2), 271-283. doi:10.3892/ijmm.2015.2428
• Link, C. D. (1995). Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci U S A, 92(20), 9368-9372. doi:10.1073/pnas.92.20.9368
• Liu, X. H., Ning, F. B., Zhao, D. P., Chang, Y. Y., Wu, H. M., Zhang, W. H., & Yu, A. L. (2021). Role of miR-211 in a PC12 cell model of Alzheimer's disease via regulation of neurogenin 2. Exp Physiol, 106(4), 1061-1071. doi:10.1113/ep088953
• Luo, L., Tully, T., & White, K. (1992). Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron, 9(4), 595-605. doi:10.1016/0896-6273(92)90024-8
• McColl, G., Roberts, B. R., Gunn, A. P., Perez, K. A., Tew, D. J., Masters, C. L., . . . Bush, A. I. (2009). The Caenorhabditis elegans A beta 1-42 model of Alzheimer disease predominantly expresses A beta 3-42. J Biol Chem, 284(34), 22697-22702. doi:10.1074/jbc.C109.028514
• McColl, G., Roberts, B. R., Pukala, T. L., Kenche, V. B., Roberts, C. M., Link, C. D., . . . Cherny, R. A. (2012). Utility of an improved model of amyloid-beta (Aβ₁₋₄₂) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease. Mol Neurodegener, 7, 57. doi:10.1186/1750-1326-7-57
• Meng, M., Zhang, L., Ai, D., Wu, H., & Peng, W. (2021). β-Asarone Ameliorates β-Amyloid-Induced Neurotoxicity in PC12 Cells by Activating P13K/Akt/Nrf2 Signaling Pathway. Front Pharmacol, 12, 659955. doi:10.3389/fphar.2021.659955
• Mesulam, M. M. (2013). Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer's disease. J Comp Neurol, 521(18), 4124-4144. doi:10.1002/cne.23415
• Meyer, K., Feldman, H. M., Lu, T., Drake, D., Lim, E. T., Ling, K. H., . . . Yankner, B. A. (2019). REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease. Cell Rep, 26(5), 1112-1127.e1119. doi:10.1016/j.celrep.2019.01.023
• Morris, M., Knudsen, G. M., Maeda, S., Trinidad, J. C., Ioanoviciu, A., Burlingame, A. L., & Mucke, L. (2015). Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci, 18(8), 1183-1189. doi:10.1038/nn.4067
• Muratore, C. R., Rice, H. C., Srikanth, P., Callahan, D. G., Shin, T., Benjamin, L. N., . . . Young-Pearse, T. L. (2014). The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet, 23(13), 3523-3536. doi:10.1093/hmg/ddu064
• Nzou, G., Wicks, R. T., Wicks, E. E., Seale, S. A., Sane, C. H., Chen, A., . . . Atala, A. J. (2018). Human Cortex Spheroid with a Functional Blood Brain Barrier for High-Throughput Neurotoxicity Screening and Disease Modeling. Sci Rep, 8(1), 7413. doi:10.1038/s41598-018-25603-5
• Ormel, P. R., Vieira de Sá, R., van Bodegraven, E. J., Karst, H., Harschnitz, O., Sneeboer, M. A. M., . . . Pasterkamp, R. J. (2018). Microglia innately develop within cerebral organoids. Nat Commun, 9(1), 4167. doi:10.1038/s41467-018-06684-2
• Park, J., Wetzel, I., Marriott, I., Dréau, D., D'Avanzo, C., Kim, D. Y., . . . Cho, H. (2018). A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat Neurosci, 21(7), 941-951. doi:10.1038/s41593-018-0175-4
• Penney, J., Ralvenius, W. T., & Tsai, L. H. (2020). Modeling Alzheimer's disease with iPSC-derived brain cells. Mol Psychiatry, 25(1), 148-167. doi:10.1038/s41380-019-0468-3
• Prüßing, K., Voigt, A., & Schulz, J. B. (2013). Drosophila melanogaster as a model organism for Alzheimer's disease. Mol Neurodegener, 8, 35. doi:10.1186/1750-1326-8-35
• Qian, X., Song, H., & Ming, G. L. (2019). Brain organoids: advances, applications and challenges. Development, 146(8). doi:10.1242/dev.166074
• Ramalingam, M., Kim, H., Lee, Y., & Lee, Y. I. (2018). Phytochemical and Pharmacological Role of Liquiritigenin and Isoliquiritigenin From Radix Glycyrrhizae in Human Health and Disease Models. Front Aging Neurosci, 10, 348. doi:10.3389/fnagi.2018.00348
• Raska, J., Hribkova, H., Klimova, H., Fedorova, V., Barak, M., Barta, T., . . . Bohaciakova, D. (2021). Generation of six human iPSC lines from patients with a familial Alzheimer's disease (n = 3) and sex- and age-matched healthy controls (n = 3). Stem Cell Res, 53, 102379. doi:10.1016/j.scr.2021.102379
• Ricciarelli, R., & Fedele, E. (2017). The Amyloid Cascade Hypothesis in Alzheimer's Disease: It's Time to Change Our Mind. Curr Neuropharmacol, 15(6), 926-935. doi:10.2174/1570159x15666170116143743
• Rodriguez-Callejas, J. D., Fuchs, E., & Perez-Cruz, C. (2016). Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset. Front Aging Neurosci, 8, 315. doi:10.3389/fnagi.2016.00315
• Sabbagh, J. J., Kinney, J. W., & Cummings, J. L. (2013). Animal systems in the development of treatments for Alzheimer's disease: challenges, methods, and implications. Neurobiol Aging, 34(1), 169-183. doi:10.1016/j.neurobiolaging.2012.02.027
• Schmidt, R., Strähle, U., & Scholpp, S. (2013). Neurogenesis in zebrafish - from embryo to adult. Neural Dev, 8, 3. doi:10.1186/1749-8104-8-3
• Schneider, L. S., Mangialasche, F., Andreasen, N., Feldman, H., Giacobini, E., Jones, R., . . . Kivipelto, M. (2014). Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med, 275(3), 251-283. doi:10.1111/joim.12191
• Selkoe, D. J., & Hardy, J. (2016). The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med, 8(6), 595-608. doi:10.15252/emmm.201606210
• Shenoy, A., Banerjee, M., Upadhya, A., Bagwe-Parab, S., & Kaur, G. (2022). The Brilliance of the Zebrafish Model: Perception on Behavior and Alzheimer's Disease. Front Behav Neurosci, 16, 861155. doi:10.3389/fnbeh.2022.861155
• Shipley, M. M., Mangold, C. A., & Szpara, M. L. (2016). Differentiation of the SH-SY5Y Human Neuroblastoma Cell Line. J Vis Exp(108), 53193. doi:10.3791/53193
• Sierra-Fonseca, J. A., Najera, O., Martinez-Jurado, J., Walker, E. M., Varela-Ramirez, A., Khan, A. M., . . . Roychowdhury, S. (2014). Nerve growth factor induces neurite outgrowth of PC12 cells by promoting Gβγ-microtubule interaction. BMC Neurosci, 15, 132. doi:10.1186/s12868-014-0132-4
• Song, L., Yuan, X., Jones, Z., Vied, C., Miao, Y., Marzano, M., . . . Li, Y. (2019). Functionalization of Brain Region-specific Spheroids with Isogenic Microglia-like Cells. Sci Rep, 9(1), 11055. doi:10.1038/s41598-019-47444-6
• Sproul, A. A., Jacob, S., Pre, D., Kim, S. H., Nestor, M. W., Navarro-Sobrino, M., . . . Noggle, S. A. (2014). Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors. PLoS One, 9(1), e84547. doi:10.1371/journal.pone.0084547
• t Hart, B. A., & Massacesi, L. (2009). Clinical, pathological, and immunologic aspects of the multiple sclerosis model in common marmosets (Callithrix jacchus). J Neuropathol Exp Neurol, 68(4), 341-355. doi:10.1097/NEN.0b013e31819f1d24
• Tardif, S. D., Mansfield, K. G., Ratnam, R., Ross, C. N., & Ziegler, T. E. (2011). The marmoset as a model of aging and age-related diseases. Ilar j, 52(1), 54-65. doi:10.1093/ilar.52.1.54
• Tardif, S. D., Smucny, D. A., Abbott, D. H., Mansfield, K., Schultz-Darken, N., & Yamamoto, M. E. (2003). Reproduction in captive common marmosets (Callithrix jacchus). Comp Med, 53(4), 364-368.
• Tong, Y., Bai, L., Gong, R., Chuan, J., Duan, X., & Zhu, Y. (2018). Shikonin Protects PC12 Cells Against β-amyloid Peptide-Induced Cell Injury Through Antioxidant and Antiapoptotic Activities. Sci Rep, 8(1), 26. doi:10.1038/s41598-017-18058-7
• Trinchese, F., Liu, S., Ninan, I., Puzzo, D., Jacob, J. P., & Arancio, O. (2004). Cell cultures from animal models of Alzheimer's disease as a tool for faster screening and testing of drug efficacy. J Mol Neurosci, 24(1), 15-21. doi:10.1385/jmn:24:1:015
• TÜİK. (2021). İstatistiklerle Yaşlılar, 2020. Retrieved from https://data.tuik.gov.tr/Bulten/Index?p=Istatistiklerle-Yaslilar-2020-37227
• Wittmann, C. W., Wszolek, M. F., Shulman, J. M., Salvaterra, P. M., Lewis, J., Hutton, M., & Feany, M. B. (2001). Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science, 293(5530), 711-714. doi:10.1126/science.1062382
• Wong, W. (2020). Economic burden of Alzheimer disease and managed care considerations. Am J Manag Care, 26(8 Suppl), S177-s183. doi:10.37765/ajmc.2020.88482
• Xicoy, H., Wieringa, B., & Martens, G. J. (2017). The SH-SY5Y cell line in Parkinson's disease research: a systematic review. Mol Neurodegener, 12(1), 10. doi:10.1186/s13024-017-0149-0
• Xie, D., Deng, T., Zhai, Z., Sun, T., & Xu, Y. (2022). The cellular model for Alzheimer's disease research: PC12 cells. Front Mol Neurosci, 15, 1016559. doi:10.3389/fnmol.2022.1016559
• Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Okano, H., & Suzuki, N. (2012). [Modeling familial Alzheimer's disease with induced pluripotent stem cells]. Rinsho Shinkeigaku, 52(11), 1134-1136. doi:10.5692/clinicalneurol.52.1134
• Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T., . . . Suzuki, N. (2011). Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet, 20(23), 4530-4539. doi:10.1093/hmg/ddr394
• Yagi, Y., Tomita, S., Nakamura, M., & Suzuki, T. (2000). Overexpression of human amyloid precursor protein in Drosophila. Mol Cell Biol Res Commun, 4(1), 43-49. doi:10.1006/mcbr.2000.0248
• Yang, J., Li, S., He, X. B., Cheng, C., & Le, W. (2016). Induced pluripotent stem cells in Alzheimer's disease: applications for disease modeling and cell-replacement therapy. Mol Neurodegener, 11(1), 39. doi:10.1186/s13024-016-0106-3
• Ye, Y., & Fortini, M. E. (1999). Apoptotic activities of wild-type and Alzheimer's disease-related mutant presenilins in Drosophila melanogaster. J Cell Biol, 146(6), 1351-1364. doi:10.1083/jcb.146.6.1351
• Yu, X., Li, Y., & Mu, X. (2020). Effect of Quercetin on PC12 Alzheimer's Disease Cell Model Induced by Aβ (25-35) and Its Mechanism Based on Sirtuin1/Nrf2/HO-1 Pathway. Biomed Res Int, 2020, 8210578. doi:10.1155/2020/8210578
• Zeng, Z., Xu, J., & Zheng, W. (2017). Artemisinin protects PC12 cells against β-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway. Redox Biol, 12, 625-633. doi:10.1016/j.redox.2017.04.003
• Zhou, H., Hu, S., Matveev, R., Yu, Q., Li, J., Khaitovich, P., . . . Tang, K. (2015). A Chronological Atlas of Natural Selection in the Human Genome during the Past Half-million Years. In: bioRxiv.
• Zuroff, L., Daley, D., Black, K. L., & Koronyo-Hamaoui, M. (2017). Clearance of cerebral Aβ in Alzheimer's disease: reassessing the role of microglia and monocytes. Cell Mol Life Sci, 74(12), 2167-2201. doi:10.1007/s00018-017-2463-7