Deneysel Alzheimer Modelleri
Özet
Alzheimer hastalığı (AH), ilerleyici hafıza kaybı ve bilişsel bozulma ile karakterize, demansın en yaygın formudur. Hastalığın temelinde amiloid-β birikimi, tau proteinlerinin anormal fosforilasyonu, kolinerjik yetersizlik, oksidatif hasar ve nöroinflamasyon yer alır. Bu patolojik süreçler özellikle hipokampus ve kortekste sinaptik işlevin bozulmasına ve nöron kayıplarına neden olur. Yaşlanan nüfusla birlikte AH insidansının artması, hastalığın biyolojik mekanizmalarını aydınlatmak ve etkili tedaviler geliştirmek amacıyla deneysel hayvan modellerine olan ihtiyacı artırmıştır. Mevcut modeller, Alzheimer patolojisinin farklı yönlerini taklit ederek araştırmalara önemli katkılar sağlamaktadır. Transgenik fare ve sıçan modelleri, APP, PSEN ve MAPT mutasyonları aracılığıyla Aβ birikimi, tau fosforilasyonu ve bilişsel bozulmayı kapsamlı biçimde yansıtır. Aβ veya tau enjeksiyonuna dayalı modeller kısa sürede plak benzeri patoloji oluştururken; D-galaktoz ve AlCl₃ gibi kimyasal modeller yaşlanma ve oksidatif stres süreçlerini öne çıkarır. Zebrafish gibi küçük omurgalılar erken dönem patolojileri incelemede avantaj sunarken, doğal ve hızlandırılmış yaşlanma modelleri herhangi bir müdahale olmaksızın yaşa bağlı bilişsel gerilemeyi taklit eder. Her model yalnızca belirli bir patolojik süreci temsil ettiğinden, tek bir model AH’nin tüm klinik ve nöropatolojik spektrumunu tam olarak yansıtamaz. Buna rağmen bu modeller, hastalığın mekanizmalarını anlamada ve terapötik stratejilerin geliştirilmesinde temel araçlar olmaya devam etmektedir.
Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive impairment. The underlying pathologies include amyloid-β accumulation, abnormal phosphorylation of tau proteins, cholinergic insufficiency, oxidative damage, and neuroinflammation. These pathological processes cause impaired synaptic function and neuronal loss, particularly in the hippocampus and cortex. The increasing incidence of AD with an aging population has heightened the need for experimental animal models to elucidate the biological mechanisms of the disease and develop effective treatments. Current models provide important contributions to research by mimicking different aspects of Alzheimer's pathology. Transgenic mouse and rat models comprehensively reflect Aβ accumulation, tau phosphorylation, and cognitive impairment through APP, PSEN, and MAPT mutations. Models based on Aβ or tau injection rapidly generate plaque-like pathology, while chemical models such as D-galactose and AlCl₃ highlight aging and oxidative stress processes. Small vertebrates such as zebrafish offer advantages in studying early-stage pathologies, while natural and accelerated aging models mimic age-related cognitive decline without any intervention. Since each model represents only a specific pathological process, no single model can fully reflect the entire clinical and neuropathological spectrum of AD. Nevertheless, these models continue to serve as fundamental tools for understanding the mechanisms of the disease and developing therapeutic strategies.
Referanslar
Kamatham PT, Shukla R, Khatri DK, Vora LK. Pathogenesis, diagnostics, and therapeutics for Alzheimer's disease: breaking the memory barrier. Ageing Research Reviews. 2024; 101: 1.
García-Font N, Günes-Bayir A, Kocyigit A, Güler EM, Bilgin MG, Ergün İS, Dadak A. Effects of carvacrol on human fibroblast (WS-1) and gastric adenocarcinoma (AGS) cells in vitro and on Wistar rats in vivo. Molecular and Cellular Biochemistry. 2018; doi:10.1007/s11010-018-3329-5.
Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends in Molecular Medicine. 2008; 14(2): 45–53.
Tay LX, Ong SC, Tay LJ, Ng T, Parumasivam T. Economic burden of Alzheimer’s disease: a systematic review. Value in Health Regional Issues. 2024; 40: 1–12.
Arayici ME, Kose A. Prevalence of Alzheimer’s disease and cardiometabolic multimorbidity in older adults aged 60 and above in Türkiye: a nationwide population-based cross-sectional study. Journal of Epidemiology and Global Health. 2025; 15(1): 86.
Ratan Y, Rajput A, Maleysm S, Pareek A, Jain V, Pareek A, Singh G. An insight into cellular and molecular mechanisms underlying the pathogenesis of neurodegeneration in Alzheimer’s disease. Biomedicines. 2023; 11(5): 1398.
Wang H, Yang F, Zhang S, Xin R, Sun Y. Genetic and environmental factors in Alzheimer’s and Parkinson’s diseases and promising therapeutic intervention via fecal microbiota transplantation. npj Parkinson’s Disease. 2021; 7(1): 70.
Hettiarachchi N, Dallas M, Al-Owais M, et al. Heme oxygenase-1 protects against Alzheimer’s amyloid-β1-42-induced toxicity via carbon monoxide production. Cell Death & Disease, 2014; 5(12): e1569.
Emerit J, Edeas M, Bricaire F. Neurodegenerative diseases and oxidative stress. Biomedicine & Pharmacotherapy. 2004; 58(1): 39–46.
Dgachi Y, Sokolov O, Luzet V, Godyń J, Panek D, Bonet A, Martin H, Iriepa I, Moraleda I, García-Iriepa C, Janockova J, Richert L, Soukup O, Malawska B, Chabchoub F, Marco-Contelles J, Ismaili L. Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy. European Journal of Medicinal Chemistry. 2017; 126: 576–589.
Tommonaro G, García-Font N, Vitale RM, Pejin B, Iodice C, Cañadas S, Marco-Contelles J, Oset-Gasque MJ. Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease. European Journal of Medicinal Chemistry. 2016; 122: 326–338.
Dawkis E, Small DH. Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer's disease. Journal of Neurochemistry. 2014; 129(5): 756–769.
Tiiman A, Palumaa P, Tõugu V. The missing link in the amyloid cascade of Alzheimer's disease – metal ions. Neurochemistry International. 2013; 62(4): 367–378.
Barage SH, Sonawane KD. Amyloid cascade hypothesis: pathogenesis and therapeutic strategies in Alzheimer's disease. Neuropeptides. 2015; 52: 1–18.
Swomley AM, Förster S, Keeney JT, Triplett J, Zhang Z, Sultana R, Butterfield DA. Aβ, oxidative stress in Alzheimer disease: evidence based on proteomics studies. Biochimica et Biophysica Acta. 2014; 1842(8): 1248–1257.
Sha S, Ren L, Xing X, Guo W, Wang Y, Li Y, Qu L. Recent advances in immunotherapy targeting amyloid-beta and tauopathies in Alzheimer’s disease. Neural Regeneration Research. 2026; 21(2): 577–587.
McDaid J, Mustaly-Kalimi S, Stutzmann GE. Ca2+ dyshomeostasis disrupts neuronal and synaptic function in Alzheimer’s disease. Cells. 2020; 9(12): 2655.
Zuo L, Hemmelgarn BT, Chuang CC, Best TM. The role of oxidative stress-induced epigenetic alterations in amyloid-β production in Alzheimer's disease. Oxidative Medicine and Cellular Longevity. 2015; 2015: 604658.
Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004; 430(7000): 631–639.
Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer's disease. Redox Biology. 2018; 14: 450–464.
Sharma P, Srivastava P, Seth A, Tripathi PN, Banerjee AG, Shrivastava SK. Comprehensive review of mechanisms of pathogenesis involved in Alzheimer's disease and potential therapeutic strategies. Progress in Neurobiology. 2019; 174: 53–89.
Stanciu GD, Luca A, Rusu RN, Bild V, Beschea Chiriac SI, Solcan C, Ababei DC. Alzheimer’s disease pharmacotherapy in relation to cholinergic system involvement. Biomolecules. 2020; 10(1): 40.
Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Molecular Neurodegeneration. 2020; 15(1): 40.
De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016; 164(4): 603–615.
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Kummer MP. Neuroinflammation in Alzheimer's disease. The Lancet Neurology. 2015; 14(4): 388–405.
Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology. 2013; 9(2): 106–118.
Chen L, Yu P, Zhang L, Zou Y, Zhang Y, Jiang L, Gao R, Xiao H, Qian Y, Wang J. Methamphetamine exposure induces neuropathic protein β-amyloid expression. Toxicology in Vitro. 2019; 54: 304–309.
Thakur A, Chun YS, October N, Yang HO, Maharaj V. Potential of South African medicinal plants targeting the reduction of Aβ42 protein as a treatment of Alzheimer's disease. Journal of Ethnopharmacology. 2019; 231: 363–373.
Miners JS, Palmer JC, Tayler H, Palmer LE, Ashby E, Kehoe PG, Love S. Aβ degradation or cerebral perfusion? Divergent effects of multifunctional enzymes. Frontiers in Aging Neuroscience. 2014; 6: 238.
Evin G, Weidemann A. Biogenesis and metabolism of Alzheimer's disease Aβ amyloid peptides. Peptides. 2002; 23(7): 1285–1297.
Dingwall CA. Copper-binding site in the cytoplasmic domain of BACE1 identifies a possible link to metal homoeostasis and oxidative stress in Alzheimer's disease. Biochemical Society Transactions. 2007; 35(Pt 3): 571–573.
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia. 2018; 14: 535–562.
Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. The Lancet Neurology. 2017; 16: 661–676.
Ossenkoppele R, Rabinovici GD, Smith R, et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2018; 320: 1151–1162.
Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, van der Flier WM. Alzheimer’s disease. The Lancet. 2021; 397(10284): 1577–1590.
Mao P, Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and therapeutics. Biochimica et Biophysica Acta. 2011; 1812: 1359–1370.
Benedikz E, Kloskowska E, Winblad B. The rat as an animal model of Alzheimer's disease. Journal of Cellular and Molecular Medicine. 2009; 13(6): 1034–1042.
Shekarian M, Komaki A, Shahidi S, Sarihi A, Salehi I, Raoufi S. Protective and therapeutic effects of vinpocetine on oxidative stress and learning and memory impairment induced by intracerebroventricular amyloid beta peptide. Behavioural Brain Research. 2020; 383: 112512. doi:10.1016/j.bbr.2020.112512.
Zhang HY, Yan H, Tang XC. Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-α in ICV β-amyloid-(1–40) infused rats and HEK293 Swedish mutant cells. Neuroscience Letters. 2004; 360(1–2): 21–24.
Wang D, Noda Y, Zhou Y, Mouri A, Mizoguchi H, Nitta A, Chen W, Nabeshima T. Allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates cognitive dysfunction in β-amyloid 25–35 ICV-injected mice: involvement of dopaminergic systems. Neuropsychopharmacology. 2007; 32(6): 1261–1271.
Thakker DR, Weatherspoon MR, Harrison J, Keene TE, Lane DS, Kaemmerer WF, Stewart GR, Shafer LL. Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated microhemorrhages in aged Tg2576 mice. Proceedings of the National Academy of Sciences USA. 2009; 106(11): 4501–4506.
Dragicevic N, Smith A, Lin X, Yuan F, Copes N, Delic V, Tan J, Cao C, Shytle RD, Bradshaw PC. Green tea EGCG and other flavonoids reduce Alzheimer’s amyloid-induced mitochondrial dysfunction. Journal of Alzheimer’s Disease. 2011; 26(3): 507–521.
Rapaka D, Adiukwu PC, Bitra VR. Experimentally induced animal models for cognitive dysfunction and Alzheimer's disease. MethodsX. 2022;9:101933.
McLarnon J. Correlated inflammatory responses and neurodegeneration in peptide-injected animal models of Alzheimer’s disease. BioMed Research International. 2014; 2014: 923670.
Noor NA, Hosny EN, Khadrawy YA, Mourad IM, Othman AI, Aboul Ezz HS, Mohammed HS. Effect of curcumin nanoparticles on streptozotocin-induced male Wistar rat model of Alzheimer’s disease. Metabolic Brain Disease. 2022; 37: 343–357. doi:10.1007/s11011-021-00897-z.
Yeo HG, Lee Y, Jeon CY, Jeong KJ, Jin YB, Kang P, Kim SU, Kim JS, Huh JW, Kim Y, Sim BW, Song BS, Park YH, Hong Y, Lee SR, Chang KT. Characterization of cerebral damage in a monkey model of Alzheimer’s disease induced by intracerebroventricular streptozotocin. Journal of Alzheimer’s Disease. 2015; 46: 989–1005. doi:10.3233/JAD-143222.
Wang JM, Qu ZQ, Wu JL, Chung P, Zeng YS. Mitochondrial protective and anti-apoptotic effects of Rhodiola crenulata extract on hippocampal neurons in a rat model of Alzheimer’s disease. Neural Regeneration Research. 2017; 12: 2025–2034. doi:10.4103/1673-5374.221160.
Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. Journal of Alzheimer’s Disease. 2006; 9(1): 1–12. doi:10.3233/JAD-2006-9101.
Akhtar A, Gupta SM, Dwivedi S, Kumar D, Shaikh MF, Negi A. Preclinical models for Alzheimer’s disease: past, present, and future approaches. ACS Omega. 2022; 7(51): 47504–47517.
Zhou S, Yu G, Chi L, Zhu J, Zhang W, Zhang Y. Neuroprotective effects of edaravone on cognitive deficit, oxidative stress and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats. Neurotoxicology. 2013; 38: 136–145.
Neha RK, Sodhi RK, Jaggi AS, Singh N. Animal models of dementia and cognitive dysfunction. Life Sciences. 2014; 109(2): 73–86.
Yang S, Zhou G, Liu H, Zhang B, Li J, Cui R. Protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a rat model of vascular dementia. BioMed Research International. 2013; 2013: 215798.
Sodhi RK, Singh N, Jaggi AS. Neuroprotective mechanisms of peroxisome proliferator-activated receptor agonists in Alzheimer’s disease. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2011; 384(2): 115–124.
Correia SC, Santos RX, Santos MS, Casadesus G, Lamanna JC, Perry G. Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer’s disease. Current Alzheimer Research. 2013; 10(4): 406–419.
Sharma M, Briyal S, Gupta YK. Effect of alpha lipoic acid, melatonin and trans-resveratrol on intracerebroventricular streptozotocin-induced spatial memory deficit in rats. Indian Journal of Physiology and Pharmacology. 2005; 49(4): 395–402.
Kumar A, Aggarwal A, Singh A, Naidu PS. Animal models in drug discovery of Alzheimer’s disease: a mini review. EC Pharmacology and Toxicology. 2016; 2(1): 60–79.
Riedel G, Kang SH, Choi DY, Platt B. Scopolamine-induced deficits in social memory in mice: reversal by donepezil. Behavioural Brain Research. 2009; 204(1): 217–225.
Klinkenberg I, Blokland A. The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neuroscience & Biobehavioral Reviews. 2010;34(8):1307–1350.
Khakpai F, Nasehi M, Haeri-Rohani A, Eidi A, Zarrindast MR. Scopolamine induced memory impairment; possible involvement of NMDA receptor mechanisms of dorsal hippocampus and/or septum. Behavioural Brain Research. 2012;231(1):1–10.
Singh P, Konar A, Kumar A, Srivas S, Thakur MK. Hippocampal chromatin-modifying enzymes are pivotal for scopolamine-induced synaptic plasticity gene expression changes and memory impairment. Journal of Neurochemistry. 2015;134(4):642–651.
Elvander E, Schött PA, Sandin J, Bjelke B, Kehr J, Yoshitake T. Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition. Neuroscience. 2004;126(3):541–557.
Rogers JL, Kesner RP. Cholinergic modulation of the hippocampus during encoding and retrieval. Neurobiology of Learning and Memory. 2003;80(3):332–342.
Wu YY, Wang X, Tan L, Liu D, Liu XH, Wang Q. Lithium attenuates scopolamine-induced memory deficits with inhibition of GSK-3β and preservation of postsynaptic components. Journal of Alzheimer’s Disease. 2013;37(3):515–527.
Niel E, Scherrmann JM. Colchicine today. Joint Bone Spine. 2006;73(6):672–678. doi:10.1016/j.jbspin.2006.03.006.
Kumar A, Seghal N, Naidu P, Padi SS, Goyal R. Colchicine-induced neurotoxicity as an animal model of sporadic dementia of Alzheimer’s type. Pharmacological Reports. 2007;59(3):274–283.
Sil S, Ghosh T, Ghosh R. NMDA receptor is involved in neuroinflammation in intracerebroventricular colchicine-injected rats. Journal of Immunotoxicology. 2016;13(4):474–489.
Evrard PA, Ragusi C, Boschi G, Verbeeck RK, Scherrmann JM. Simultaneous microdialysis in brain and blood of the mouse: extracellular and intracellular brain colchicine disposition. Brain Research. 1998;786(1–2):122–127.
Mahdi O, Baharuldin MTH, Nor NHM, Chiroma SM, Jagadeesan S, Moklas MAM. Chemicals used for the induction of Alzheimer’s disease-like cognitive dysfunctions in rodents. Biomedical Research and Therapy. 2019;6(11):3460–3484.
Kamat PK, Tota S, Saxena G, Shukla R, Nath C. Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity. Brain Research. 2010;1309:66–74.
Song XY, Hu JF, Chu SF, Zhang Z, Xu S, Yuan YH, Han N, Liu Y, Niu F, He X, Chen NH. Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3β/tau signaling pathway and the Aβ formation prevention in rats. European Journal of Pharmacology. 2013;710(1–3):29–38. doi:10.1016/j.ejphar.2013.03.051.
Zhang Z, Simpkins JW. An okadaic acid-induced model of tauopathy and cognitive deficiency. Brain Research. 2010;1359:233–246. doi:10.1016/j.brainres.2010.08.077.
Kamat PK, Tota S, Shukla R, Ali S, Najmi AK, Nath C. Mitochondrial dysfunction: a crucial event in okadaic acid (ICV) induced memory impairment and apoptotic cell death in rat brain. Pharmacology Biochemistry and Behavior. 2011;100(2):311–319.
Abbas F, Eladl MA, El-Sherbiny M, Abozied N, Nabil A, Mahmoud SM, Mokhtar HI, Zaitone SA, Ibrahim D. Celastrol and thymoquinone alleviate aluminum chloride-induced neurotoxicity: behavioral psychomotor performance, neurotransmitter level, oxidative-inflammatory markers, and BDNF expression in rat brain. Biomedicine & Pharmacotherapy. 2022;151:113072. doi:10.1016/j.biopha.2022.113072.
Exley C, Clarkson E. Aluminium in human brain tissue from donors without neurodegenerative disease: A comparison with Alzheimer’s disease, multiple sclerosis and autism. Scientific Reports. Nature Publishing Group; 2020;10(1):7770.
Chiroma SM, Mohd Moklas MA, Mat Taib CN, Baharuldin MTH, Amon Z. d-galactose and aluminium chloride induced rat model with cognitive impairments. Biomedicine & Pharmacotherapy. Elsevier; 2018;103:1602–1608.
Khan K, Emad NA, Sultana Y. Inducing agents for Alzheimer’s disease in animal models. Journal of Exploratory Research in Pharmacology. 2024;9(3):169–179.
Firdaus Z, Kumar D, Singh SK, Singh TD. Centella asiatica alleviates AlCl₃-induced cognitive impairment, oxidative stress, and neurodegeneration by modulating cholinergic activity and oxidative burden in rat brain. Biological Trace Element Research. 2022;200(12):5115–5126.
Zhao Y, Dang M, Zhang W. Neuroprotective effects of syringic acid against aluminium chloride induced oxidative stress mediated neuroinflammation in rat model of Alzheimer’s disease. Journal of Functional Foods. 2020;71:104009.
Chen X, Zhang M, Ahmed M, Surapaneni KM, Veeraraghavan VP, Arulselvan P. Neuroprotective effects of ononin against the aluminium chloride-induced Alzheimer’s disease in rats. Saudi Journal of Biological Sciences. 2021;28(8):4232–4239.
Prajapat M, Kaur G, Choudhary G, Pahwa P, Bansal S, Joshi R, et al. A systematic review for the development of Alzheimer’s disease in in vitro models: a focus on different inducing agents. Frontiers in Aging Neuroscience. 2023;15:1296919.
Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Scientific Reports. 2019;9(1):5790.
Skrzypczak-Wiercioch A, Salat K. Lipopolysaccharide-induced model of neuroinflammation: mechanisms of action, research application and future directions for its use. Molecules. 2022;27(17):5481.
Zakaria R, Wan Yaacob WMH, Othman Z, Long I, Ahmad AH, Al-Rahbi B. Lipopolysaccharide-induced memory impairment in rats: a model of Alzheimer’s disease. Physiological Research. 2017;66.
Xu QQ, Yang W, Zhong M, Lin ZX, Gray NE, Xian YF. Animal models of Alzheimer’s disease: preclinical insights and challenges. Acta Materia Medica. 2023;2(2):192–215.
Tsai SJ, Chiu CP, Yang HT, Yin MC. S-allyl cysteine, S-ethyl cysteine, and S-propyl cysteine alleviate β-amyloid, glycative, and oxidative injury in brain of mice treated by D-galactose. Journal of Agricultural and Food Chemistry. 2011;59:6319–6326. doi:10.1021/jf201160a.
Yu CC, Wang J, Ye SS, Gao S, Li J, Wang L, et al. Preventive electroacupuncture ameliorates D-galactose-induced Alzheimer’s disease-like pathology and memory deficits probably via inhibition of GSK3β/mTOR signaling pathway. Evidence-Based Complementary and Alternative Medicine. 2020;2020(1):1428752.
Hong XP, Chen T, Yin NN, Han YM, Yuan F, Duan YJ, et al. Puerarin ameliorates D-galactose induced enhanced hippocampal neurogenesis and tau hyperphosphorylation in rat brain. Journal of Alzheimer’s Disease. 2016;51:605–617. doi:10.3233/JAD-150566.
Luo Y, Niu F, Sun Z, Cao W, Zhang X, Guan D, et al. Altered expression of Aβ metabolism-associated molecules from D-galactose/AlCl3 induced mouse brain. Mechanisms of Ageing and Development. 2009;130(4):248–252.
More SV, Kumar H, Cho DY, Yun YS, Choi DK. Toxin-induced experimental models of learning and memory impairment. International Journal of Molecular Sciences. 2016;17(9):1447.
LaFerla FM, Green KN. Animal models of Alzheimer disease. Cold Spring Harbor Perspectives in Medicine. 2012;2(11):a006320.
Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet. 2016;388:505–517.
Sarasa M, Pesini P. Natural non-transgenic animal models for research in Alzheimer’s disease. Current Alzheimer Research. 2009;6(2):171–178.
Do Carmo S, Cuello AC. Modeling Alzheimer’s disease in transgenic rats. Molecular Neurodegeneration. 2013;8(1):37.
Sadigh-Eteghad S, Sabermarouf B, Majdi A, et al. Amyloid-beta: A crucial factor in Alzheimer’s disease. Medical Principles and Practice. 2015;24:1–10.
Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature. 1995;373:523–527. doi:10.1038/373523a0.
Tütüncü S, Tezel H, Özyurt AB, Yirün A, Baydar T, Erkekoğlu P. Alzheimer hastalığı in vivo modelleri: geleneksel derleme. Journal of Literature Pharmacy Sciences. 2023;12(1):8–19.
Dineley KT, Jahrling JB, Denner L. Insulin resistance in Alzheimer’s disease. Neurobiology of Disease. 2014;72:92–103.
Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, et al. A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. Journal of Alzheimer’s Disease. 2010;20:113–126. doi:10.3233/JAD-2010-1349.
Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, et al. Monoclonal antibodies that target pathological assemblies of Aβ. Journal of Neurochemistry. 2007;100:23–35. doi:10.1111/j.1471-4159.2006.04157.x.
Hanzel CE, Pichet-Binette A, Cuello AC. Early inflammatory process in a novel transgenic rat model of Alzheimer’s disease. Society for Neuroscience Abstracts. 2012;New Orleans, USA.
Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL. Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Molecular Medicine. 2004;10:36–44. doi:10.2119/2003-00044.herrera.
Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, et al. A transgenic rat that develops Alzheimer’s disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiology of Disease. 2008;31:46–57. doi:10.1016/j.nbd.2008.03.005.
Zahorsky-Reeves J, Lawson G, Chu DK, Schimmel A, Ezell PC, Dang M, Couto M. Maintaining longevity in a triple transgenic rat model of Alzheimer’s disease. Journal of the American Association for Laboratory Animal Science. 2007;46:124.
Duyckaerts C, Potier MC, Delatour B. Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathologica. 2008;115:5–38.
Hutton M. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology. 2001;56:S21–S25.
Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genetics. 2000;25(4):402–405.
Sharma H, Chang KA, Hulme J, An SSA. Mammalian models in Alzheimer’s research: an update. Cells. 2023;12(20):2459.
Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiology of Aging. 2003;24:1063–1070.
Rodriguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, Oddo S, Verkhratsky A. Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS ONE. 2008;3:e2935.
Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Aβ causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron. 2005;45(5):675–688.
Alves SS, Servilha-Menezes G, Rossi L, da Silva Junior RMP, Garcia-Cairasco N. Evidence of disturbed insulin signaling in animal models of Alzheimer’s disease. Neuroscience & Biobehavioral Reviews. 2023;152:105326. doi:10.1016/j.neubiorev.2023.105326.
Sodhi RK, Jaggi AS, Singh N. Animal models of dementia and cognitive dysfunction. Life Sciences. 2014;109(2):73–86.
Butterfield DA, Poon HF. The senescence-accelerated prone mouse (SAMP8): a model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer's disease. Experimental Gerontology. 2005;40(10):774–783.
Liu B, Liu J, Shi JS. SAMP8 mice as a model of age-related cognition decline with underlying mechanisms in Alzheimer’s disease. Journal of Alzheimer’s Disease. 2020;75:385–395.
Stefanova N, Kozhevnikova O, Vitovtov A, Maksimova K, Logvinov S, Rudnitskaya E, et al. Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease. Cell Cycle. 2014;13(6):898–909.
Fernandez-Funez P, de Mena L, Rincon-Limas DE. Modeling the complex pathology of Alzheimer's disease in Drosophila. Experimental Neurology. 2015;274:58–71. doi:10.1016/j.expneurol.2015.05.013.
Alexander AG, Marfil V, Li C. Use of Caenorhabditis elegans as a model to study Alzheimer's disease and other neurodegenerative diseases. Frontiers in Genetics. 2014;5:279. doi:10.3389/fgene.2014.00279.
Paquet D, Bhat R, Sydow A, Mandelkow EM, Berg S, Hellberg S, et al. A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. Journal of Clinical Investigation. 2009;119:1382–1395. doi:10.1172/JCI37537.
Hannan SB, Drager NM, Rasse TM, Voigt A, Jahn TR. Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models. Journal of Neurochemistry. 2016;137:12–25. doi:10.1111/jnc.13532.
Drummond E, Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathologica. 2017;133(2):155–175.
Kalueff AV, Echevarria DJ, Stewart MA. Gaining translational momentum: More zebrafish models for neuroscience research. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2014a;55:1–6.
Chen MQ, Martins RN, Lardelli M. Complex splicing and neural expression of duplicated tau genes in zebrafish embryos. Journal of Alzheimer’s Disease. 2009;18(2):305–317.
Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, et al. The zebrafish reference genome sequence and its relationship to the human genome. Nature. 2013;496(7446):498–503.
Chen ZY, Zhang Y. Animal models of Alzheimer’s disease: Applications, evaluation, and perspectives. Zoological Research. 2022;43(6):1026.
Kalueff AV, Stewart AM, Gerlai R. Zebrafish as an emerging model for studying complex brain disorders. Trends in Pharmacological Sciences. 2014b;35(2):63–75.
Best JD, Berghmans S, Hunt JJFG, Clarke SC, Fleming A, Goldsmith P, et al. Non-associative learning in larval zebrafish. Neuropsychopharmacology. 2008;33(5):1206–1215.
Nery LR, Eltz NS, Hackman C, Fonseca R, Altenhofen S, Guerra HN, … Vianna MRM. Brain intraventricular injection of amyloid-β in zebrafish embryo impairs cognition and increases tau phosphorylation, effects reversed by lithium. PLoS One. 2014;9(9):e105862.
Vitek MP, Araujo JA, Fossel M, Greenberg BD, Howell GR, Rizzo SJS, et al. Translational animal models for Alzheimer’s disease: An Alzheimer’s Association Business Consortium Think Tank. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2020;6:e12114.
Braidy N, Poljak A, Jayasena T, Mansour H, Inestrosa NC, Sachdev PS. Accelerating Alzheimer’s research through ‘natural’ animal models. Current Opinion in Psychiatry. 2015;28:155–164.
Cotman CW, Head E. The canine (dog) model of human aging and disease: Dietary, environmental and immunotherapy approaches. Journal of Alzheimer’s Disease. 2008;15:685–707.
Head E. A canine model of human aging and Alzheimer’s disease. Biochimica et Biophysica Acta. 2013;1832:1384–1389.
Gearing M, Rebeck GW, Hyman BT, Tigges J, Mirra SS. Neuropathology and apolipoprotein E profile of aged chimpanzees: Implications for Alzheimer disease. Proceedings of the National Academy of Sciences USA. 1994;91:9382–9386.
Gearing M, Tigges J, Mori H, Mirra SS. Beta-amyloid (Aβ) deposition in the brains of aged orangutans. Neurobiology of Aging. 1997;18:139–146.
Li B, He D-J, Li X-J, Guo X-Y. Modeling neurodegenerative diseases using non-human primates: Advances and challenges. Ageing Neurodegenerative Diseases. 2022;2:12.
Frye BM, Craft S, Register TC, Kim J, Whitlow CT, Barcus RA, et al. Early Alzheimer’s disease-like reductions in gray matter and cognitive function with aging in nonhuman primates. Alzheimer’s Dementia. 2022;8:e12284.
Emborg ME. Nonhuman primate models of neurodegenerative disorders. ILAR Journal. 2017;58:190–201.
