Approaches to experimental modeling of neuroinflammation in neurodegenerative diseases: part 1 — in vivo models

Given the increasing prevalence of the neurodegenerative diseases worldwide, the development of new methods for correction of neuroinflammation contributing to neurodegenerative diseases is a highly relevant and important issue in the field of biomedical research. Neuroinflammation experimental models are essential tools for developing novel therapies for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis sclerosis (ALS), epilepsy, and depression. Currently used models can generally be divided into in vitro and in vivo models or according to the method of action on the body – on chemical (exposure to neurotoxins and endogenous substances), genetic (transgenic and knockout animals), physical (injury, stress). Each of these experimental paradigms reproduce neuroinflammation in one aspect and not able to provide a complete picture of this complex process. Another problem is a lack of congruity between experimental model and clinical trials due to an unsuitable choice of the model, its unreliability or experiment conditions. This prevents the search of effective solutions for neurodegenerative disease treatment. Therefore, the current review aims to summarize the different experimental paradigms used to reproduce neuroinflammation and its main strengths and weaknesses, helping to choose the model that better suits each specific research aim.

1. Mayne K, White JA, McMurran CE, et al. Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe? Front Aging Neurosci. 2020 Sep 23;12:572090. doi: 10.3389/fnagi.2020.572090.

2. Shi Q, Chowdhury S, Ma R, et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017 May 31;9(392):eaaf6295. doi: 10.1126/scitranslmed.aaf6295.

3. Zhang W, Xiao D, Mao Q, Xia H. Role of neuroinflammation in neurodegeneration development. Signal Transduct Target Ther. 2023 Jul 12;8(1):267. doi: 10.1038/s41392-023-01486-5.

4. Krstic D, Madhusudan A, Doehner J, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation. 2012 Jul 2;9:151. doi: 10.1186/1742-2094-9-151.

5. Nazem A, Sankowski R, Bacher M, Al-Abed Y. Rodent models of neuroinflammation for Alzheimer's disease. J Neuroinflammation. 2015 Apr 17;12:74. doi: 10.1186/s12974-015-0291-y.

6. Guerreiro R, Wojtas A, Bras J, et al; Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. doi: 10.1056/NEJMoa1211851.

7. Naj AC, Jun G, Beecham GW, et al. Common variants at MS4A4/ MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011 May;43(5):436-41. doi: 10.1038/ng.801.

8. Saxena S, Kruys V, Vamecq J, Maze M. The Role of Microglia in Perioperative Neuroinflammation and Neurocognitive Disorders. Front Aging Neurosci. 2021 May 28;13:671499. doi: 10.3389/fnagi.2021.671499.

9. Kuzmin EA, Shamitko ZV, Piavchenko GA, et al. Biomarkers of neuroinflammation in the diagnosis of traumatic brain injury and neurodegenerative diseases: a literature review. Sechenov Medical Journal. 2024;15(1):20-35. (In Russ.). doi: 10.47093/2218-7332.2024.15.1.20-35.

10. Olanrewaju AA, Hakami RM. The Messenger Apps of the cell: Extracellular Vesicles as Regulatory Messengers of Microglial Function in the CNS. J Neuroimmune Pharmacol. 2020 Sep;15(3):473-486. doi: 10.1007/s11481-020-09916-9.

11. Rapaka D, Adiukwu PC, Bitra VR. Experimentally induced animal models for cognitive dysfunction and Alzheimer's disease. MethodsX. 2022 Nov 24;9:101933. doi: 10.1016/j.mex.2022.101933.

12. Mostafavinia A, Amini A, Ghorishi SK, et al. The effects of dosage and the routes of administrations of streptozotocin and alloxan on induction rate of type1 diabetes mellitus and mortality rate in rats. Lab Anim Res. 2016 Sep;32(3):160-165. doi: 10.5625/lar.2016.32.3.160.

13. Kamat PK. Streptozotocin induced Alzheimer's disease like changes and the underlying neural degeneration and regeneration mechanism. Neural Regen Res. 2015 Jul;10(7):1050-2. doi: 10.4103/1673-5374.160076.

14. Kadhim HJ, Al-Mumen H, Nahi HH, Hamidi SM. Streptozotocininduced Alzheimer's disease investigation by one-dimensional plasmonic grating chip. Sci Rep. 2022 Dec 19;12(1):21878. doi: 10.1038/s41598-022-26607-y.

15. Ravelli KG, Rosário BD, Camarini R, et al. Intracerebroventricular Streptozotocin as a Model of Alzheimer's Disease: Neurochemical and Behavioral Characterization in Mice. Neurotox Res. 2017 Apr;31(3):327-333. doi: 10.1007/s12640-016-9684-7.

16. Noor NA, Hosny EN, Khadrawy YA, et al. Effect of curcumin nanoparticles on streptozotocin-induced male Wistar rat model of Alzheimer's disease. Metab Brain Dis. 2022 Feb;37(2):343-357. doi: 10.1007/s11011-021-00897-z.

17. Dhapola R, Sarma P, Medhi B, et al. Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease. Mol Neurobiol. 2022 Jan;59(1):535-555. doi: 10.1007/s12035-021-02612-6.

18. Yılmaz ŞG, Almasri S, Karabulut YY, et al. Okadaic Acid-Induced Alzheimer's in Rat Brain: Phytochemical Cucurbitacin E Contributes to Memory Gain by Reducing TAU Protein Accumulation. OMICS. 2023 Jan;27(1):34-44. doi: 10.1089/omi.2022.0175.

19. Neha, Sodhi RK, Jaggi AS, Singh N. Animal models of dementia and cognitive dysfunction. Life Sci. 2014 Jul 30;109(2):73-86. doi: 10.1016/j.lfs.2014.05.017.

20. Xu AH, Yang Y, Sun YX, Zhang CD. Exogenous brain-derived neurotrophic factor attenuates cognitive impairment induced by okadaic acid in a rat model of Alzheimer's disease. Neural Regen Res. 2018 Dec;13(12):2173-2181. doi: 10.4103/1673-5374.241471.

21. Nasiripour S, Zamani F, Farasatinasab M. Can Colchicine as an Old Anti-Inflammatory Agent Be Effective in COVID-19? J Clin Pharmacol. 2020 Jul;60(7):828-829. doi: 10.1002/jcph.1645.

22. Bakhta O, Blanchard S, Guihot AL, et al. Cardioprotective Role of Colchicine Against Inflammatory Injury in a Rat Model of Acute Myocardial Infarction. J Cardiovasc Pharmacol Ther. 2018 Sep;23(5):446-455. doi: 10.1177/1074248418763611.

23. Sil S, Ghosh T. Role of cox-2 mediated neuroinflammation on the neurodegeneration and cognitive impairments in colchicine induced rat model of Alzheimer's Disease. J Neuroimmunol. 2016 Feb 15;291:115-24. doi: 10.1016/j.jneuroim.2015.12.003.

24. Kumar A, Seghal N, Naidu PS, et al. Colchicines-induced neurotoxicity as an animal model of sporadic dementia of Alzheimer's type. Pharmacol Rep. 2007 May-Jun;59(3):274-83.

25. Ganguly R, Guha D. Alteration of brain monoamines & EEG wave pattern in rat model of Alzheimer's disease & protection by Moringa oleifera. Indian J Med Res. 2008 Dec;128(6):744-51.

26. Saini N, Singh D, Sandhir R. Bacopa monnieri prevents colchicineinduced dementia by anti-inflammatory action. Metab Brain Dis. 2019 Apr;34(2):505-518. doi: 10.1007/s11011-018-0332-1.

27. da Silva AAF, Fiadeiro MB, Bernardino LI, et al. "Lipopolysaccharideinduced animal models for neuroinflammation - An overview". J Neuroimmunol. 2024 Feb 15;387:578273. doi: 10.1016/j.jneuroim.2023.578273.

28. Skrzypczak-Wiercioch A, Sałat K. Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use. Molecules. 2022 Aug 26;27(17):5481. doi: 10.3390/molecules27175481.

29. Lehnardt S, Massillon L, Follett P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9. doi: 10.1073/pnas.1432609100.

30. Li R, Zhou Y, Zhang S, et al. The natural (poly)phenols as modulators of microglia polarization via TLR4/NF-κB pathway exert anti-inflammatory activity in ischemic stroke. Eur J Pharmacol. 2022 Jan 5;914:174660. doi: 10.1016/j.ejphar.2021.174660.

31. Seemann S, Zohles F, Lupp A. Comprehensive comparison of three different animal models for systemic inflammation. J Biomed Sci. 2017 Aug 24;24(1):60. doi: 10.1186/s12929-017-0370-8.

32. Sanfeliu C, Bartra C, Suñol C, Rodríguez-Farré E. New insights in animal models of neurotoxicity-induced neurodegeneration. Front Neurosci. 2024 Jan 8;17:1248727. doi: 10.3389/fnins.2023.1248727.

33. de Oliveira AC, Yousif NM, Bhatia HS, et al. Poly(I:C) increases the expression of mPGES-1 and COX-2 in rat primary microglia. J Neuroinflammation. 2016 Jan 18;13:11. doi: 10.1186/s12974-015-0473-7.

34. Steer SA, Moran JM, Christmann BS, et al. Role of MAPK in the regulation of double-stranded RNA- and encephalomyocarditis virus-induced cyclooxygenase-2 expression by macrophages. J Immunol. 2006 Sep 1;177(5):3413-20. doi: 10.4049/jimmunol.177.5.3413.

35. Budni J, de Oliveira J. Amyloid beta 1–42-induced animal model of dementia: a review. In: Martin CR, Preedy VR, editors. The Neuroscience of Dementia. Academic Press; 2020. p. 865-880. doi: 10.1016/B978-0-12-815868-5.00054-2.

36. Kubo T, Nishimura S, Kumagae Y, Kaneko I. In vivo conversion of racemized beta-amyloid ([D-Ser 26]A beta 1-40) to truncated and toxic fragments ([D-Ser 26]A beta 25-35/40) and fragment presence in the brains of Alzheimer's patients. J Neurosci Res. 2002 Nov 1;70(3):474-83. doi: 10.1002/jnr.10391.

37. Zhang S, Wang P, Ren L, et al. Protective effect of melatonin on soluble Aβ1-42-induced memory impairment, astrogliosis, and synaptic dysfunction via the Musashi1/Notch1/Hes1 signaling pathway in the rat hippocampus. Alzheimers Res Ther. 2016 Sep 15;8(1):40. doi: 10.1186/s13195-016-0206-x.

38. Samant NP, Gupta GL. Avicularin Attenuates Memory Impairment in Rats with Amyloid Beta-Induced Alzheimer's Disease. Neurotox Res. 2022 Feb;40(1):140-153. doi: 10.1007/s12640-021-00467-2.

39. Shi R, Page JC, Tully M. Molecular mechanisms of acrolein-mediated myelin destruction in CNS trauma and disease. Free Radic Res. 2015;49(7):888-95. doi: 10.3109/10715762.2015.1021696.

40. Liu-Snyder P, McNally H, Shi R, Borgens RB. Acrolein-mediated mechanisms of neuronal death. J Neurosci Res. 2006 Jul;84(1):209-18. doi: 10.1002/jnr.20863.

41. Takano K, Ogura M, Yoneda Y, Nakamura Y. Oxidative metabolites are involved in polyamine-induced microglial cell death. Neuroscience. 2005;134(4):1123-31. doi: 10.1016/j.neuroscience.2005.05.014.

42. Jia Z, Zhu H, Li Y, Misra HP. Cruciferous nutraceutical 3H-1,2-dithiole-3-thione protects human primary astrocytes against neurocytotoxicity elicited by MPTP, MPP(+), 6-OHDA, HNE and acrolein. Neurochem Res. 2009 Nov;34(11):1924-34. doi: 10.1007/s11064-009-9978-8.

43. Wang YT, Lin HC, Zhao WZ, et al. Acrolein acts as a neurotoxin in the nigrostriatal dopaminergic system of rat: involvement of synuclein aggregation and programmed cell death. Sci Rep. 2017 Apr 12;7:45741. doi: 10.1038/srep45741.

44. Chen C, Lu J, Peng W, et al. Acrolein, an endogenous aldehyde induces Alzheimer's disease-like pathologies in mice: A new sporadic AD animal model. Pharmacol Res. 2022 Jan;175:106003. doi: 10.1016/j.phrs.2021.106003.

45. Huang YJ, Jin MH, Pi RB, et al. Acrolein induces Alzheimer's diseaselike pathologies in vitro and in vivo. Toxicol Lett. 2013 Mar 13;217(3):184-91. doi: 10.1016/j.toxlet.2012.12.023.

46. Rashedinia M, Lari P, Abnous K, Hosseinzadeh H. Protective effect of crocin on acrolein-induced tau phosphorylation in the rat brain. Acta Neurobiol Exp (Wars). 2015;75(2):208-19. doi: 10.55782/ane-2015-2029.

47. Li L, Jiang L, Geng C, et al. The role of oxidative stress in acroleininduced DNA damage in HepG2 cells. Free Radic Res. 2008 Apr;42(4):354-61. doi: 10.1080/10715760802008114.

48. Daroi PA, Dhage SN, Juvekar AR. p-Coumaric acid protects against D-galactose induced neurotoxicity by attenuating neuroinflammation and apoptosis in mice brain. Metab Brain Dis. 2022 Oct;37(7):2569-2579. doi: 10.1007/s11011-022-01007-3.

49. Chen P, Chen F, Zhou BH. Leonurine ameliorates D-galactose-induced aging in mice through activation of the Nrf2 signalling pathway. Aging (Albany NY). 2019 Sep 17;11(18):7339-7356. doi: 10.18632/aging.101733.

50. Ahmad A, Ali T, Rehman SU, Kim MO. Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment. J Clin Med. 2019 Jun 14;8(6):850. doi: 10.3390/jcm8060850.

51. Lu J, Wu DM, Zheng YL, et al. Purple sweet potato color alleviates D-galactose-induced brain aging in old mice by promoting survival of neurons via PI3K pathway and inhibiting cytochrome C-mediated apoptosis. Brain Pathol. 2010 May;20(3):598-612. doi: 10.1111/j.1750-3639.2009.00339.x.

52. Ko SY, Ko HA, Chu KH, et al. The Possible Mechanism of Advanced Glycation End Products (AGEs) for Alzheimer's Disease. PLoS One. 2015 Nov 20;10(11):e0143345. doi: 10.1371/journal.pone.0143345.

53. Villa M, Parravano M, Micheli A, et al. A quick, simple method for detecting circulating fluorescent advanced glycation end-products: Correlation with in vitro and in vivo non-enzymatic glycation. Metabolism. 2017 Jun;71:64-69. doi: 10.1016/j.metabol.2017.03.004.

54. Li W, Wang S, Wang H, Wang J, Jin F, Fang F, Fang C. Astragaloside IV Prevents Memory Impairment in D-galactose-induced Aging Rats Via the AGEs/RAGE/ NF-B Axis. Arch Med Res. 2022 Jan;53(1):20-28. doi: 10.1016/j.arcmed.2021.05.005.

55. Rehman SU, Shah SA, Ali T, et al. Anthocyanins Reversed D-Galactose-Induced Oxidative Stress and Neuroinflammation Mediated Cognitive Impairment in Adult Rats. Mol Neurobiol. 2017 Jan;54(1):255-271. doi: 10.1007/s12035-015-9604-5.

56. Lu J, Zheng YL, Wu DM, et al. Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. Biochem Pharmacol. 2007 Oct 1;74(7):1078-90. doi: 10.1016/j.bcp.2007.07.007.

57. Tsai SJ, Chiu CP, Yang HT, Yin MC. s-Allyl cysteine, s-ethyl cysteine, and s-propyl cysteine alleviate amyloid, glycative, and oxidative injury in brain of mice treated by D-galactose. J Agric Food Chem. 2011 Jun 8;59(11):6319-26. doi: 10.1021/jf201160a.

58. Chowdhury AA, Gawali NB, Bulani VD, et al. In vitro antiglycating effect and in vivo neuroprotective activity of Trigonelline in d-galactose induced cognitive impairment. Pharmacol Rep. 2018 Apr;70(2):372-377. doi: 10.1016/j.pharep.2017.09.006.

59. Hong XP, Chen T, Yin NN, et al. Puerarin Ameliorates D-Galactose Induced Enhanced Hippocampal Neurogenesis and Tau Hyperphosphorylation in Rat Brain. J Alzheimers Dis. 2016;51(2):605-17. doi: 10.3233/JAD-150566.