Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jul 2

PMID 34200792

Citations 17

Authors

Amany Tawfik

Nehal M Elsherbiny

Yusra Zaidi

Pragya Rajpurohit

Affiliations

Soon will be listed here.

Abstract

Hyperhomocysteinemia (HHcy) is remarkably common among the aging population. The relation between HHcy and the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and eye diseases, and age-related macular degeneration (AMD) and diabetic retinopathy (DR) in elderly people, has been established. Disruption of the blood barrier function of the brain and retina is one of the most important underlying mechanisms associated with HHcy-induced neurodegenerative and retinal disorders. Impairment of the barrier function triggers inflammatory events that worsen disease pathology. Studies have shown that AD patients also suffer from visual impairments. As an extension of the central nervous system, the retina has been suggested as a prominent site of AD pathology. This review highlights inflammation as a possible underlying mechanism of HHcy-induced barrier dysfunction and neurovascular injury in aging diseases accompanied by HHcy, focusing on AD.

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References

Maccioni R, Gonzalez A, Andrade V, Cortes N, Tapia J, Guzman-Martinez L . Alzheimer´s Disease in the Perspective of Neuroimmunology. Open Neurol J. 2018; 12:50-56. PMC: 6040210. DOI: 10.2174/1874205X01812010050. View

Shen X, Li J, Wang H, Li H, Huang Y, Yang Y . Plasma amyloid, tau, and neurodegeneration biomarker profiles predict Alzheimer's disease pathology and clinical progression in older adults without dementia. Alzheimers Dement (Amst). 2020; 12(1):e12104. PMC: 7513626. DOI: 10.1002/dad2.12104. View

Zhuo J, Portugal G, Kruger W, Wang H, Gould T, Pratico D . Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer's disease. Curr Alzheimer Res. 2009; 7(2):140-9. PMC: 3880573. DOI: 10.2174/156720510790691326. View

Lei X, Zeng G, Zhang Y, Li Q, Zhang J, Bai Z . Association between homocysteine level and the risk of diabetic retinopathy: a systematic review and meta-analysis. Diabetol Metab Syndr. 2018; 10:61. PMC: 6071377. DOI: 10.1186/s13098-018-0362-1. View

Kamat P, Mallonee C, George A, Tyagi S, Tyagi N . Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism. Alcohol Clin Exp Res. 2016; 40(12):2474-2481. PMC: 5133158. DOI: 10.1111/acer.13234. View

Chen S, Dong Z, Cheng M, Zhao Y, Wang M, Sai N . Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized STAT3 overactivation following ischemic stroke. J Neuroinflammation. 2017; 14(1):187. PMC: 5604224. DOI: 10.1186/s12974-017-0963-x. View

Bescond A, Augier T, Chareyre C, Garcon D, Hornebeck W, Charpiot P . Influence of homocysteine on matrix metalloproteinase-2: activation and activity. Biochem Biophys Res Commun. 1999; 263(2):498-503. DOI: 10.1006/bbrc.1999.1391. View

Weiss N, Heydrick S, Zhang Y, Bierl C, Cap A, Loscalzo J . Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine beta-synthase-deficient mice. Arterioscler Thromb Vasc Biol. 2002; 22(1):34-41. DOI: 10.1161/hq1201.100456. View

Wang R, Reddy P . Role of Glutamate and NMDA Receptors in Alzheimer's Disease. J Alzheimers Dis. 2016; 57(4):1041-1048. PMC: 5791143. DOI: 10.3233/JAD-160763. View

10.

Mohamed R, Sharma I, Ibrahim A, Saleh H, Elsherbiny N, Fulzele S . Hyperhomocysteinemia Alters Retinal Endothelial Cells Barrier Function and Angiogenic Potential via Activation of Oxidative Stress. Sci Rep. 2017; 7(1):11952. PMC: 5607263. DOI: 10.1038/s41598-017-09731-y. View

11.

Ho P, Ortiz D, Rogers E, Shea T . Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res. 2002; 70(5):694-702. DOI: 10.1002/jnr.10416. View

12.

Ibrahim A, Mander S, Hussein K, Elsherbiny N, Smith S, Al-Shabrawey M . Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration. Oncotarget. 2016; 7(8):8532-45. PMC: 4890985. DOI: 10.18632/oncotarget.7384. View

13.

Luchsinger J, Tang M, Miller J, Green R, Mayeux R . Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch Neurol. 2007; 64(1):86-92. DOI: 10.1001/archneur.64.1.86. View

14.

Beard Jr R, Bearden S . Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research. Am J Physiol Heart Circ Physiol. 2010; 300(1):H13-26. PMC: 3023265. DOI: 10.1152/ajpheart.00598.2010. View

15.

Andrieu S, Coley N, Aisen P, Carrillo M, DeKosky S, Durga J . Methodological issues in primary prevention trials for neurodegenerative dementia. J Alzheimers Dis. 2009; 16(2):235-70. DOI: 10.3233/JAD-2009-0971. View

16.

Troen A, Shea-Budgell M, Shukitt-Hale B, Smith D, Selhub J, Rosenberg I . B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice. Proc Natl Acad Sci U S A. 2008; 105(34):12474-9. PMC: 2517600. DOI: 10.1073/pnas.0805350105. View

17.

Zenaro E, Piacentino G, Constantin G . The blood-brain barrier in Alzheimer's disease. Neurobiol Dis. 2016; 107:41-56. PMC: 5600438. DOI: 10.1016/j.nbd.2016.07.007. View

18.

Jaul E, Barron J . Age-Related Diseases and Clinical and Public Health Implications for the 85 Years Old and Over Population. Front Public Health. 2018; 5:335. PMC: 5732407. DOI: 10.3389/fpubh.2017.00335. View

19.

Braun D, Dimayuga E, Morganti J, Van Eldik L . Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model of Alzheimer's disease. J Neuroinflammation. 2020; 17(1):274. PMC: 7499995. DOI: 10.1186/s12974-020-01938-7. View

20.

Tawfik A, Samra Y, Elsherbiny N, Al-Shabrawey M . Implication of Hyperhomocysteinemia in Blood Retinal Barrier (BRB) Dysfunction. Biomolecules. 2020; 10(8). PMC: 7463551. DOI: 10.3390/biom10081119. View