Postoperative cognitive dysfunction,
confusion, and
delirium are common after
general anesthesia in the elderly, with symptoms persisting for months or years in some patients. Even middle-aged patients are likely to have
postoperative cognitive dysfunction for months after surgery, and
Alzheimer's disease (AD) patients appear to be particularly at risk of deterioration after
anesthesia. Several investigators have thus examined whether
general anesthesia is associated with AD, with some studies suggesting that exposure to
anesthetics may increase the risk of AD. However, little is known on the biochemical consequences of
anesthesia on pathogenic pathways in vivo. Here, we investigated the effect of
anesthesia on tau phosphorylation and
amyloid precursor
protein (APP) metabolism in mouse brain. We found that, regardless of the
anesthetic used,
anesthesia induced rapid and massive hyperphosphorylation of tau, rapid and prolonged
hypothermia, inhibition of Ser/Thr PP2A (
protein phosphatase 2A), but no changes in APP metabolism or Abeta (
beta-amyloid peptide) accumulation. Reestablishing normothermia during
anesthesia completely rescued tau phosphorylation to normal levels. Our results indicate that changes in tau phosphorylation were not a result of
anesthesia per se, but a consequence of
anesthesia-
induced hypothermia, which led to inhibition of
phosphatase activity and subsequent hyperphosphorylation of tau. These findings call for careful monitoring of core temperature during
anesthesia in laboratory animals to avoid artifactual elevation of
protein phosphorylation. Furthermore, a thorough examination of the effect of
anesthesia-
induced hypothermia on the risk and progression of AD is warranted.