Abstract
Chronic stress is a risk factor in the development of cognitive decline and even Alzheimer’s disease (AD), although its underlying mechanism is not fully understood. Our previous data demonstrated that the level of homocysteine (Hcy) was significantly elevated in the plasma of stressed animals, which suggests the possibility that Hcy is a link between stress and cognitive decline. To test this hypothesis, we compared the cognitive function, plasma concentrations of Hcy, and the brain beta-amyloid (Aβ) level between rats with or without chronic unexpected mild stress (CUMS). A lower performance by rats in behavioral tests indicated that a significant cognitive decline was induced by CUMS. Stress also disturbed the normal processing of Aβ precursor protein (APP) and resulted in the accumulation of Aβ in the brains of rats, which showed a positive correlation with the hyperhomocysteinemia (HHcy) that appeared in stressed rats. Hcy-targeting intervention experiments were used to verify further the involvement of Hcy in stress-induced APP misprocessing and related cognitive decline. The results showed that diet-induced HHcy could mimic the cognitive impairment and APP misprocessing in the same manner as CUMS, while Hcy reduction by means of vitamin B complex supplements and betaine could alleviate the cognitive deficits and dysregulation of Aβ metabolism in CUMS rats. Taken together, the novel evidence from our present study suggests that Hcy is likely to be involved in chronic stress-evoked APP misprocessing and related cognitive deficits. Our results also suggested the possibility of Hcy as a target for therapy and the potential value of vitamin B and betaine intake in the prevention of stress-induced cognitive decline.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- Aβ:
-
beta-amyloid peptides
- AD:
-
Alzheimer’s disease
- APP:
-
Aβ precursor protein
- BACE:
-
β-site APP-cleaving enzyme
- CBS:
-
cystathionine β-synthase
- CUMS:
-
chronic unexpected mild stress
- Hcy:
-
homocysteine
- HHcy:
-
hyperhomocysteinemia
- HPA:
-
hypothalamic pituitary adrenal
- IDE:
-
insulin-degrading enzyme
- PS-1:
-
presenilin
- VitB:
-
vitamin B
References
Briones A et al. (2012) Stress-induced anhedonia is associated with an increase in Alzheimer’s disease-related markers. Br J Pharmacol 165:897–907. doi:10.1111/j.1476-5381.2011.01602.x
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. doi:10.1007/s11239-012-0856-x
Catania C, Sotiropoulos I, Silva R, Onofri C, Breen KC, Sousa N, Almeida OF (2009) The amyloidogenic potential and behavioral correlates of stress. Mol Psychiatry 14:95–105. doi:10.1038/sj.mp.4002101
Chai GS et al. (2013) Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine. J Neurochem 124:388–396. doi:10.1111/jnc.12094
Chengfeng S, Wei L, Xinxing W, Lei W, Rui Z, Lingjia Q (2014) Hyperhomocysteinemia is a result, rather than a cause, of depression under chronic stress. PLoS One 9:e106625. doi:10.1371/journal.pone.0106625
de Jager CA (2014) Critical levels of brain atrophy associated with homocysteine and cognitive decline. Neurobiol Aging 35(Suppl 2):S35–S39. doi:10.1016/j.neurobiolaging.2014.03.040
de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475. doi:10.1038/nrn1683
Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res 31:47–59
Gu HF et al. (2014) Epigallocatechin-3-gallate attenuates impairment of learning and memory in chronic unpredictable mild stress-treated rats by restoring hippocampal autophagic flux. PLoS One 9:e112683. doi:10.1371/journal.pone.0112683
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356. doi:10.1126/science.1072994
Hasegawa T et al. (2012) Urinary homocysteic acid levels correlate with mini-mental state examination scores in Alzheimer’s disease patients. J Alzheimers Disease JAD 31:59–64. doi:10.3233/JAD-2012-120022
Hasegawa T, Mikoda N, Kitazawa M, LaFerla FM (2010) Treatment of Alzheimer’s disease with anti-homocysteic acid antibody in 3xTg-AD male mice. PLoS One 5:e8593. doi:10.1371/journal.pone.0008593
Johansson L, Guo X, Waern M, Ostling S, Gustafson D, Bengtsson C, Skoog I (2010) Midlife psychological stress and risk of dementia: a 35-year longitudinal population study. Brain J Neurol 133:2217–2224. doi:10.1093/brain/awq116
Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, Wagner DD (2006) Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 107:591–593. doi:10.1182/blood-2005-06-2506
Kidd PM (2008) Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev J Clin Ther 13:85–115
Kim JJ, Diamond DM (2002) The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 3:453–462. doi:10.1038/nrn849
LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8:499–509. doi:10.1038/nrn2168
Li JG, Chu J, Barrero C, Merali S, Pratico D (2014) Homocysteine exacerbates beta-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles. Ann Neurol 75:851–863. doi:10.1002/ana.24145
Liu D et al. (2014) Resveratrol prevents impaired cognition induced by chronic unpredictable mild stress in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 49:21–29. doi:10.1016/j.pnpbp.2013.10.017
Liu X et al. (2009) Proteomic analysis of homocysteine induced proliferation of cultured neonatal rat vascular smooth muscle cells. Biochim Biophys Acta 1794:177–184. doi:10.1016/j.bbapap.2008.10.001
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445. doi:10.1038/nrn2639
Machado A et al. (2014) Chronic stress as a risk factor for Alzheimer’s disease. Rev Neurosci 25:785–804. doi:10.1515/revneuro-2014-0035
Marin MF et al. (2011) Chronic stress, cognitive functioning and mental health. Neurobiol Learn Mem 96:583–595. doi:10.1016/j.nlm.2011.02.016
Martisova E, Solas M, Gerenu G, Milagro FI, Campion J, Ramirez MJ (2012) Mechanisms involved in BACE upregulation associated to stress. Curr Alzheimer Res 9:822–829
McEwen BS, Gianaros PJ (2010) Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Ann N Y Acad Sci 1186:190–222. doi:10.1111/j.1749-6632.2009.05331.x
Morris MS (2012) The role of B vitamins in preventing and treating cognitive impairment and decline. Adv Nutr 3:801–812. doi:10.3945/an.112.002535
Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60
Obeid R, Herrmann W (2006) Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 580:2994–3005. doi:10.1016/j.febslet.2006.04.088
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344. doi:10.1056/NEJMra0909142
Ravaglia G et al. (2005) Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 82:636–643
Rothman SM et al. (2012) 3xTgAD mice exhibit altered behavior and elevated Abeta after chronic mild social stress. Neurobiol Aging 33:830 . doi:10.1016/j.neurobiolaging.2011.07.005e831-812
Rothman SM, Mattson MP (2010) Adverse stress, hippocampal networks, and Alzheimer’s disease. Neruomol Med 12:56–70. doi:10.1007/s12017-009-8107-9
Sandi C (2004) Stress, cognitive impairment and cell adhesion molecules. Nat Rev Neurosci 5:917–930. doi:10.1038/nrn1555
Seo JS, Lee KW, Kim TK, Baek IS, Im JY, Han PL (2011) Behavioral stress causes mitochondrial dysfunction via ABAD up-regulation and aggravates plaque pathology in the brain of a mouse model of Alzheimer disease. Free Radic Biol Med 50:1526–1535. doi:10.1016/j.freeradbiomed.2011.02.035
Seshadri S (2006) Elevated plasma homocysteine levels: risk factor or risk marker for the development of dementia and Alzheimer’s disease? J Alzheimers Dis JAD 9:393–398
Wang HX, Wahlberg M, Karp A, Winblad B, Fratiglioni L (2012) Psychosocial stress at work is associated with increased dementia risk in late life. Alzheimers Dement J Alzheimers Assoc 8:114–120. doi:10.1016/j.jalz.2011.03.001
Wang Y et al. (2011) Glucocorticoids facilitate astrocytic amyloid-beta peptide deposition by increasing the expression of APP and BACE1 and decreasing the expression of amyloid-beta-degrading proteases. Endocrinology 152:2704–2715. doi:10.1210/en.2011-0145
Williams JH, Pereira EA, Budge MM, Bradley KM (2002) Minimal hippocampal width relates to plasma homocysteine in community-dwelling older people. Age Ageing 31:440–444
Xie F, Zhang JC, Fu H, Chen J (2013) Age-related decline of myelin proteins is highly correlated with activation of astrocytes and microglia in the rat CNS. Int J Mol Med 32:1021–1028. doi:10.3892/ijmm.2013.1486
Xinxing W, Wei L, Lei W, Rui Z, Baoying J, Lingjia Q (2014) A neuroendocrine mechanism of co-morbidity of depression-like behavior and myocardial injury in rats. PLoS One 9:e88427. doi:10.1371/journal.pone.0088427
Zhang CE et al. (2009) Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am J Pathol 174:1481–1491. doi:10.2353/ajpath.2009.081036
Zhang ZH, LN W, Song JG, Li WQ (2012) Correlations between cognitive impairment and brainderived neurotrophic factor expression in the hippocampus of post-stroke depression rats. Mol Med Rep 6:889–893. doi:10.3892/mmr.2012.1009
Zhao Y, Qian L (2014) Homocysteine-mediated intestinal epithelial barrier dysfunction in the rat model of irritable bowel syndrome caused by maternal separation. Acta Biochim Biophys Sin 46:917–919. doi:10.1093/abbs/gmu076
Zhao Y et al. (2013) Inhibition of cystathionine beta-synthase is associated with glucocorticoids over-secretion in psychological stress-induced hyperhomocystinemia rat liver. Cell Stress Chaperones 18:631–641. doi:10.1007/s12192-013-0416-0
Zhuo JM, Pratico D (2010) Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by a folate, vitamin B6 and B12-deficient diet. Exp Gerontol 45:195–201. doi:10.1016/j.exger.2009.12.005
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (No. 81401041, No. 81302602, No. 31571173, No. 31400948, and No. 81500454).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that they have no competing interests.
Additional information
Fang Xie and Yun Zhao contributed equally to this work.
Rights and permissions
About this article
Cite this article
Xie, F., Zhao, Y., Ma, J. et al. The involvement of homocysteine in stress-induced Aβ precursor protein misprocessing and related cognitive decline in rats. Cell Stress and Chaperones 21, 915–926 (2016). https://doi.org/10.1007/s12192-016-0718-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12192-016-0718-0