Neuroscience Bulletin

, Volume 35, Issue 2, pp 325–335 | Cite as

Folate/Vitamin B Alleviates Hyperhomocysteinemia-Induced Alzheimer-Like Pathologies in Rat Retina

  • Jing Guo
  • Shaozhou Ni
  • Qihang Li
  • Jian-Zhi WangEmail author
  • Ying YangEmail author
Original Article


Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer’s disease (AD). Visual dysfunction is commonly found and is positively correlated with the severity of cognitive defects in AD patients. Our previous study demonstrated that Hhcy induces memory deficits with AD-like tau and amyloid-β (Aβ) pathologies in the hippocampus, and supplementation with folate and vitamin B12 (FB) prevents the Hhcy-induced AD-like pathologies in the hippocampus. Here, we investigated whether Hhcy also induces AD-like pathologies in the retina and the effects of FB. An Hhcy rat model was produced by vena caudalis injection of homocysteine for 14 days, and the effects of FB were assessed by simultaneous supplementation with FB in drinking water. We found that Hhcy induced vessel damage with Aβ and tau pathologies in the retina, while simultaneous supplementation with FB remarkably attenuated the Hhcy-induced tau hyperphosphorylation at multiple AD-related sites and Aβ accumulation in the retina. The mechanisms involved downregulation of amyloid precursor protein (APP), presenilin-1, beta-site APP-cleaving enzyme 1, and protein phosphatase-2A. Our data suggest that the retina may serve as a window for evaluating the effects of FB on hyperhomocysteinemia-induced Alzheimer-like pathologies.


Hyperhomocysteinemia Alzheimer’s disease Retina Folate Vitamin B12 



We thank Prof. Xiangtian Zhou of the School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College, China, for technical support. This work was supported in part by the Natural Science Foundation of China (91632305, 91632111, 31730035, and 81721005), and by the Ministry of Science and Technology of China (2016YFC1305800).

Compliance with Ethical Standards

Conflict of interest

The authors declare no competing interests.

Supplementary material

12264_2018_293_MOESM1_ESM.pdf (120 kb)
Supplementary material 1 (PDF 121 kb)


  1. 1.
    Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, et al. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 2007, 14: e1–26.CrossRefGoogle Scholar
  2. 2.
    Wang QH, Wang X, Bu XL, Lian Y, Xiang Y, Luo HB, et al. Comorbidity burden of dementia: a hospital-based retrospective study from 2003 to 2012 in seven cities in china. Neurosci Bull 2017, 33: 703–710.CrossRefGoogle Scholar
  3. 3.
    Hardy J. A hundred years of Alzheimer’s disease research. Neuron 2006, 52: 3–13.CrossRefGoogle Scholar
  4. 4.
    Mendes D, Oliveira MM, Moreira PI, Coutinho J, Nunes FM, Pereira DM, et al. Beneficial effects of white wine polyphenols-enriched diet on Alzheimer’s disease-like pathology. J Nutr Biochem 2018, 55: 165–177.CrossRefGoogle Scholar
  5. 5.
    Sun BL, Li WW, Zhu C, Jin WS, Zeng F, Liu YH, et al. Clinical research on Alzheimer’s disease: progress and perspectives. Neurosci Bull 2018. Scholar
  6. 6.
    Archibald NK, Clarke MP, Mosimann UP, Burn DJ. The retina in Parkinson’s disease. Brain 2009, 132: 1128–1145.CrossRefGoogle Scholar
  7. 7.
    Calabresi PA, Balcer LJ, Frohman EM. Retinal pathology in multiple sclerosis: insight into the mechanisms of neuronal pathology. Brain 2010, 133: 1575–1577.CrossRefGoogle Scholar
  8. 8.
    Ong YT, De Silva DA, Cheung CY, Chang HM, Chen CP, Wong MC, et al. Microvascular structure and network in the retina of patients with ischemic stroke. Stroke 2013, 44: 2121–2127.CrossRefGoogle Scholar
  9. 9.
    Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MK, Black KL, et al. Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage 2011, 54 Suppl 1: S204–217.CrossRefGoogle Scholar
  10. 10.
    La Morgia C, Ross-Cisneros FN, Koronyo Y, Hannibal J, Gallassi R, Cantalupo G, et al. Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann Neurol 2016, 79: 90–109.CrossRefGoogle Scholar
  11. 11.
    Hart NJ, Koronyo Y, Black KL, Koronyo-Hamaoui M. Ocular indicators of Alzheimer’s: exploring disease in the retina. Acta Neuropathol 2016, 132: 767–787.CrossRefGoogle Scholar
  12. 12.
    Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002, 346: 476–483.CrossRefGoogle Scholar
  13. 13.
    Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998, 55: 1449–1455.CrossRefGoogle Scholar
  14. 14.
    Hooshmand B, Solomon A, Kareholt I, Leiviska J, Rusanen M, Ahtiluoto S, et al. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology 2010, 75: 1408–1414.CrossRefGoogle Scholar
  15. 15.
    Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005, 82: 636–643.CrossRefGoogle Scholar
  16. 16.
    Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev 2003, 8: 7–19.Google Scholar
  17. 17.
    Ho PI, Ortiz D, Rogers E, Shea TB. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res 2002, 70: 694–702.CrossRefGoogle Scholar
  18. 18.
    Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, et al. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 2006, 107: 591–593.CrossRefGoogle Scholar
  19. 19.
    Pacheco-Quinto J, Rodriguez de Turco EB, DeRosa S, Howard A, Cruz-Sanchez F, Sambamurti K, et al. Hyperhomocysteinemic Alzheimer’s mouse model of amyloidosis shows increased brain amyloid beta peptide levels. Neurobiol Dis 2006, 22: 651–656.CrossRefGoogle Scholar
  20. 20.
    Zhang CE, Wei W, Liu YH, Peng JH, Tian Q, Liu GP, et al. Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am J Pathol 2009, 174: 1481–1491.CrossRefGoogle Scholar
  21. 21.
    Zhang CE, Tian Q, Wei W, Peng JH, Liu GP, Zhou XW, et al. Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus. Neurobiol Aging 2008, 29: 1654–1665.CrossRefGoogle Scholar
  22. 22.
    Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001, 345: 1593–1600.CrossRefGoogle Scholar
  23. 23.
    Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003, 26: 137–146.CrossRefGoogle Scholar
  24. 24.
    Sasaki K, Duan J, Murohara T, Ikeda H, Shintani S, Shimada T, et al. Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation. J Am Coll Cardiol 2003, 42: 364–372.CrossRefGoogle Scholar
  25. 25.
    Gupta SK, Kumar B, Nag TC, Agrawal SS, Agrawal R, Agrawal P, et al. Curcumin prevents experimental diabetic retinopathy in rats through its hypoglycemic, antioxidant, and anti-inflammatory mechanisms. J Ocul Pharmacol Ther 2011, 27: 123–130.CrossRefGoogle Scholar
  26. 26.
    Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012, 9: 671–675.CrossRefGoogle Scholar
  27. 27.
    Brion JP, Couck AM, Conreur JL. Calcineurin (phosphatase 2B) is present in neurons containing neurofibrillary tangles and in a subset of senile plaques in Alzheimer’s disease. Neurodegeneration 1995, 4: 13–21.CrossRefGoogle Scholar
  28. 28.
    Minthon L, Hesse C, Sjogren M, Englund E, Gustafson L, Blennow K. The apolipoprotein E epsilon4 allele frequency is normal in fronto-temporal dementia, but correlates with age at onset of disease. Neurosci Lett 1997, 226: 65–67.CrossRefGoogle Scholar
  29. 29.
    Takahashi M, Tsujioka Y, Yamada T, Tsuboi Y, Okada H, Yamamoto T, et al. Glycosylation of microtubule-associated protein tau in Alzheimer’s disease brain. Acta Neuropathol 1999, 97: 635–641.CrossRefGoogle Scholar
  30. 30.
    Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E. Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 1993, 11: 153–163.CrossRefGoogle Scholar
  31. 31.
    Vincent IJ, Davies P. Phosphorylation characteristics of the A68 protein in Alzheimer’s disease. Brain Res 1990, 531: 127–135.CrossRefGoogle Scholar
  32. 32.
    Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 2008, 85: 148–175.CrossRefGoogle Scholar
  33. 33.
    Liu Y, Su Y, Wang J, Sun S, Wang T, Qiao X, et al. Rapamycin decreases tau phosphorylation at Ser214 through regulation of cAMP-dependent kinase. Neurochem Int 2013, 62: 458–467.CrossRefGoogle Scholar
  34. 34.
    Collin L, Bohrmann B, Gopfert U, Oroszlan-Szovik K, Ozmen L, Gruninger F. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 2014, 137: 2834–2846.CrossRefGoogle Scholar
  35. 35.
    Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 2011, 10: 698–712.CrossRefGoogle Scholar
  36. 36.
    Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 2014, 88: 640–651.CrossRefGoogle Scholar
  37. 37.
    Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, et al. Tramiprosate in mild-to-moderate Alzheimer’s disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 2011, 7: 102–111.CrossRefGoogle Scholar
  38. 38.
    Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014, 370: 311–321.CrossRefGoogle Scholar
  39. 39.
    Golde TE, Schneider LS, Koo EH. Anti-abeta therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron 2011, 69: 203–213.CrossRefGoogle Scholar
  40. 40.
    Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009, 302: 2557–2564.CrossRefGoogle Scholar
  41. 41.
    McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry 1998, 13: 235–239.CrossRefGoogle Scholar
  42. 42.
    Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 2006, 580: 2994–3005.CrossRefGoogle Scholar
  43. 43.
    Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem 1990, 1: 228–237.CrossRefGoogle Scholar
  44. 44.
    Sontag JM, Nunbhakdi-Craig V, Montgomery L, Arning E, Bottiglieri T, Sontag E. Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation. J Neurosci 2008, 28: 11477–11487.CrossRefGoogle Scholar
  45. 45.
    Troen AM, Shukitt-Hale B, Chao W-H, Albuquerque B, Smith DE, Selhub J, et al. The cognitive impact of nutritional homocysteinemia in Apolipoprotein-E deficient mice. J Alzheimers Dis 2006, 9: 381–392.CrossRefGoogle Scholar
  46. 46.
    Ong SS, Doraiswamy PM, Lad EM. Controversies and future directions of ocular biomarkers in Alzheimer disease. JAMA Neurol 2018, 75: 650–651.CrossRefGoogle Scholar
  47. 47.
    Ascaso FJ, Cruz N, Modrego PJ, Lopez-Anton R, Santabarbara J, Pascual LF, et al. Retinal alterations in mild cognitive impairment and Alzheimer’s disease: an optical coherence tomography study. J Neurol 2014, 261: 1522–1530.CrossRefGoogle Scholar
  48. 48.
    Koronyo Y, Biggs D, Barron E, Boyer DS, Pearlman JA, Au WJ, et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease. JCI Insight 2017, 2.Google Scholar
  49. 49.
    Ho CY, Troncoso JC, Knox D, Stark W, Eberhart CG. Beta-amyloid, phospho-tau and alpha-synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer’s and Parkinson’s disease patients. Brain Pathol 2014, 24: 25–32.CrossRefGoogle Scholar
  50. 50.
    Regland B, Abrahamsson L, Gottfries CG, Magnus E. Vitamin B12 analogues, homocysteine, methylmalonic acid, and transcobalamins in the study of vitamin B12 deficiency in primary degenerative dementia. Dement Geriatr Cogn Disord 1990, 1: 272–277.CrossRefGoogle Scholar
  51. 51.
    Shu XJ, Li ZF, Chang YW, Liu SY, Wang WH, Li X. Different doses of folic acid and vitamin B12 to treat rabbits with deep venous thrombosis and hyperhomocysteinemia. Exp Ther Med 2018, 15: 2874–2878.Google Scholar
  52. 52.
    Guilliams TG. Homocysteine - a risk factor for vascular diseases: guidelines for the clinical practice. JANA 2004, 7: 11–24.Google Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory for Neurological Disorders of the Ministry of Education of China, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Co-innovation Center of NeuroregenerationNantong UniversityNantongChina
  3. 3.Emergency DepartmentZhongnan Hospital of Wuhan UniversityWuhanChina
  4. 4.School of Optometry and Ophthalmology and Eye HospitalWenzhou Medical CollegeWenzhouChina

Personalised recommendations