Fig. 10: S1P and YAPdeltaC rescue ER instability and necrosis in genome-edited iPSC-derived AD neurons. | Nature Communications

Fig. 10: S1P and YAPdeltaC rescue ER instability and necrosis in genome-edited iPSC-derived AD neurons.

From: YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology

Fig. 10

a Protocol for the rescue effect of S1P on ER instability and cell death. b Time-lapse images of non-treated iPSC-derived AD neurons exhibited ER ballooning (white arrows) and rupture. S1P treatment stabilized the ER and decreased necrosis. Aβ accumulation in ER (yellow area) and the leak to cytoplasm (green arrow). Representative images are shown in Supplementary Movie 7-12. c S1P did not change %BTA1-positive iPSC-derived AD neurons. d, e Suppressive effect of S1P on ER ballooning and necrosis of iPSC-derived AD neurons d and BTA1-positive neurons e. f Protocol for the rescue effect of YAPdeltaC on ER instability and cell death. AAV-NINS: AAV-CMV-no inset. g Time-lapse images showed ER ballooning (white arrows) and rupture of iPSC-derived AD neurons, which were suppressed by YAPdeltaC expression. Aβ was mainly accumulated in ER (yellow area), but a portion leaked into the cytoplasm (green arrow). Representative images are shown in Supplementary Movie 13-18. h YAPdeltaC did not change %BTA1-positive iPSC-derived AD neurons. i Suppressive effect of YAPdeltaC on ER ballooning and necrosis in iPSC-derived AD neurons i and BTA1-positive neurons j. k, l. Rescue of transcriptional function, as determined using TEAD-responsive element reporter plasmid in iPSC-derived neurons. S1P k and YAPdeltaC l restored TEAD-YAP/YAPdeltaC-dependent transcription, which was suppressed in iPSC-derived AD neurons. **p < 0.01 (N = 6 wells), Tukey’s HSD test. m Time-lapse images of shrinkage apoptosis and ballooning necrosis (arrow). n The ratio of each type of cell death (shrinkage apoptosis, rupture necrosis and ballooning necrosis) to total neurons that occurred naturally during 24 h of time-lapse imaging in normal and iPSC-derived AD neurons. ##p < 0.01 (N = 3 wells, n = 10 visual fields), Tukey’s HSD test. o. The ratio of each type of cell death to total neurons that occurred during 24 h after transfection of YAP-siRNA or scrambled-siRNA. **p < 0.01 (N = 3 wells, n = 10 visual fields), Wilcoxon’s rank sum test. c, d, e, h, i, j **p < 0.01 (N = 3 wells, n = 10 visual fields) by Wilcoxon’s rank–sum test with post-hoc Bonferroni correction. Box plots show the median, quartiles and whiskers that represent 1.5× the interquartile range. Source data are provided as a “Source Data file”.

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