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In vivo hippocampal microdialysis reveals impairment of NMDA receptor-cGMP signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer's transgenic mice.
Neurochem Int. 2012 Dec; 61(7):976-80.NI

Abstract

Transgenic (Tg) mice overexpressing human amyloid precursor protein (APP) mutants reproduce features of early Alzheimer's disease (AD) including memory deficit, presence of β-amyloid (Aβ) oligomers, and age-associated formation of amyloid deposits. In this study we used hippocampal microdialysis to characterize the signaling of N-methyl-d-aspartic acid receptors (NMDA-Rs) in awake and behaving AD Tg mice. The NMDA-R signaling is central to hippocampal synaptic plasticity underlying memory formation and several lines of evidence implicate the role of Aβ oligomers in effecting NMDA-R dysfunction. CA1 NMDA-Rs were stimulated by NMDA infused through reverse microdialysis while changes in the cyclic guanosine monophosphate (cGMP) concentration in the brain interstitial fluid (ISF) were used to determine NMDA-Rs responsiveness. While 4 months old wild type C57BL/6 mice mounted robust cGMP response to the NMDA challenge, the same stimulus failed to significantly change the cGMP level in 4 and 15 months old APP(SW) and 4 months old APP(SW)/PS1(L166P) Tg mice, which were all on C57BL/6 background. Lack of response to NMDA in AD Tg mice occurred in the absence of changes in expression levels of several synaptic proteins including synaptophysin, NR1 NMDA-R subunit and postsynaptic density protein 95, which indicates lack of profound synaptic degeneration. Aβ oligomers were detected in all three AD Tg mice groups and their concentration in the hippocampus ranged from 40.5±3.6ng/g in 4 months old APP(SW) mice to 60.8±15.9ng/g in 4 months old APP(SW)/PS1(L166P) mice. Four months old APP(SW) mice had no Aβ amyloid plaques, while the other two AD Tg mice groups showed evidence of incipient Aβ amyloid plaque formation. Our studies describes a novel approach useful to study the function of NMDA-Rs in awake and behaving AD Tg mice and demonstrate impairment of NMDA-R response in the presence of endogenously formed Aβ oligomers but predating onset of Aβ amyloidosis.

Authors+Show Affiliations

Department of Neurology, New York University School of Medicine, New York, NY, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22841892

Citation

Duszczyk, Malgorzata, et al. "In Vivo Hippocampal Microdialysis Reveals Impairment of NMDA receptor-cGMP Signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer's Transgenic Mice." Neurochemistry International, vol. 61, no. 7, 2012, pp. 976-80.
Duszczyk M, Kuszczyk M, Guridi M, et al. In vivo hippocampal microdialysis reveals impairment of NMDA receptor-cGMP signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer's transgenic mice. Neurochem Int. 2012;61(7):976-80.
Duszczyk, M., Kuszczyk, M., Guridi, M., Lazarewicz, J. W., & Sadowski, M. J. (2012). In vivo hippocampal microdialysis reveals impairment of NMDA receptor-cGMP signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer's transgenic mice. Neurochemistry International, 61(7), 976-80. https://doi.org/10.1016/j.neuint.2012.07.017
Duszczyk M, et al. In Vivo Hippocampal Microdialysis Reveals Impairment of NMDA receptor-cGMP Signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer's Transgenic Mice. Neurochem Int. 2012;61(7):976-80. PubMed PMID: 22841892.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo hippocampal microdialysis reveals impairment of NMDA receptor-cGMP signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer's transgenic mice. AU - Duszczyk,Malgorzata, AU - Kuszczyk,Magdalena, AU - Guridi,Maitea, AU - Lazarewicz,Jerzy W, AU - Sadowski,Martin J, Y1 - 2012/07/27/ PY - 2012/04/06/received PY - 2012/07/18/revised PY - 2012/07/19/accepted PY - 2012/7/31/entrez PY - 2012/7/31/pubmed PY - 2013/6/6/medline SP - 976 EP - 80 JF - Neurochemistry international JO - Neurochem Int VL - 61 IS - 7 N2 - Transgenic (Tg) mice overexpressing human amyloid precursor protein (APP) mutants reproduce features of early Alzheimer's disease (AD) including memory deficit, presence of β-amyloid (Aβ) oligomers, and age-associated formation of amyloid deposits. In this study we used hippocampal microdialysis to characterize the signaling of N-methyl-d-aspartic acid receptors (NMDA-Rs) in awake and behaving AD Tg mice. The NMDA-R signaling is central to hippocampal synaptic plasticity underlying memory formation and several lines of evidence implicate the role of Aβ oligomers in effecting NMDA-R dysfunction. CA1 NMDA-Rs were stimulated by NMDA infused through reverse microdialysis while changes in the cyclic guanosine monophosphate (cGMP) concentration in the brain interstitial fluid (ISF) were used to determine NMDA-Rs responsiveness. While 4 months old wild type C57BL/6 mice mounted robust cGMP response to the NMDA challenge, the same stimulus failed to significantly change the cGMP level in 4 and 15 months old APP(SW) and 4 months old APP(SW)/PS1(L166P) Tg mice, which were all on C57BL/6 background. Lack of response to NMDA in AD Tg mice occurred in the absence of changes in expression levels of several synaptic proteins including synaptophysin, NR1 NMDA-R subunit and postsynaptic density protein 95, which indicates lack of profound synaptic degeneration. Aβ oligomers were detected in all three AD Tg mice groups and their concentration in the hippocampus ranged from 40.5±3.6ng/g in 4 months old APP(SW) mice to 60.8±15.9ng/g in 4 months old APP(SW)/PS1(L166P) mice. Four months old APP(SW) mice had no Aβ amyloid plaques, while the other two AD Tg mice groups showed evidence of incipient Aβ amyloid plaque formation. Our studies describes a novel approach useful to study the function of NMDA-Rs in awake and behaving AD Tg mice and demonstrate impairment of NMDA-R response in the presence of endogenously formed Aβ oligomers but predating onset of Aβ amyloidosis. SN - 1872-9754 UR - https://www.unboundmedicine.com/medline/citation/22841892/In_vivo_hippocampal_microdialysis_reveals_impairment_of_NMDA_receptor_cGMP_signaling_in_APP_SW__and_APP_SW_/PS1_L166P__Alzheimer's_transgenic_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(12)00243-4 DB - PRIME DP - Unbound Medicine ER -