β 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 (Aβ) and elevated Ca(2+) have been implicated as proximal and likely interactive features of the disease process. We tested the hypothesis that proximity to Aβ plaque might exacerbate activity-dependent neuronal Ca(2+) signaling in hippocampal pyramidal neurons from APPSWE/PS1M146V mice. Using combined approaches of whole cell patch clamp recording and 2-photon imaging of neuronal Ca(2+) signals with thioflavin-S plaque labeling in hippocampal slices, we found no correlation between thioflavin-S labeled Aβ plaque proximity and Ca(2+) 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 Aβ plaque proximity. Consistent with previous studies, RyR-evoked Ca(2+) release in APPSWE/PS1M146V mice was greater than in nontransgenic controls. Within the soma, RyR-evoked Ca(2+) release was elevated in older APPSWE/PS1M146V mice compared with younger APPSWE/PS1M146V mice, but was still independent of plaque proximity. The results indicate that early Ca(2+) signaling disruptions can become yet more severe with age through mechanisms independent of Aβ plaques, suggesting that alternative pathogenic mechanisms might contribute to AD-associated dysfunction.