Anesthesia and/or surgery may promote Alzheimer's disease (AD) by accelerating 
its neuropathogenesis. Other studies showed different findings. However, the 
potential sex difference among these studies has not been well considered, and 
it is unknown whether male or female AD patients are more vulnerable to develop 
postoperative cognitive dysfunction. We therefore set out to perform a proof of 
concept study to determine whether anesthesia and surgery can have different 
effects in male and female AD transgenic (Tg) mice, and in female AD Tg plus 
Cyclophilin D knockout (CypD KO) mice. The mice received an abdominal surgery 
under sevoflurane anesthesia (anesthesia/surgery). Fear Conditioning System 
(FCS) was used to assess the cognitive function. Hippocampal levels of synaptic 
marker postsynaptic density 95 (PSD-95) and synaptophysin (SVP) were measured 
using western blot analysis. Here we showed that the anesthesia/surgery 
decreased the freezing time in context test of FCS at 7 days after the 
anesthesia/surgery in female, but not male, mice. The anesthesia/surgery reduced 
hippocampus levels of synaptic marker PSD-95 and SVP in female, but not male, 
mice. The anesthesia/surgery induced neither reduction in freezing time in FCS 
nor decreased hippocampus levels of PSD-95 and SVP in the AD Tg plus CypD KO 
mice. These data suggest that the anesthesia/surgery induced a sex-dependent 
cognitive impairment and reduction in hippocampus levels of synaptic markers in 
AD Tg mice, potentially via a mitochondria-associated mechanism. These findings 
could promote clinical investigations to determine whether female AD patients 
are more vulnerable to the development of postoperative cognitive dysfunction.