Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer’s Disease-Like Pathology, Blood–Brain Barrier Disruption, and Synaptic Disorder

Abstract

Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer’s disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-d-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood–brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca2+ indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy-induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H2S for cerebrovascular diseases such as Alzheimer’s disease.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

References

  1. 1.

    Brustolin S, Giugliani R, Felix TM (2010) Genetics of homocysteine metabolism and associated disorders. Braz J Med Biol Res 43:1–7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Nilsson K, Gustafson L, Hultberg B (2010) Plasma homocysteine and cognition in elderly patients with dementia or other psychogeriatric diseases. Dement Geriatr Cogn Disord 30:198–204

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346:476–483

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C (2001) Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 12:309–313

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    McCaddon A, Regland B (2006) Homocysteine and cognition—no longer a hypothesis? Med Hypotheses 66:682–683

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R (2004) Plasma homocysteine levels and risk of Alzheimer disease. Neurology 62:1972–1976

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Ravaglia G, Forti P, Maioli F, Scali RC, Saccheitti L, Talerico T, Mantovani V, Bianchin M (2004) Homocysteine and cognitive performance in healthy elderly subjects. Arch Gerontol Geriatr Suppl 9:349–357

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Zhuo JM, Wang H, Pratico D (2011) Is hyperhomocysteinemia an Alzheimer’s disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol Sci 32:562–571

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Collingridge GL, Isaac JT, Wang YT (2004) Receptor trafficking and synaptic plasticity. Nat Rev Neurosci 5:952–962

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Perez-Otano I, Ehlers MD (2004) Learning from NMDA receptor trafficking: clues to the development and maturation of glutamatergic synapses. Neurosignals 13:175–189

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Rai S, Kamat PK, Nath C, Shukla R (2013) A study on neuroinflammation and NMDA receptor function in STZ (ICV) induced memory impaired rats. J Neuroimmunol 254:1–9

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Lee SH, Sharma M, Sudhof TC, Shen J (2014) Synaptic function of nicastrin in hippocampal neurons. Proc Natl Acad Sci U S A 111:8973–8978

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ethell IM, Ethell DW (2007) Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res 85:2813–2823

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Bozdagi O, Nagy V, Kwei KT, Huntley GW (2007) In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity. J Neurophysiol 98:334–344

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Michaluk P, Mikasova L, Groc L, Frischknecht R, Choquet D, Kaczmarek L (2009) Matrix metalloproteinase-9 controls NMDA receptor surface diffusion through integrin beta1 signaling. J Neurosci 29:6007–6012

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Kalani A, Kamat PK, Tyagi SC, Tyagi N (2013) Synergy of homocysteine, microRNA, and epigenetics: a novel therapeutic approach for stroke. Mol Neurobiol 48:157–168

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Okulski P, Dzwonek J, Costa RM, Silva AJ et al (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 26:1923–1934

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kamat PK, Kalani A, Givvimani S, Sathnur PB, Tyagi SC, Tyagi N (2013) Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebral-administered homocysteine in mice. Neuroscience 252:302–319

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kamat PK, Rai S, Swarnkar S, Shukla R, Ali S, Najmi AK, Nath C (2013) Okadaic acid-induced Tau phosphorylation in rat brain: role of NMDA receptor. Neuroscience 238:97–113

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Lyon L, Saksida LM, Bussey TJ (2012) Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models. Psychopharmacology (Berl) 220:647–672

    CAS  Article  Google Scholar 

  21. 21.

    Lominadze D, Tyagi N, Sen U, Ovechkin A, Tyagi SC (2012) Homocysteine alters cerebral microvascular integrity and causes remodeling by antagonizing GABA-A receptor. Mol Cell Biochem 371:89–96

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain. I. The disposition of [3H] norepinephrine, [3H] dopamine and [3H] dopa in various regions of the brain. J Neurochem 13:655–669

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ravaglia G, Forti P, Maioli F, Zanardi V, Dalmonte E, Grossi G, Cucinotta D, Macini P et al (2000) Blood homocysteine and vitamin B levels are not associated with cognitive skills in healthy normally ageing subjects. J Nutr Health Aging 4:218–222

    CAS  PubMed  Google Scholar 

  24. 24.

    O’Brien JT, Eagger S, Syed GM, Sahakian BJ, Levy R (1992) A study of regional cerebral blood flow and cognitive performance in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 55:1182–1187

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Prohovnik I, Mayeux R, Sackeim HA, Smith G, Stern Y, Alderson PO (1988) Cerebral perfusion as a diagnostic marker of early Alzheimer’s disease. Neurology 38:931–937

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Nash DT, Fillit H (2006) Cardiovascular disease risk factors and cognitive impairment. Am J Cardiol 97:1262–1265

    Article  PubMed  Google Scholar 

  27. 27.

    Tota S, Kamat PK, Awasthi H, Singh N, Raghubir R, Nath C, Hanif K (2009) Candesartan improves memory decline in mice: involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin. Behav Brain Res 199:235–240

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Claudio L (1996) Ultrastructural features of the blood–brain barrier in biopsy tissue from Alzheimer’s disease patients. Acta Neuropathol 91:6–14

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Kook SY, Seok Hong H, Moon M, Mook-Jung I (2013) Disruption of blood–brain barrier in Alzheimer disease pathogenesis. Tissue Barriers 1:e23993

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Rosenberg GA (2002) Matrix metalloproteinases in neuroinflammation. Glia 39:279–291

    Article  PubMed  Google Scholar 

  31. 31.

    Yong VW, Power C, Forsyth P, Edwards DR (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2:502–511

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Foster CA, Mechtcheriakova D, Storch MK, Balatoni B, Howard LM, Bornancin F, Wlachos A, Sobanov J et al (2009) FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol 19:254–266

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Frohman EM, Frohman TC, Gupta S, de Fougerolles A, van den Noort S (1991) Expression of intercellular adhesion molecule 1 (ICAM-1) in Alzheimer’s disease. J Neurol Sci 106:105–111

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Wilker EH, Alexeeff SE, Poon A, Litonjua AA, Sparrow D, Vokonas PS, Mittleman MA, Schwartz J (2009) Candidate genes for respiratory disease associated with markers of inflammation and endothelial dysfunction in elderly men. Atherosclerosis 206:480–485

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Rai S, Kamat PK, Nath C, Shukla R (2014) Glial activation and post-synaptic neurotoxicity: the key events in Streptozotocin (ICV) induced memory impairment in rats. Pharmacol Biochem Behav 117:104–117

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Kamat PK, Rai S, Swarnkar S, Shukla R, Nath C (2014) Mechanism of synapse redox stress in Okadaic acid (ICV) induced memory impairment: role of NMDA receptor. Neurochem Int 76:32–41

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Lee H, Lee EJ, Song YS, Kim E (2014) Long-term depression-inducing stimuli promote cleavage of the synaptic adhesion molecule NGL-3 through NMDA receptors, matrix metalloproteinases and presenilin/gamma-secretase. Philos Trans R Soc Lond B Biol Sci 369:20130158

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Li W, Yu J, Liu Y, Huang X, Abumaria N, Zhu Y, Huang X, Xiong W et al (2014) Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer inverted question marks disease mouse model. Mol Brain 7:65

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Spires-Jones TL, Hyman BT (2014) The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82:756–771

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    van der Zee EA (2014) Synapses, spines and kinases in mammalian learning and memory, and the impact of aging. Neurosci Biobehav Rev 50C:77–85

    Google Scholar 

Download references

Acknowledgments

Financial support from National Institutes of Health grants HL107640-NT is greatly acknowledged.

Conflict of Interest

None.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Neetu Tyagi.

Additional information

Pradip K. Kamat and Philip Kyles contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kamat, P.K., Kyles, P., Kalani, A. et al. Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer’s Disease-Like Pathology, Blood–Brain Barrier Disruption, and Synaptic Disorder. Mol Neurobiol 53, 2451–2467 (2016). https://doi.org/10.1007/s12035-015-9212-4

Download citation

Keywords

  • Homocysteine
  • Blood–brain barrier dysfunction
  • Cerebrovascular pathology
  • Alzheimer’s disease
  • Dementia