Neurochemical Research

, Volume 40, Issue 8, pp 1709–1718 | Cite as

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

  • Zdena Kristofikova
  • Jan Ricny
  • Jana Sirova
  • Daniela Ripova
  • Irit Lubitz
  • Michal Schnaider-Beeri
Original Paper


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.


NMDA 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.

Ethical standard

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.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Zdena Kristofikova
    • 1
  • Jan Ricny
    • 1
  • Jana Sirova
    • 1
  • Daniela Ripova
    • 1
  • Irit Lubitz
    • 2
  • Michal Schnaider-Beeri
    • 2
    • 3
  1. 1.Alzheimer’s Disease CenterNational Institute of Mental HealthKlecanyCzech Republic
  2. 2.The Joseph Sagol Neuroscience CenterSheba Medical CenterRamat GanIsrael
  3. 3.Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkUSA

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