Premium
P2‐290: Impairment of NMDA receptor signaling in the CA1 sector of APP SW /PS1 dE9 AD Tg mice precedes Aß deposition
Author(s) -
Duszczyk Malgorzata,
Kuszczyk Magdalena,
Guridi Maitea,
Lazarewicz Jerzy W.,
Sadowski Martin
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1340
Subject(s) - nmda receptor , long term potentiation , synaptic plasticity , hippocampus , agonist , receptor , nitric oxide , chemistry , hippocampal formation , biology , endocrinology , medicine , microbiology and biotechnology , neuroscience , biochemistry
Background: Alzheimer’s disease (AD) is associated with synaptic loss and memory impairment. AD transgenic mice (Tg) models, over-expressing mutated forms of the amyloid precursor protein demonstrate memory deficit and inhibition of the long-term potentiation prior to the appearance of Aß plaques, which implicates toxicity of soluble Aß oligomeric species in the early pathogenesis of memory dysfunction. Experiments in primary cultures of hippocampal neurons showed preferential binding of Aß oligomers to Nmethyl-D-aspartic acid (NMDA) receptors resulting over time in their down regulation. NMDA receptor signaling involves Ca for intracellular signal transduction and is pivotal for the synaptic plasticity in the hippocampus, which underlies memory formation. The goal of our experiments was to characterize impairment of NMDA receptor signaling AD Tg mice, which has not been done before. Methods: NMDA receptor signaling in the CA1 sector of the hippocampus was investigated using microdialysis in awake and behaving 3.5-4 month old APPSW/PS1dE9 AD Tg mice. Under physiological conditions stimulation of NMDA receptor results in a massive increase in the intracellular Ca concentration, which via Ca/ calmodulin / nitric oxide synthase / nitric oxide / soluble guanyl cyclase pathway stimulates production of cGMP. Thus cGMP released to the interstitial fluid can serve as a measure of NMDA receptor function. Results: Stimulation of the NMDA receptor with 500mM NMDA (a selective NMDA agonist) administered through reverse microdialysis resulted in 32% increase in the baseline cGMP level in four month old wild type mice (p < 0.05, paired ttest). In contrast, only 2%, non-significant change in 3.5-4 month old APPSW/PS1dE9 Tg mice was noticed (n 1⁄4 8). Examination of APPSW/ PS1dE9 Tg mice brains revealed minimal Aß plaque load in the CA1 hippocampal sector. These mice had high tissue concentration of Aß species, with predominance of oligomerization prone Aß42. Conclusions: Our experiments provide direct proof of the NMDA receptor signaling impairment in AD Tg mice, which is associated with presence of Aß oligomers but not Aß deposits. Biochemical analysis of NMDA receptor and other post-synaptic proteins is close to explaining whether impairment of the NMDA receptor signaling is associated with down regulation of its expression.