Vitamin E therapy prevents the accumulation of congophilic amyloid plaques and neurofibrillary tangles in the hippocampus in a rat model of Alzheimer’s disease

Document Type : Original Article


1 Neuroscience Research Center, Department of Anatomy, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

2 Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran


Objective(s): Vitamin E may have beneficial effects on oxidative stress and Aβ-associated reactive oxygen species production in Alzheimer’s disease. But, the exact role of vitamin E as a treatment for Alzheimer’s disease pathogenesis still needs to be studied. Hence, we examined the therapeutic effects of vitamin E on the density of congophilic amyloid plaques and neurofibrillary tangles in rats’ hippocampi.
Materials and Methods: Wistar rats were randomly assigned to control (no drug treatment), sham scopolamine (3 mg/kg)+saline and Sham scopolamine+sesame oil groups, and three experimental groups that received scopolamine+vitamin E (25, 50, and 100 mg/kg/day) daily for 14 days after scopolamine injection. The rats’ brains were collected immediately following transcardial perfusion and fixed in 4% paraformaldehyde. Pathological brain alterations were monitored through Congo red and bielschowsky silver staining.
Results: Scopolamine treatment led to a significant increase in the density of congophilic amyloid plaques and neurofibrillary tangles in the hippocampus. IP injection of vitamin E in three doses (25, 50, and 100 mg/kg/day) significantly reversed the scopolamine-induced increase of the congophilic amyloid plaque density and density of neurofibrillary tangles in the hippocampus. Although vitamin E (25 and 50 mg/kg/day) doses were also effective, but a 100 mg/kg/day dose of vitamin E was more effective in the reduction of congophilic amyloid plaque and neurofibrillary tangle density.
Conclusion: Vitamin E could exert a therapeutic effect in the reduction of congophilic amyloid plaque and neurofibrillary tangle density in the hippocampus of scopolamine-treated rats and it is useful for Alzheimer’s disease.


1. Bright J, Hussain S, Dang V, Wright S, Cooper B, Byun T, et al. Human secreted tau increases amyloid-beta production. Neurobiol Aging 2015; 36:693-709.
2. Cai P, Fang SQ, Yang XL, Wu JJ, Liu QH, Hong H, et al. Rational design and multibiological profiling of novel donepezil–trolox hybrids against Alzheimer’s disease, with cholinergic, antioxidant, neuroprotective, and cognition enhancing properties. ACS Chem Neurosci 2017; 8:2496-2511.
3. Selkoe DJ. Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 2004; 6:1054-1061.
4. Huebbe P, Rimbach G. Apolipoprotein E genotype, vitamin E, and Alzheimer’s disease prevention. J Appl Bot Food Qual 2008; 82:69-75.
5. Ferreira IL, Resende R, Ferreiro E, Rego AC, Pereira CF. Multiple defects in energy metabolism in Alzheimer’s disease. Curr Drug Targets 2010; 11:1193-1206.
6. Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer’s disease. Med Princ Pract 2015; 24:1-10.
7. Klinkenberg I, Blokland A. The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev 2010; 34:1307-1350.
8. Kulshreshtha A, Piplani P. Ameliorative effects of amide derivatives of 1, 3, 4-thiadiazoles on scopolamine induced cognitive dysfunction. Eur J Med Chem 2016; 122:557-573.
9. Seifhosseini S, Jahanshahi M, Moghimi A, Aazami N-S. The effect of scopolamine on avoidance memory and hippocampal neurons in male Wistar rats. Basic and Clinical Neuroscience 2011; 3:9-15.
10. Chen C, Li XH, Zhang S, Tu Y, Wang YM, Sun HT. 7, 8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunction. Rejuvenation Res 2014; 17:249-254.
11. Hafez HS, Ghareeb DA, Saleh SR, Abady MM, El Demellawy MA, Hussien H, et al. Neuroprotective effect of ipriflavone against scopolamine-induced memory impairment in rats. Psychopharmacology 2017; 234:3037-3053.
12. Nikmahzar E, Jahanshahi M, Babakordi F. Ginkgo biloba extract decreases scopolamine-induced congophilic amyloid plaques accumulation in male rat’s brain. Jundishapur J Nat Pharm Prod 2018; 13:e69143.
13. Luan K, Rosales JL, Lee KY. Crosstalks between neurofibrillary tangles and amyloid plaque formation. Ageing Res Rev 2013; 12:174-181.
14. Chen Q, Du Y, Zhang K, Liang Z, Li J, Yu H, et al. Tau-Targeted multifunctional nanocomposite for combinational therapy of Alzheimer’s disease. ACS Nano 2018; 12:1321-1338.
15. Boutajangout A, Wisniewski T. Tau-based therapeutic approaches for Alzheimer’s disease-a mini-review. Gerontology 2014; 60:381-385.
16. Gouras GK, Olsson TT, Hansson O. β-amyloid peptides and amyloid plaques in Alzheimer’s Disease. Neurotherapeutics 2015; 12:3-11.
17. Findeis MA. The role of amyloid β peptide 42 in Alzheimer’s disease. Pharmacol Ther 2007; 116:266-286.
18. Gugliandolo A, Bramanti P, Mazzon E. Role of vitamin E in the treatment of Alzheimer’s disease: Evidence from animal models. Int J Mol Sci 2017; 18:2504.
19. Asadi E, Jahanshahi M, Golalipour MJ. Effect of vitamin E on oocytes apoptosis in nicotine-treated Mice. Iranian journal of basic medical sciences 2012; 15:880–884.
20. Adalier N, Parker H. Vitamin E, turmeric and saffron in treatment of Alzheimer’s disease. Antioxidants 2016; 5:40.
21. Yang Sg, Wang Wy, Ling Tj, Feng Y, Du Xt, Zhang X, et al. Alpha-tocopherol quinone inhibits beta-amyloid aggregation and cytotoxicity, disaggregates preformed fibrils and decreases the production of reactive oxygen species, NO and inflammatory cytokines. Neurochem Int 2010; 57:914-922.
22. Gaedicke S, Zhang X, Huebbe P, Boesch-Saadatmandi C, Lou Y, Wiswedel I, et al. Dietary vitamin E, brain redox status and expression of Alzheimer’s disease-relevant genes in rats. Br J Nutr 2009; 102:398-406.
23. Mangialasche F, Kivipelto M, Mecocci P, Rizzuto D, Palmer K, Winblad B, et al. High plasma levels of vitamin E forms and reduced Alzheimer’s disease risk in advanced age. J Alzheimers Dis 2010; 20:1029-1037.
24. Li FJ, Shen L, Ji HF. Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer’s disease: a meta-analysis. J Alzheimers Dis 2012; 31:253-258.
25. Farina N, Llewellyn D, Isaac MGEKN, Tabet N. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev 2017; 1:CD002854.
26. Grimm MO, Mett J, Hartmann T. The impact of vitamin E and other fat-soluble vitamins on Alzheimer´ s disease. Int J Mol Sci 2016; 17:1785-1803.
27. Rota C, Rimbach G, Minihane A-M, Stoecklin E, Barella L. Dietary vitamin E modulates differential gene expression in the rat hippocampus: potential implications for its neuroprotective properties. Nutr Neurosci 2005; 8:21-29.
28. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease Cooperative Study. N Engl J Med 1997; 336:1216-1222.
29. Klatte ET, Scharre DW, Nagaraja HN, Davis RA, Beversdorf DQ. Combination therapy of donepezil and vitamin E in Alzheimer disease. Alzheimer Dis Assoc Disord 2003; 17:113-116.
30. Fillenbaum GG, Kuchibhatla MN, Hanlon JT, Artz MB, Pieper CF, Schmader KE, et al. Dementia and Alzheimer’s disease in community-dwelling elders taking vitamin C and/or vitamin E. Ann Pharmacother 2005; 39:2009-2014.
31. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005; 352:2379-2388.
32. Kryscio RJ, Abner EL, Caban-Holt A, Lovell M, Goodman P, Darke AK, et al. Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADViSE). JAMA Neurol 2017; 74:567-573.
33. Giraldo E, Lloret A, Fuchsberger T, Viña J. Aβ and tau toxicities in Alzheimer’s are linked via oxidative stress-induced p38 activation: protective role of vitamin E. Redox Biol 2014; 2:873-877.
34. Boccardi V, Baroni M, Mangialasche F, Mecocci P. Vitamin E family: role in the pathogenesis and treatment of Alzheimer’s disease. Alzheimers Dement (N Y) 2016; 2:182-191.
35. Sayyahi A, Jahanshahi M, Amini H, Sepehri H. Vitamin E can compensate the density of M1 receptors in the hippocampus of scopolamine-treated rats. Folia Neuropathol 2018; 56:215-228.
36. Nikmahzar E, Jahanshahi M, Elyasi L, Saeidi M, Babakordi F, Bahlakeh G. Human chorionic gonadotropin attenuates amyloid-β plaques induced by streptozotocin in the rat brain by affecting cytochrome c-ir neuron density. Iran J Basic Med Sci 2019; 22:166-172.
37. Shi XM, Zhang H, Zhou ZJ, Ruan YY, Pang J, Zhang L, et al. Effects of safflower yellow on beta-amyloid deposition and activation of astrocytes in the brain of APP/PS1 transgenic mice. Biomed Pharmacother 2018; 98:553-565.
38. Bihaqi SW, Singh AP, Tiwari M. Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and Amyloid precursor protein (AβPP) expression in rat brain. Indian J Pharmacol 2012; 44:593–598.
39. Choi DY, Lee YJ, Lee SY, Lee YM, Lee HH, Choi IS, et al. Attenuation of scopolamine-induced cognitive dysfunction by obovatol. Arch Pharm Res 2012; 35:1279-1286.
40. Asadi Z, Jahanshahi M, Vaezi G, Hosseini SM. Effects of taurine on phosphorylated tau protein level in the hippocampus of scopolamine-treated adult male rats. J Mazandaran Univ Med Sci 2018; 28:152-157.
41. Sung S, Yao Y, Uryu K, Yang H, Lee VM, Trojanowski JQ, et al. Early vitamin E supplementation in young but not aged mice reduces Aβ levels and amyloid deposition in a transgenic model of Alzheimer’s disease. FASEB J 2004; 18:323-325.
42. Conte V, Uryu K, Fujimoto S, Yao Y, Rokach J, Longhi L, et al. Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury. J Neurochem 2004; 90:758-764.
43. Ali AA, Ahmed HI, Abu-Elfotuh K. The potential effect of epigallocatechin-3-gallate alone or in combination with vitamin E and selenium on Alzheimer’s disease induced by aluminum in rats. J Alzheimers Parkinsonism Dement 2016; 10:2.
44. Dong S, Huang X, Zhen J, Van Halm-Lutterodt N, Wang J, Zhou C, et al. Dietary vitamin E status dictates oxidative stress outcomes by modulating effects of fish oil supplementation in Alzheimer disease model APP swe/PS1 dE9 mice. Mol Neurobiol 2018; 55:9204-9219.
45. Harrison FE, Allard J, Bixler R, Usoh C, Li L, May JM, et al. Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice. Nutr Neurosci 2009; 12:203-218.
46. Nakashima H, Ishihara T, Yokota O, Terada S, Trojanowski JQ, Lee VMY, et al. Effects of α-tocopherol on an animal model of tauopathies. Free Radic Biol Med 2004; 37:176-186.
47. Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB. Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 2007; 117:236-245.