A) Pseudocolored multiphoton image of transgenic mouse treated with FK-506. Daily intraperitoneal injection of FK-506 (10 mg/kg) prevented the neuritic beading and severe calcium overload typically seen in APP/PS1 mice near plaques (in white). B) Multiphoton image of APP/PS1 mouse that was sham-treated. Moderate and severe calcium overloaded neurites surround a plaque with varying morphologies. C) In the calcium-overloaded neurites, there was a significant reduction in the resting calcium (p< 0.01, Mann-Whitney U-test). D) The reduction in [Ca2+]i can be explained by a reduction in the percentage of neurites that exhibit neuritic beading—only 33% of calcium-overloaded neurites exhibit a beaded and severe elevation of [Ca2+]i compared to 54% in sham-treatment (n = 3 mice in each group, n = 159 calcium-overloaded neurites, p < 0.05, Chi-Squared Test). E) Morphologically normal processes (spiny dendrites and aspiny processes) exhibit nearly the same [Ca2+]i in FK-506 treated or sham-treated mice (n = 82 neurites, p = 0.6807, students T-test) whereas there is a slight, but significant, reduction in the [Ca2+]i in those neurites with an abnormal morphology (n = 87 neurites, p < 0.05, student’s T-test).