Login Register Cart 0
Current Pharmaceutical Design

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Exploring Neurodegenerative Diseases: Bridging the Gap between in vitro and in vivo Models

Author(s): Abubaker El Elhajorcid of author and Mehmet Emin Onger*

Volume 32, Issue 6, 2026

Published on: 24 June, 2025

Page: [407 - 414] Pages: 8

DOI: 10.2174/0113816128374254250605070049

Price: $65

Become a Editorial Board Member
Become a Reviewer
Become a Editor
Become a Section Editor

Abstract

Neurological disorders are brain conditions characterized by the loss of nerve cells, leading to a decline in function. Standard examples include dementia, tremors, involuntary movements, muscle weakness, and autoimmune attacks. The most common form of dementia is Alzheimer's, affecting over 5 million elderly individuals, while tremors, stiffness, and slow movement are caused by Parkinson's. Involuntary movements and emotional problems are caused by Huntington's, while muscle weakness and eventual demise are caused by Amyotrophic lateral sclerosis. Vision problems, fatigue, and difficulty walking are caused by Multiple sclerosis (MS), an autoimmune disease that attacks the myelin sheath. In vitro models provide cost and complexity reduction, environmental control, and high-throughput. Researchers employ both cell-based (in vitro) and animal- based (in vivo) models to investigate neurodegenerative illnesses and endeavor to formulate novel treatments for diverse conditions. In vitro models provide cost and complexity reduction, environment control, and high-throughput screening of potential therapeutic agents compared to in vivo models. Nevertheless, they possess constraints, including the absence of intricate interactions that transpire in the entire organism and the inability to reproduce the disease progression completely.

Keywords: Degenerative diseases, Alzheimer’s disease, Parkinson’s disease, in vivo models, in vitro models, immunological disorders.

Next »
[1]
Abdeltawab, M.S.A.; Abdel-Shafi, I.R.; Aboulhoda, B.E.; Mahfoz, A.M.; Hamed, A.M.R. The neuroprotective potential of curcumin on T. Spiralis infected mice. BMC Complementary Med Ther, 2024, 24(1), 99.
[http://dx.doi.org/10.1186/s12906-024-04399-0] [PMID: 38388410]
[2]
Tanaka, M.; Toldi, J.; Vécsei, L. Exploring the etiological links behind neurodegenerative diseases: Inflammatory cytokines and bioactive kynurenines. Int. J. Mol. Sci., 2020, 21(7), 2431.
[http://dx.doi.org/10.3390/ijms21072431] [PMID: 32244523]
[3]
Hansson, O. Biomarkers for neurodegenerative diseases. Nat. Med., 2021, 27(6), 954-963.
[http://dx.doi.org/10.1038/s41591-021-01382-x] [PMID: 34083813]
[4]
Alzheimer's Association 2018 Alzheimer’s disease facts and figures. Alzheimers Dement., 2018, 14(3), 367-429.
[http://dx.doi.org/10.1016/j.jalz.2018.02.001]
[5]
Itoh, Y.; Voskuhl, R.R. Cell specificity dictates similarities in gene expression in multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. PLoS One, 2017, 12(7), e0181349.
[http://dx.doi.org/10.1371/journal.pone.0181349] [PMID: 28715462]
[6]
Bashir, H. Emerging therapies in Huntington’s disease. Expert Rev. Neurother., 2019, 19(10), 983-995.
[http://dx.doi.org/10.1080/14737175.2019.1631161] [PMID: 31181964]
[7]
Achenbach, J.; Thiels, C.; Lücke, T.; Saft, C. Clinical manifestation of juvenile and pediatric HD patients: A retrospective case series. Brain Sci., 2020, 10(6), 340.
[http://dx.doi.org/10.3390/brainsci10060340] [PMID: 32503138]
[8]
Bakels, H.S.; Roos, R.A.C.; van Roon-Mom, W.M.C.; de Bot, S.T. Juvenile-onset Huntington disease pathophysiology and neurodevelopment: A review. Mov. Disord., 2022, 37(1), 16-24.
[http://dx.doi.org/10.1002/mds.28823] [PMID: 34636452]
[9]
Tsvetkova, D.; Ivanova, S.; Obreshkova, D. Neurodegenerative multioethiology Lou Gehrig’s disease–genetic mutations, pharmacological mechanisms and applications of rilusole. Int. J. Pharm. Res. Allied Sci., 2023, 12(3), 61-70.
[http://dx.doi.org/10.51847/w9fRJSNXjp]
[10]
Veronese, S.; Gallo, G.; Valle, A.; Cugno, C.; Chiò, A.; Calvo, A.; Cavalla, P.; Zibetti, M.; Rivoiro, C.; Oliver, D.J. Specialist palliative care improves the quality of life in advanced neurodegenerative disorders: NE-PAL, a pilot randomised controlled study. BMJ Support. Palliat. Care, 2017, 7(2), 164-172.
[http://dx.doi.org/10.1136/bmjspcare-2014-000788] [PMID: 26182947]
[11]
Colle, D.; Farina, M.; Ceccatelli, S.; Raciti, M. Paraquat and maneb exposure alters rat neural stem cell proliferation by inducing oxidative stress: New insights on pesticide-induced neurodevelopmental toxicity. Neurotox. Res., 2018, 34(4), 820-833.
[http://dx.doi.org/10.1007/s12640-018-9916-0] [PMID: 29859004]
[12]
Domenighetti, C.; Sugier, P.E.; Sreelatha, A.A.K.; Schulte, C.; Grover, S.; Mohamed, O.; Portugal, B.; May, P.; Bobbili, D.R.; Radivojkov-Blagojevic, M.; Lichtner, P.; Singleton, A.B.; Hernandez, D.G.; Edsall, C.; Mellick, G.D.; Zimprich, A.; Pirker, W.; Rogaeva, E.; Lang, A.E.; Koks, S.; Taba, P.; Lesage, S.; Brice, A.; Corvol, J.C.; Chartier-Harlin, M.C.; Mutez, E.; Brockmann, K.; Deutschländer, A.B.; Hadjigeorgiou, G.M.; Dardiotis, E.; Stefanis, L.; Simitsi, A.M.; Valente, E.M.; Petrucci, S.; Duga, S.; Straniero, L.; Zecchinelli, A.; Pezzoli, G.; Brighina, L.; Ferrarese, C.; Annesi, G.; Quattrone, A.; Gagliardi, M.; Matsuo, H.; Kawamura, Y.; Hattori, N.; Nishioka, K.; Chung, S.J.; Kim, Y.J.; Kolber, P.; van de Warrenburg, B.P.C.; Bloem, B.R.; Aasly, J.; Toft, M.; Pihlstrøm, L.; Guedes, L.C.; Ferreira, J.J.; Bardien, S.; Carr, J.; Tolosa, E.; Ezquerra, M.; Pastor, P.; Diez-Fairen, M.; Wirdefeldt, K.; Pedersen, N.L.; Ran, C.; Belin, A.C.; Puschmann, A.; Hellberg, C.; Clarke, C.E.; Morrison, K.E.; Tan, M.; Krainc, D.; Burbulla, L.F.; Farrer, M.J.; Krüger, R.; Gasser, T.; Sharma, M.; Elbaz, A. Mendelian randomisation study of smoking, alcohol, and coffee drinking in relation to Parkinson’s disease. J. Parkinsons Dis., 2022, 12(1), 267-282.
[http://dx.doi.org/10.3233/JPD-212851] [PMID: 34633332]
[13]
Ball, N.; Teo, W.P.; Chandra, S.; Chapman, J. Parkinson’s disease and the environment. Front. Neurol., 2019, 10, 218.
[http://dx.doi.org/10.3389/fneur.2019.00218] [PMID: 30941085]
[14]
Tarnacka, B.; Jopowicz, A.; Maślińska, M. Copper, iron, and manganese toxicity in neuropsychiatric conditions. Int. J. Mol. Sci., 2021, 22(15), 7820.
[http://dx.doi.org/10.3390/ijms22157820] [PMID: 34360586]
[15]
Spencer, P.S.; Berntsson, S.G.; Buguet, A.; Butterfield, P.; Calne, D.B.; Calne, S.M.; Giménez-Roldán, S.; Hugon, J.; Kahlon, S.; Kisby, G.E.; Lagrange, E.; Landtblom, A.M.E.; Ludolph, A.C.; Nunn, P.B.; Palmer, V.S.; Reis, J.; Román, G.C.; Sipilä, J.O.T.; Spencer, S.S.; Angues, R.V.; Vernoux, J.P.; Yabushita, M. Brain health: Pathway to primary prevention of neurodegenerative disorders of environmental origin. J. Neurol. Sci., 2025, 468, 123340.
[http://dx.doi.org/10.1016/j.jns.2024.123340] [PMID: 39667295]
[16]
Feigin, V.L.; Vos, T.; Nichols, E.; Owolabi, M.O.; Carroll, W.M.; Dichgans, M.; Deuschl, G.; Parmar, P.; Brainin, M.; Murray, C. The global burden of neurological disorders: Translating evidence into policy. Lancet Neurol., 2020, 19(3), 255-265.
[http://dx.doi.org/10.1016/S1474-4422(19)30411-9] [PMID: 31813850]
[17]
Logroscino, G.; Urso, D.; Savica, R. Descriptive epidemiology of neurodegenerative diseases: What are the critical questions? Neuroepidemiology, 2022, 56(5), 309-318.
[http://dx.doi.org/10.1159/000525639] [PMID: 35728570]
[18]
Pohl, F.; Lin, PKT The potential use of plant natural products and plant extracts with antioxidant properties for the prevention/treatment of neurodegenerative diseases: In vitro, in vivo and clinical trials. Molecules, 2018, 23(12), 3283.
[http://dx.doi.org/10.3390/molecules23123283] [PMID: 30544977]
[19]
D’Antoni, C.; Mautone, L.; Sanchini, C.; Tondo, L.; Grassmann, G.; Cidonio, G.; Bezzi, P.; Cordella, F.; Di Angelantonio, S. Unlocking neural function with 3D in vitro models: A technical review of self-assembled, guided, and bioprinted brain organoids and their applications in the study of neurodevelopmental and neurodegenerative disorders. Int. J. Mol. Sci., 2023, 24(13), 10762.
[http://dx.doi.org/10.3390/ijms241310762] [PMID: 37445940]
[20]
Segeritz, C-P.; Vallier, L. Cell culture: Growing cells as model systems in vitro. In: Basic science methods for clinical researchers; Elsevier, 2017; pp. 151-172.
[http://dx.doi.org/10.1016/B978-0-12-803077-6.00009-6]
[21]
Li, A.; Pereira, C.; Hill, E.E.; Vukcevich, O.; Wang, A. In vitro, in vivo and ex vivo models for peripheral nerve injury and regeneration. Curr. Neuropharmacol., 2022, 20(2), 344-361.
[http://dx.doi.org/10.2174/1570159X19666210407155543] [PMID: 33827409]
[22]
Marvian, A.T.; Koss, D.J.; Aliakbari, F.; Morshedi, D.; Outeiro, T.F. In vitro models of synucleinopathies: Informing on molecular mechanisms and protective strategies. J. Neurochem., 2019, 150(5), 535-565.
[http://dx.doi.org/10.1111/jnc.14707] [PMID: 31004503]
[23]
Dunkel, P.; Chai, C.L.L.; Sperlágh, B.; Huleatt, P.B.; Mátyus, P. Clinical utility of neuroprotective agents in neurodegenerative diseases: Current status of drug development for Alzheimer’s, Parkinson’s and Huntington’s diseases, and amyotrophic lateral sclerosis. Expert Opin. Investig. Drugs, 2012, 21(9), 1267-1308.
[http://dx.doi.org/10.1517/13543784.2012.703178] [PMID: 22741814]
[24]
Slanzi, A.; Iannoto, G.; Rossi, B.; Zenaro, E.; Constantin, G. In vitro models of neurodegenerative diseases. Front. Cell Dev. Biol., 2020, 8, 328.
[http://dx.doi.org/10.3389/fcell.2020.00328] [PMID: 32528949]
[25]
Louit, A.; Galbraith, T.; Berthod, F. In vitro 3D modeling of neurodegenerative diseases. Bioengineering, 2023, 10(1), 93.
[http://dx.doi.org/10.3390/bioengineering10010093] [PMID: 36671665]
[26]
Miny, L.; Maisonneuve, B.G.C.; Quadrio, I.; Honegger, T. Modeling neurodegenerative diseases using in vitro compartmentalized microfluidic devices. Front. Bioeng. Biotechnol., 2022, 10, 919646.
[http://dx.doi.org/10.3389/fbioe.2022.919646] [PMID: 35813998]
[27]
Osaki, T.; Shin, Y.; Sivathanu, V.; Campisi, M.; Kamm, R.D. In vitro microfluidic models for neurodegenerative disorders. Adv. Healthc. Mater., 2018, 7(2), 1700489.
[http://dx.doi.org/10.1002/adhm.201700489] [PMID: 28881425]
[28]
Haenseler, W.; Rajendran, L. Concise review: Modeling neurodegenerative diseases with human pluripotent stem cell-derived microglia. Stem Cells, 2019, 37(6), 724-730.
[http://dx.doi.org/10.1002/stem.2995] [PMID: 30801863]
[29]
Holloway, P.M.; Willaime-Morawek, S.; Siow, R.; Barber, M.; Owens, R.M.; Sharma, A.D.; Rowan, W.; Hill, E.; Zagnoni, M. Advances in microfluidic in vitro systems for neurological disease modeling. J. Neurosci. Res., 2021, 99(5), 1276-1307.
[http://dx.doi.org/10.1002/jnr.24794] [PMID: 33583054]
[30]
Fanizza, F.; Campanile, M.; Forloni, G.; Giordano, C.; Albani, D. Induced pluripotent stem cell-based organ-on-a-chip as personalized drug screening tools: A focus on neurodegenerative disorders. J. Tissue Eng., 2022, 13, 20417314221095339.
[http://dx.doi.org/10.1177/20417314221095339] [PMID: 35570845]
[31]
Cummings, J.; Montes, A.; Kamboj, S.; Cacho, J.F. The role of basket trials in drug development for neurodegenerative disorders. Alzheimers Res. Ther., 2022, 14(1), 73.
[http://dx.doi.org/10.1186/s13195-022-01015-6] [PMID: 35614479]
[32]
Matthews, D.C.; Mao, X.; Dowd, K.; Tsakanikas, D.; Jiang, C.S.; Meuser, C.; Andrews, R.D.; Lukic, A.S.; Lee, J.; Hampilos, N.; Shafiian, N.; Sano, M.; David Mozley, P.; Fillit, H.; McEwen, B.S.; Shungu, D.C.; Pereira, A.C. Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer’s disease. Brain, 2021, 144(12), 3742-3755.
[http://dx.doi.org/10.1093/brain/awab222] [PMID: 34145880]
[33]
Shin, C.Y.; Kim, H.S.; Cha, K.H.; Won, D.H.; Lee, J.Y.; Jang, S.W.; Sohn, U.D. The effects of donepezil, an acetylcholinesterase inhibitor, on impaired learning and memory in rodents. Biomol. Ther., 2018, 26(3), 274-281.
[http://dx.doi.org/10.4062/biomolther.2017.189] [PMID: 29463072]
[34]
Calabresi, P.; Ghiglieri, V.; Mazzocchetti, P.; Corbelli, I.; Picconi, B. Levodopa-induced plasticity: A double-edged sword in Parkinson’s disease? Philos. Trans. R. Soc. Lond. B Biol. Sci., 2015, 370(1672), 20140184.
[http://dx.doi.org/10.1098/rstb.2014.0184] [PMID: 26009763]
[35]
Bhalerao, A.; Sivandzade, F.; Archie, S.R.; Chowdhury, E.A.; Noorani, B.; Cucullo, L. In vitro modeling of the neurovascular unit: Advances in the field. Fluids Barriers CNS, 2020, 17(1), 22.
[http://dx.doi.org/10.1186/s12987-020-00183-7] [PMID: 32178700]
[36]
Perretta, G. Non-human primate models in neuroscience research. Scand. J. Lab. Anim. Sci., 2009, 36(1), 77-85.
[37]
Tello, J.A.; Williams, H.E.; Eppler, R.M.; Steinhilb, M.L.; Khanna, M. Animal models of neurodegenerative disease: Recent advances in fly highlight innovative approaches to drug discovery. Front. Mol. Neurosci., 2022, 15, 883358.
[http://dx.doi.org/10.3389/fnmol.2022.883358] [PMID: 35514431]
[38]
Vissers, M.F.J.M.; Heuberger, J.A.A.C.; Groeneveld, G.J. Targeting for success: Demonstrating proof-of-concept with mechanistic early phase clinical pharmacology studies for disease-modification in neurodegenerative disorders. Int. J. Mol. Sci., 2021, 22(4), 1615.
[http://dx.doi.org/10.3390/ijms22041615] [PMID: 33562713]
[39]
Rizzo, SJS; Crawley, J.N. Behavioral phenotyping assays for genetic mouse models of neurodevelopmental, neurodegenerative, and psychiatric disorders. Annu. Rev. Anim. Biosci., 2017, 5(1), 371-389.
[http://dx.doi.org/10.1146/annurev-animal-022516-022754] [PMID: 28199172]
[40]
Ruan, J.; Yao, Y. Behavioral tests in rodent models of stroke. Brain Hemorrhages, 2020, 1(4), 171-184.
[http://dx.doi.org/10.1016/j.hest.2020.09.001] [PMID: 34322665]
[41]
Korte, SM; De Boer, S.F. A robust animal model of state anxiety: Fear-potentiated behaviour in the elevated plus-maze. Eur. J. Pharmacol., 2003, 463(1-3), 163-175.
[http://dx.doi.org/10.1016/S0014-2999(03)01279-2] [PMID: 12600708]
[42]
Huang, P.; Zhang, M. Magnetic resonance imaging studies of neurodegenerative disease: From methods to translational research. Neurosci. Bull., 2023, 39(1), 99-112.
[http://dx.doi.org/10.1007/s12264-022-00905-x] [PMID: 35771383]
[43]
Chen, J.J. Functional MRI of brain physiology in aging and neurodegenerative diseases. Neuroimage, 2019, 187, 209-225.
[http://dx.doi.org/10.1016/j.neuroimage.2018.05.050] [PMID: 29793062]
[44]
Leuzy, A.; Chiotis, K.; Lemoine, L.; Gillberg, P.G.; Almkvist, O.; Rodriguez-Vieitez, E.; Nordberg, A. Tau PET imaging in neurodegenerative tauopathies—still a challenge. Mol. Psychiatry, 2019, 24(8), 1112-1134.
[http://dx.doi.org/10.1038/s41380-018-0342-8] [PMID: 30635637]
[45]
Ehrenberg, A.J. Relevance of biomarkers across different neurodegenerative diseases. Alzheimers Res. Ther., 2020, 12, 1-11.
[46]
Amartumur, S.; Nguyen, H.; Huynh, T.; Kim, T.S.; Woo, R.S.; Oh, E.; Kim, K.K.; Lee, L.P.; Heo, C. Neuropathogenesis-on-chips for neurodegenerative diseases. Nat. Commun., 2024, 15(1), 2219.
[http://dx.doi.org/10.1038/s41467-024-46554-8] [PMID: 38472255]
[47]
Rey, F.; Barzaghini, B.; Nardini, A.; Bordoni, M.; Zuccotti, G.V.; Cereda, C.; Raimondi, M.T.; Carelli, S. Advances in tissue engineering and innovative fabrication techniques for 3-D-structures: Translational applications in neurodegenerative diseases. Cells, 2020, 9(7), 1636.
[http://dx.doi.org/10.3390/cells9071636] [PMID: 32646008]
[48]
Pandey, S.; Jirásko, M.; Lochman, J.; Chvátal, A.; Dvorakova, MC; Kučera, R. iPSCs in neurodegenerative disorders: A unique platform for clinical research and personalized medicine. J. Pers. Med., 2022, 12(9), 1485.
[http://dx.doi.org/10.3390/jpm12091485] [PMID: 36143270]
[49]
Nwabufo, C.K.; Aigbogun, O.P. Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease. J. Neurol., 2022, 269(11), 5762-5786.
[http://dx.doi.org/10.1007/s00415-022-11267-9] [PMID: 35831620]
[50]
Obrador, E.; Salvador-Palmer, R.; López-Blanch, R.; Dellinger, R.W.; Estrela, J.M. NAD+ precursors and antioxidants for the treatment of amyotrophic lateral sclerosis. Biomedicines, 2021, 9(8), 1000.
[http://dx.doi.org/10.3390/biomedicines9081000] [PMID: 34440204]
[51]
Hubrecht, R.C.; Carter, E. The 3Rs and humane experimental technique: Implementing change. Animals, 2019, 9(10), 754.
[http://dx.doi.org/10.3390/ani9100754] [PMID: 31575048]
[52]
Domínguez-Oliva, A.; Hernández-Ávalos, I.; Martínez-Burnes, J.; Olmos-Hernández, A.; Verduzco-Mendoza, A.; Mota-Rojas, D. The importance of animal models in biomedical research: Current insights and applications. Animals, 2023, 13(7), 1223.
[http://dx.doi.org/10.3390/ani13071223] [PMID: 37048478]
[53]
Holm, A.; Hansen, S.N.; Klitgaard, H.; Kauppinen, S. Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases. RNA Biol., 2022, 19(1), 594-608.
[http://dx.doi.org/10.1080/15476286.2022.2066334] [PMID: 35482908]
[54]
Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative stress: A key modulator in neurodegenerative diseases. Molecules, 2019, 24(8), 1583.
[http://dx.doi.org/10.3390/molecules24081583] [PMID: 31013638]
[55]
Solana-Manrique, C.; Sánchez-Pérez, A.M.; Paricio, N.; Muñoz-Descalzo, S. Two- and three-dimensional in vitro models of Parkinson’s and Alzheimer’s diseases: State-of-the-art and applications. Int. J. Mol. Sci., 2025, 26(2), 620.
[http://dx.doi.org/10.3390/ijms26020620] [PMID: 39859333]
[56]
Masserdotti, G. Late onset Alzheimer’s disease: Modeling disease hallmarks via in vitro 3D iNeuron cultures. Signal Transduct. Target. Ther., 2024, 9(1), 284.
[http://dx.doi.org/10.1038/s41392-024-01999-7] [PMID: 39389939]
[57]
Balestri, W.; Sharma, R.; da Silva, V.A.; Bobotis, B.C.; Curle, A.J.; Kothakota, V.; Kalantarnia, F.; Hangad, M.V.; Hoorfar, M.; Jones, J.L.; Tremblay, M.È.; El-Jawhari, J.J.; Willerth, S.M.; Reinwald, Y. Modeling the neuroimmune system in Alzheimer’s and Parkinson’s diseases. J. Neuroinflammation, 2024, 21(1), 32.
[http://dx.doi.org/10.1186/s12974-024-03024-8] [PMID: 38263227]
[58]
Teli, P.; Kale, V.; Vaidya, A. Beyond animal models: Revolutionizing neurodegenerative disease modeling using 3D in vitro organoids, microfluidic chips, and bioprinting. Cell Tissue Res., 2023, 394(1), 75-91.
[http://dx.doi.org/10.1007/s00441-023-03821-2] [PMID: 37572163]

Rights & Permissions Print Cite
Article Metrics
Pdf icon 26
Html icon 2
Find your institution