Anesthesia and Surgery Induce Sex-dependent Tau Phosphorylation and Behavior Changes in Aged Mice

Preoperative blood Tau phosphorylated at threonine 217 (Tau-PT217), a newly identified blood biomarker of Alzheimer disease, is associated with postoperative delirium in patients. Anesthesia/surgery is also associated with postoperative increased blood Tau-PT217 amounts in patients. Moreover, in female aged mice, anesthesia/surgery increases Tau-PT217 in lungs, blood, and brain tissues, leading to behavioral changes. However, whether these effects are sex-dependent remains largely undetermined.

Eighteen-month-old female and male mice (C57BL/6J) underwent abdominal surgery during general anesthesia (1.4% isoflurane and 40% oxygen). Levels of Tau-PT217, inflammatory markers, and glycogen synthase kinase 3 β (GSK3β) activity were measured in lungs, blood, and brain tissues of aged mice using Nanoneedle technology, Western blot, immunohistochemistry, reverse-transcription polymerase chain reaction, and others. Postoperative delirium-like behavior was assessed using a battery of behavioral tests (buried food, open field, and Y-maze). To explore causality, the authors performed orchiectomy and administered androgen receptor antagonist enzalutamide in aged male mice. Finally, testosterone was delivered via inhalation to aged female mice.

Anesthesia/surgery increased the amounts of Tau-PT217 in lungs (2.29 ± 0.16-fold vs. 1.15 ± 0.71-fold; P < 0.01), blood, and brain tissues of aged female but not male mice compared to control condition, leading to postoperative delirium-like behavior, as evidenced by increases in the composite Z-score (3.74 ± 1.46 vs. 0.60 ± 1.17; P < 0.01) in the aged female but not male mice. Anesthesia/surgery elevated inflammatory markers and GSK3β activity in aged female mice, which exhibited lower baseline testosterone levels and androgen receptor expression in lungs compared to males. Both orchiectomy and enzalutamide treatment in male mice reduced testosterone levels and androgen receptor expression, leading to elevation of Tau-PT217 amounts and behavior changes after anesthesia/surgery. Conversely, testosterone inhalation in aged female mice mitigated the anesthesia/surgery-induced elevation of Tau-PT217 amounts and behavior changes.

Testosterone and androgen receptor signaling may contribute to the sex-dependent differences in Tau phosphorylation and postoperative behavior changes in aged mice.