Beta amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP/PS1 Alzheimer's disease mice

Alzheimer's disease (AD) is a multifactorial disorder of unknown etiology. Mechanistically, beta amyloid peptides (A beta) and elevated Ca2+ have been implicated as proximal and likely interactive features of the disease process. We tested the hypothesis that proximity to A beta plaque might exacerbate activity-dependent neuronal Ca2+ signaling in hippocampal pyramidal neurons from APP(SWE)/PS1(M146V) mice. Using combined approaches of whole cell patch clamp recording and 2-photon imaging of neuronal Ca2+ signals with thioflavin-S plaque labeling in hippocampal slices, we found no correlation between thioflavin-S labeled A beta plaque proximity and Ca2+ responses triggered by ryanodine receptor (RyR) activation or action potentials in either dendrites or somata of AD mice, regardless of age. Baseline and RyR-stimulated spontaneous excitatory postsynaptic potentials also showed little difference in relation to A beta plaque proximity. Consistent with previous studies, RyR-evoked Ca2+ release in APP(SWE)/PS1(M146V) mice was greater than in nontransgenic controls. Within the soma, RyR-evoked Ca2+ release was elevated in older APP(SWE)/PS1(M146V) mice compared with younger APP(SWE)/PS1(M146V) mice, but was still independent of plaque proximity. The results indicate that early Ca2+ signaling disruptions can become yet more severe with age through mechanisms independent of A beta plaques, suggesting that alternative pathogenic mechanisms might contribute to AD-associated dysfunction. (C) 2013 Elsevier Inc. All rights reserved.