Abstract
The present study aimed to evaluate the effect of folic acid treatment in an animal model of aging induced by D-galactose (D-gal). For this propose, adult male Wistar rats received D-gal intraperitoneally (100 mg/kg) and/or folic acid orally (5 mg/kg, 10 mg/kg or 50 mg/kg) for 8 weeks. D-gal caused habituation memory impairment, and folic acid (10 mg/kg and 50 mg/kg) reversed this effect. However, folic acid 50 mg/kg per se caused habituation memory impairment. D-gal increased the lipid peroxidation and oxidative damage to proteins in the prefrontal cortex and hippocampus from rats. Folic acid (5 mg/kg, 10 mg/kg, or 50 mg/kg) partially reversed the oxidative damage to lipids in the hippocampus, but not in the prefrontal cortex, and reversed protein oxidative damage in the prefrontal cortex and hippocampus. D-gal induced synaptophysin and BCL-2 decrease in the hippocampus and phosphorylated tau increase in the prefrontal cortex. Folic acid was able to reverse these D-gal-related alterations in the protein content. The present study shows folic acid supplementation as an alternative during the aging to prevent cognitive impairment and brain alterations that can cause neurodegenerative diseases. However, additional studies are necessary to elucidate the effect of folic acid in aging.
Similar content being viewed by others
References
Agnew-Blais JC, Wassertheil-Smoller S, Kang JH, Hogan PE, Coker LH et al (2015) Folate, vitamin B6 and vitamin B12 intake and mild cognitive impairment and probable dementia in the women’s health initiative memory study. J Acad Nutr Diet 115:231–241. https://doi.org/10.1016/j.jand.2014.07.006
Amin J, Paquet C, Baker A, Asuni AA, Love S et al (2015) Effect of amyloid-beta (Abeta) immunization on hyperphosphorylated tau: a potential role for glycogen synthase kinase (GSK)-3beta. Neuropathol Appl Neurobiol 41:445–457. https://doi.org/10.1111/nan.12205
Anderson CAM, Jee SH, Charleston J, Narrett M, Appel LJ (2010) Effects of folic acid supplementation on serum folate and plasma homocysteine concentrations in older adults: a dose-response trial. Am J Epidemiol 172:932–941. https://doi.org/10.1093/aje/kwq197
Apostolova LG, Green AE, Babakchanian S, Hwang KS, Chou YY et al (2012) Hippocampal atrophy and ventricular enlargement in normal aging, mild cognitive impairment (MCI), and Alzheimer disease. Alzheimer Dis Assoc Disord 26:17–27. https://doi.org/10.1097/WAD.0b013e3182163b62
Araújo JR, Martel F, Borges N, Araújo JM, Keating E (2015) Folates and aging: role in mild cognitive impairment, dementia and depression. Ageing Res Rev 22:9–19. https://doi.org/10.1016/j.arr.2015.04.005
Avramut M, Achim CL (2003) Immunophilins in nervous system degeneration and regeneration. Curr Top Med Chem 3:1376–1382. https://doi.org/10.2174/1568026033451871
Bartsch T, Schönfeld R, Müller FJ, Alfke K, Leplow B et al (2010) Focal lesions of human hippocampal CA1 neurons in transient global amnesia impair place memory. Science 328:1412–1415. https://doi.org/10.1126/science.1188160
Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535. https://doi.org/10.1038/nature08983
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. https://doi.org/10.1007/s00401-006-0127-z
Budni J, Zomkowski AD, Engel D, Santos DB, dos Santos AA et al (2013) Folic acid prevents depressive-like behavior and hippocampal antioxidant imbalance induced by restraint stress in mice. Exp Neurol 240:112–121. https://doi.org/10.1016/j.expneurol.2012.10.024
Budni J, Pacheco R, da Silva S, Garcez ML, Mina F et al (2015) Oral administration of d-galactose induces cognitive impairments and oxidative damage in rats. Behav Brain Res 302:35–43. https://doi.org/10.1016/j.bbr.2015.12.041
Burke SN, Foster TC (2019) Chapter 2 - animal models of cognitive aging and circuit-specific vulnerability. In: Dekosky ST, Asthana S (eds) Handbook of clinical neurology, vol 167. Elsevier, pp 19-36. https://doi.org/10.1016/B978-0-12-804766-8.00002-9
Cacciapuoti F (2013) Lowering homocysteine levels with folic acid and B-vitamins do not reduce early atherosclerosis, but could interfere with cognitive decline and Alzheimer’s disease. J Thromb Thrombolysis 36:258–262. https://doi.org/10.1007/s11239-012-0856-x
Collaboration HLT (1998) Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 316:894–898
Conti V, Izzo V, Corbi G, Russomanno G, Manzo V, de Lise F, di Donato A, Filippelli A (2016) Antioxidant supplementation in the treatment of aging-associated diseases. Front Pharmacol 7:24. https://doi.org/10.3389/fphar.2016.00024
Cui X, Zuo P, Zhang Q, Li X, Hu Y et al (2006) Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. J Neurosci Res 84:647–654. https://doi.org/10.1002/jnr.20899
Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431
Eussen SJ, de Groot LC, Joosten LW, Bloo RJ, Clarke R et al (2006) Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr 84:361–370
Farooqui AA, Horrocks LA (2006) Phospholipase A2-generated lipid mediators in the brain: the good, the bad, and the ugly. Neuroscientist 12:245–260. https://doi.org/10.1177/1073858405285923
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ et al (2009) One-year brain atrophy evident in healthy aging. J Neurosci 29:15223–15231. https://doi.org/10.1523/jneurosci.3252-09.2009
Gao J, Zhou R, You X, Luo F, He H et al (2016) Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer's disease via SIRT1/NF-kappaB pathway. Metab Brain Dis 31:771–778. https://doi.org/10.1007/s11011-016-9813-2
Garcez ML, de Carvalho CA, Mina F, Bellettini-Santos T, Schiavo GL et al (2018) Sodium butyrate improves memory and modulates the activity of histone deacetylases in aged rats after the administration of d-galactose. Exp Gerontol 113:209–217. https://doi.org/10.1016/j.exger.2018.10.005
Girotto F, Scott L, Avchalumov Y, Harris J, Iannattone S, Drummond-Main C, Tobias R, Bello-Espinosa L, Rho JM, Davidsen J, Teskey GC, Colicos MA (2013) High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring. Sci Rep 3:1465. https://doi.org/10.1038/srep01465
Gordon SL, Harper CB, Smillie KJ, Cousin MA (2016) A fine balance of synaptophysin levels underlies efficient retrieval of synaptobrevin II to synaptic vesicles. PLoS ONE 11:e0149457. https://doi.org/10.1371/journal.pone.0149457
Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300
Head E, Corrada MM, Kahle-Wrobleski K, Kim RC, Sarsoza F et al (2009) Synaptic proteins, neuropathology and cognitive status in the oldest-old. Neurobiol Aging 30:1125–1134. https://doi.org/10.1016/j.neurobiolaging.2007.10.001
Hermann PM, Watson SN, Wildering WC (2014) Phospholipase A2 - nexus of aging, oxidative stress, neuronal excitability, and functional decline of the aging nervous system? Insights from a snail model system of neuronal aging and age-associated memory impairment. Front Genet 5:419. https://doi.org/10.3389/fgene.2014.00419
Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D et al (2001) Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 78:249–253
Hsieh HM, Wu WM, Hu ML (2009) Soy isoflavones attenuate oxidative stress and improve parameters related to aging and Alzheimer’s disease in C57BL/6J mice treated with D-galactose. Food Chem Toxicol 47:625–632. https://doi.org/10.1016/j.fct.2008.12.026
Hua X, Lei M, Zhang Y, Ding J, Han Q et al (2007) Long-term D-galactose injection combined with ovariectomy serves as a new rodent model for Alzheimer’s disease. Life Sci 80:1897–1905. https://doi.org/10.1016/j.lfs.2007.02.030
Hughes CF, Ward M, Hoey L, McNulty H (2013) Vitamin B12 and ageing: current issues and interaction with folate. Ann Clin Biochem 50:315–329. https://doi.org/10.1177/0004563212473279
Iqbal K, Liu F, Gong C-X, Alonso AC, Grundke-Iqbal I (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118:53–69. https://doi.org/10.1007/s00401-009-0486-3
Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J et al (2016) Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol 79:110–119. https://doi.org/10.1002/ana.24546
Kok DEG, Dhonukshe-Rutten RAM, Lute C, Heil SG, Uitterlinden AG et al (2015) The effects of long-term daily folic acid and vitamin B(12) supplementation on genome-wide DNA methylation in elderly subjects. Clin Epigenetics 7:121. https://doi.org/10.1186/s13148-015-0154-5
Krause D, Roupas P (2015) Effect of vitamin intake on cognitive decline in older adults: evaluation of the evidence. J Nutr Health Aging 19:745–753. https://doi.org/10.1007/s12603-015-0539-3
Kumar A, Dogra S, Prakash A (2009) Effect of carvedilol on behavioral, mitochondrial dysfunction, and oxidative damage against D-galactose induced senescence in mice. Naunyn-Schmiedeberg’s Arch Pharmacol 380:431–441. https://doi.org/10.1007/s00210-009-0442-8
Lauretti E, Dincer O, Praticò D (1867) Glycogen synthase kinase-3 signaling in Alzheimer’s disease Biochimica et biophysica acta. Mol Cell Res 2020:118664. https://doi.org/10.1016/j.bbamcr.2020.118664
Lei M, Hua X, Xiao M, Ding J, Han Q et al (2008a) Impairments of astrocytes are involved in the d-galactose-induced brain aging. Biochem Biophys Res Commun 369:1082–1087. https://doi.org/10.1016/j.bbrc.2008.02.151
Lei M, Su Y, Hua X, Ding J, Han Q et al (2008b) Chronic systemic injection of D-galactose impairs the septohippocampal cholinergic system in rats. Neuroreport 19:1611–1615. https://doi.org/10.1097/WNR.0b013e3283136a1f
Levine RL, Williams JA, Stadtman ER, Shacter E (1994) Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 233:346–357
Lewerin C, Matousek M, Steen G, Johansson B, Steen B et al (2005) Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr 81:1155–1162
Li W, Jiang M, Xiao Y, Zhang X, Cui S et al (2015a) Folic acid inhibits tau phosphorylation through regulation of PP2A methylation in SH-SY5Y cells. J Nutr Health Aging 19:123–129. https://doi.org/10.1007/s12603-014-0514-4
Li W, Jiang M, Zhao S, Liu H, Zhang X et al (2015b) Folic acid inhibits amyloid beta-peptide production through modulating DNA Methyltransferase activity in N2a-APP cells. Int J Mol Sci 16:25002–25013. https://doi.org/10.3390/ijms161025002
Liang Z, Liu F, Iqbal K, Grundke-Iqbal I, Gong C-X (2009) Dysregulation of tau phosphorylation in mouse brain during excitotoxic damage. JAD 17:531–539. https://doi.org/10.3233/JAD-2009-1069
Loscalzo J (2002) Homocysteine and Dementias. N Engl J Med 346:466–468. https://doi.org/10.1056/NEJM200202143460702
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Lubitz I, Ricny J, Atrakchi-Baranes D, Shemesh C, Kravitz E et al (2016) High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Abeta deposition in an Alzheimer mouse model. Aging Cell. https://doi.org/10.1111/acel.12436
Luevano-Contreras C, Chapman-Novakofski K (2010) Dietary advanced glycation end products and aging. Nutrients 2:1247–1265. https://doi.org/10.3390/nu2121247
Mattson MP, Shea TB (2003) Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 26:137–146. https://doi.org/10.1016/S0166-2236(03)00032-8
McNulty H, Pentieva K, Hoey L, Strain J, Ward M (2012) Nutrition throughout life: folate International journal for vitamin and nutrition research. Int J Vitam Nutr Res 82:348–354. https://doi.org/10.1024/0300-9831/a000130
Moore EM, Ames D, Mander AG, Carne RP, Brodaty H et al (2014) Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. JAD 39:661–668. https://doi.org/10.3233/jad-131265
Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, Gertz HJ, Xuereb JH et al (2000) Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol 157:623–636. https://doi.org/10.1016/s0002-9440(10)64573-7
Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (2007) Trends in oxidative aging theories. Free Radic Biol Med 43:477–503. https://doi.org/10.1016/j.freeradbiomed.2007.03.034
Munch G, Westcott B, Menini T, Gugliucci A (2012) Advanced glycation endproducts and their pathogenic roles in neurological disorders. Amino Acids 42:1221–1236. https://doi.org/10.1007/s00726-010-0777-y
Neddens J, Temmel M, Flunkert S, Kerschbaumer B, Hoeller C, Loeffler T, Niederkofler V, Daum G, Attems J, Hutter-Paier B (2018) Phosphorylation of different tau sites during progression of Alzheimer’s disease. Acta Neuropathol Commun 6:52. https://doi.org/10.1186/s40478-018-0557-6
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381. https://doi.org/10.1097/NEN.0b013e31825018f7
Pizzimenti S, Ciamporcero E, Daga M, Pettazzoni P, Arcaro A, Cetrangolo G, Minelli R, Dianzani C, Lepore A, Gentile F, Barrera G (2013) Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol 4:242. https://doi.org/10.3389/fphys.2013.00242
Prisila Dulcy C, Singh HK, Preethi J, Rajan KE (2012) Standardized extract of Bacopa monniera (BESEB CDRI-08) attenuates contextual associative learning deficits in the aging rat's brain induced by D-galactose. J Neurosci Res 90:2053–2064. https://doi.org/10.1002/jnr.23080
Rahimi VB, Askari VR, Mousavi SH (2018) Ellagic acid reveals promising anti-aging effects against d-galactose-induced aging on human neuroblastoma cell line, SH-SY5Y: a mechanistic study. Biomed Pharmacother 108:1712–1724. https://doi.org/10.1016/j.biopha.2018.10.024
Regan P, Whitcomb DJ, Cho K (2016) Physiological and pathophysiological implications of synaptic tau. Neuroscientist. https://doi.org/10.1177/1073858416633439
Remigante A, Morabito R, Spinelli S, Trichilo V, Loddo S et al (2020) D-Galactose decreases anion exchange capability through band 3 protein in human erythrocytes. Antioxidants 9:689
Rezk BM, Haenen GR, van der Vijgh WJ, Bast A (2003) Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore. FEBS Lett 555:601–605
Robinson JL, Molina-Porcel L, Corrada MM, Raible K, Lee EB et al (2014) Perforant path synaptic loss correlates with cognitive impairment and Alzheimer’s disease in the oldest-old. Brain J Neurol 137:2578–2587. https://doi.org/10.1093/brain/awu190
Shen Y, Gao H, Shi X, Wang N, Ai D et al (2014) Glutamine synthetase plays a role in d-galactose-induced astrocyte aging in vitro and in vivo. Exp Gerontol 58:166–173. https://doi.org/10.1016/j.exger.2014.08.006
Sinclair LI, Tayler HM, Love S (2015) Synaptic protein levels altered in vascular dementia. Neuropathol Appl Neurobiol 41:533–543. https://doi.org/10.1111/nan.12215
Singh R, Kanwar SS, Sood PK, Nehru B (2011) Beneficial effects of folic acid on enhancement of memory and antioxidant status in aged rat brain. Cell Mol Neurobiol 31:83–91. https://doi.org/10.1007/s10571-010-9557-1
Srivastav S, Singh SK, Yadav AK, Srikrishna S (2015) Folic acid supplementation ameliorates oxidative stress, metabolic functions and developmental anomalies in a novel fly model of Parkinson’s disease. Neurochem Res 40:1350–1359. https://doi.org/10.1007/s11064-015-1598-x
Ullah F, Ali T, Ullah N, Kim MO (2015) Caffeine prevents d-galactose-induced cognitive deficits, oxidative stress, neuroinflammation and neurodegeneration in the adult rat brain. Neurochem Int 90:114–124. https://doi.org/10.1016/j.neuint.2015.07.001
Vianna MR, Alonso M, Viola H, Quevedo J, de Paris F et al (2000) Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat. Learn memory 7:333–340
Wang X, Michaelis E (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2. https://doi.org/10.3389/fnagi.2010.00012
Wang J-Z, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25:59–68. https://doi.org/10.1111/j.1460-9568.2006.05226.x
Wang XX, Zhang B, Xia R, Jia QY (2020) Inflammation, apoptosis and autophagy as critical players in vascular dementia. Eur Rev Med Pharmacol Sci 24:9601–9614. https://doi.org/10.26355/eurrev_202009_23048
Wiedenmann B, Franke WW (1985) Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell 41:1017–1028
Wisse LEM, Biessels GJ, Heringa SM, Kuijf HJ, Koek DL et al (2014) Hippocampal subfield volumes at 7T in early Alzheimer’s disease and normal aging. Neurobiol Aging 35:2039–2045. https://doi.org/10.1016/j.neurobiolaging.2014.02.021
Xu J, Sinclair KD (2015) One-carbon metabolism and epigenetic regulation of embryo development. Reprod Fertil Dev. https://doi.org/10.1071/rd14377
Yeung ST, Myczek K, Kang AP, Chabrier MA, Baglietto-Vargas D et al (2014) Impact of hippocampal neuronal ablation on neurogenesis and cognition in the aged brain. Neuroscience 259:214–222. https://doi.org/10.1016/j.neuroscience.2013.11.054
Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59. https://doi.org/10.1038/nrm2308
Yu HL, Li L, Zhang XH, Xiang L, Zhang J et al (2009) Neuroprotective effects of genistein and folic acid on apoptosis of rat cultured cortical neurons induced by beta-amyloid 31-35. Br J Nutr 102:655–662. https://doi.org/10.1017/s0007114509243042
Yu Y, Feng L, Li J, Lan X, L A et al (2017) The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits. Behav Brain Res 334:155–162. https://doi.org/10.1016/j.bbr.2017.07.003
Yuki D, Sugiura Y, Zaima N, Akatsu H, Takei S et al (2014) DHA-PC and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer’s disease. Sci Rep 4:7130. https://doi.org/10.1038/srep07130
Zhan PY, Peng CX, Zhang LH (2014) Berberine rescues D-galactose-induced synaptic/memory impairment by regulating the levels of Arc. Pharmacol Biochem Behav 117:47–51. https://doi.org/10.1016/j.pbb.2013.12.006
Zhao H, Liang J, Li X, Yu H, Li X et al (2010) Folic acid and soybean isoflavone combined supplementation protects the post-neural tube closure defects of rodents induced by cyclophosphamide in vivo and in vitro. NeuroToxicology 31:180–187. https://doi.org/10.1016/j.neuro.2009.12.011
Acknowledgments
Experimental Neurology Laboratory (Brazil) is funded by grants from National Council for Scientific and Technological Development (CNPq), Brazilian Coordination of Improvement of Higher Education Personnel (CAPES), Foundation for Support of Research and Innovation of Santa Catarina (FAPESC) and University of Southern Santa Catarina (UNESC).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Disclosure
The authors declare that there is no conflict of interests regarding the publication of this paper.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Garcez, M.L., Cassoma, R.C.S., Mina, F. et al. Folic acid prevents habituation memory impairment and oxidative stress in an aging model induced by D-galactose. Metab Brain Dis 36, 213–224 (2021). https://doi.org/10.1007/s11011-020-00647-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-020-00647-7