Differences Between Tg2576 and Wild Type Mice in the NMDA Receptor–Nitric Oxide Pathway After Prolonged Application of a Diet High in Advanced Glycation End Products
- 190 Downloads
It has been suggested that advanced glycation end (AGE) products, via cognate receptor activation, are implicated in several diseases, including Alzheimer’s disease. The NMDA receptor–nitric oxide pathway appears to be influenced by AGE products and involved in the pathogenesis of this type of dementia. In this study, C57BL/6J (WT) and transgenic (Tg2576) mice expressing human mutant amyloid precursor protein were kept on prolonged (8 months) diets containing regular or high amounts of AGE products. After the decapitation of 11-months old mice, brain tissue analyses were performed [expressions of the NR1, NR2A and NR2B subunits of NMDA receptors, activities of neuronal, endothelial and inducible nitric oxide synthase (nNOS, eNOS and iNOS)]. Moreover, levels of malondialdehyde and of human amyloid β 1–42 were estimated. We found increased activity of nNOS in WT mice maintained on a high compared to regular AGE diet; however, no similar differences were found in Tg2576 mice. In addition, we observed an increase in NR1 expression in Tg2576 compared to WT mice, both kept on a diet high in AGE products. Correlation analyses performed on mice kept on the regular AGE diet supported close links between particular subunits (NR2A–NR2B, in WT as well as in Tg2576 mice), between subunits and synthase (NR2A/NR2B–nNOS, only in WT mice) or between particular synthases (nNOS–iNOS, only in WT). Correlation analysis also revealed differences between WT mice kept on both diets (changed correlations between NR2A/NR2B–nNOS, between nNOS–eNOS and between eNOS–iNOS). Malondialdehyde levels were increased in both Tg2576 groups when compared to the corresponding WT mice, but no effects of the diets were observed. Analogously, no significant effects of diets were found in the levels of soluble or insoluble amyloid β 1–42 in Tg2576 mice. Our results demonstrate that prolonged ingestion of AGE products can influence the NMDA receptor–nitric oxide pathway in the brain and that only WT mice, not Tg2576 mice, are able to maintain homeostasis among subunits and synthases or among particular synthases. The prolonged application of AGE products enhanced differences between 11-months old Tg2576 and WT mice regarding this pathway. Observed differences in the pathway between WT mice kept on regular or high AGE diets suggest that the prolonged application of a diet low in AGE products could have beneficial effects in older or diabetic people and perhaps also in people with Alzheimer’s disease.
KeywordsNMDA receptor subunits Nitric oxide synthases Advanced glycation end products Mouse model of Alzheimer’s disease
The research was supported by Ministry of Education, Youth and Sports of the Czech Republic (Project KONTAKT II-LH13254) and by Grant Agency of the Czech Republic (Project P304/12/6069).
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in the study were in accordance with the ethical standards and were approved by the Institutional Animal Care and Use Committee of the Sheba Medical Center.
- 5.Sparvero LJ, Asafu-Adjei D, Kang R, Tang D, Amin N, Im J, Rutlege R, Lin B, Amoscato AA, Zeh HJ, Lotze MT (2009) RAGE (receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med 7:17. doi: 10.1186/1479-5876-7-17 PubMedCentralCrossRefPubMedGoogle Scholar
- 11.Kristofikova Z, Vrajova M, Sirova J, Vales K, Petrasek T, Schönig K, Tews B, Schwab M, Bartsch D, Stuchlik A, Ripova D (2013) N-methyl-d-aspartate receptor–nitric oxide synthase pathway in the cortex of Nogo-A-deficient rats in relation to brain laterality and schizophrenia. Front Behav Neurosci 7:90. doi: 10.3389/fnbeh.2013.00090 PubMedCentralCrossRefPubMedGoogle Scholar
- 18.Seftel AD, Vaziri ND, Ni Z, Razmjouei K, Fogarty J, Hampel N, Polak J, Wang RZ, Ferguson K, Block C, Haas C (1997) Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition, and possible effect through iNOS and eNOS. Urology 50:1016–1026CrossRefPubMedGoogle Scholar
- 23.Wu F, Feng JZ, Qiu YH, Yu FB, Zhang JZ, Zhou W, Yu F, Wang GK, An LN, Ni FH, Wu H, Zhao XX, Qin YW, Luo HD (2013) Activation of receptor for advanced glycation end products contributes to aortic remodeling and endothelial dysfunction in sinoaortic denervated rats. Atherosclerosis 229:287–294CrossRefPubMedGoogle Scholar
- 27.Shimazawa M, Inokuchi Y, Okuno T, Nakajima Y, Sakaguchi G, Kato A, Oku H, Sugiyama T, Kudo T, Ikeda T, Takeda M, Hara H (2008) Reduced retinal function in amyloid precursor protein-overexpressing transgenic mice via attenuating glutamate-N-methyl-d-aspartate receptor signaling. J Neurochem 107:279–290CrossRefPubMedGoogle Scholar
- 28.Klingner M, Apelt J, Kumar A, Sorger D, Sabri O, Steinbach J, Scheunemann M, Schliebs R (2003) Alterations in cholinergic and non-cholinergic neurotransmitter receptor densities in transgenic Tg2576 mouse brain with β-amyloid plaque pathology. Int J Dev Neurosci 21:357–369CrossRefPubMedGoogle Scholar
- 32.Hartlage-Rübsamen M, Apelt J, Schliebs R (2001) Fibrillary beta-amyloid deposits are closely associated with atropic nitric oxide synthase (NOS)-expressing neurons but do not upregulate the inducible NOS in transgenic Tg2576 mouse brain with Alzheimer pathology. Neurosci Lett 302:73–76CrossRefPubMedGoogle Scholar
- 33.Apelt J, Bigl M, Wunderlich P, Schliebs R (2004) Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology. Int J Dev Neurosci 22:475–484CrossRefPubMedGoogle Scholar
- 38.Lubitz I, Ricny J, Baranes D, Shemesh C, Kravitz E, Liraz-Zaltsman S, Maksin-Matveev A, Cooper I, Leibowitz A, Uribarri J, Schmeidler J, Kristofikova Z, Ripova D, LeRoith D, Schnaider-Beeri M High dietary advanced glycation end products impair spatial learning and accelerate Aβ deposition in an Alzheimer mouse model. Aging Cell (in review)Google Scholar
- 43.Wang L, Chen K, Liu K, Zhou Y, Zhang T, Wang B, Mi M (2015) DHA inhibited AGEs-induced retinal microglia activation via suppression of the PPARγ/NFκB pathway and reduction of signal transducers in the AGEs/RAGE axis recruitment into lipid rafts. Neurochem Res. doi: 10.1007/s11064-015-1517-1 PubMedCentralGoogle Scholar