. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci. 2007 Mar 21;27(12):3090-7. PubMed.


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  1. The work by Planel et al. shows that a treatment with anesthetic chloral hydrate, pentobarbital sodium, or isoflurane can induce tau hyperphosphorylation via inhibition of phosphatase activity by hypothermia in mice. The anesthesia was induced by intraperitoneal injections of chloral hydrate (500 mg/kg), pentobarbital sodium (100 mg/kg) or by exposure to inhaled isoflurane. The results suggest that the changes in tau phosphorylation were not a result of anesthesia per se, but rather a consequence of anesthesia-induced hypothermia. Since hypothermia can happen in the operation room, these studies indicate that it is important to maintain normal temperature for patients under surgery.

    Chloral hydrate and pentobarbital sodium are not clinical anesthetics; therefore, the clinical relevance of the present results is unclear. Moreover, mice may develop hypotension, hypoxia, and hypercapnia [Editor’s note: i.e., blood carbon dioxide overload] following the anesthesia, which could affect Alzheimer disease neuropathogenesis, as well. Data of blood pressure and blood gas after anesthesia would be useful to assess these potential effects.

    Isoflurane is in clinical use. Recent studies (Eckenhoff et al., 2004; Xie et al., 2006; Xie et al., 2007) showed that a treatment with 1.2 to 2.5 percent isoflurane for 6 hours can enhance Aβ oligomerization, affect APP processing, and increase Aβ generation in cultured cells. In Fig. 2 of the present study, the authors show that anesthesia under the conditions used affected neither APP processing nor Aβ levels in mouse brain. However, the concentration of isoflurane and duration of exposure to isoflurane have not been provided in the studies. For this reason, it is difficult to determine the effects of isoflurane on APP processing and Aβ generation based solely on these experiments. It is conceivable that a treatment with different concentrations of isoflurane and different exposure times may affect APP processing and Aβ levels.

    More in vivo studies systematically assessing the effects of clinically relevant anesthetics (e.g., isoflurane, sevoflurane, desflurane, propofol, morphine, fentanyl) on APP processing, Aβ generation, and tau protein metabolism are warranted before we can conclude whether anesthesia itself versus anesthesia-induced hypothermia can affect Alzheimer disease neuropathogenesis.


    . Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology. 2004 Sep;101(3):703-9. PubMed.

    . Isoflurane-induced apoptosis: a potential pathogenic link between delirium and dementia. J Gerontol A Biol Sci Med Sci. 2006 Dec;61(12):1300-6. PubMed.

    . The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci. 2007 Feb 7;27(6):1247-54. PubMed.

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  2. Improvements in medical and surgical procedures have resulted in longer human lifespan. However, surgery could promote collateral damage in neurons due to the use of different types of anesthesia. It has been suggested that exposure to anesthetic agents could promote cognitive dysfunction (1). Now, Planel et al. (2) clearly indicate a mechanism to explain how anesthesia is a risk for increasing tau pathology in Alzheimer disease (AD). In well-performed work, Planel et al. show that anesthesia leads to tau hyperphosphorylation similar to that occurring in AD. They have shown that tau hyperphosphorylation was not the consequence of an increase in kinase activity but of a decrease in phosphatase (PP2A) activity, with anesthesia-induced hypothermia being the cause for phosphatase inhibition.

    This work supports a previous observation by Planel et al. (3) indicating that hypothermia, promoted by different causes, results in the appearance of aberrant tau phosphorylation. A clinical implication of Planel’s results is a call for monitoring the body (brain) temperature during anesthesia to avoid prolonged hypothermia and to have a fast return to normal temperature.

    Also, a result of great interest from the work of Planel et al. is that hypothermia did not change APP metabolism or Aβ accumulation, suggesting that PP2A inhibition, induced by anesthesia, did not play a role in Aβ pathology. However, this point has been previously discussed (4). Thus, it has been shown that some anesthetic compounds promote Aβ secretion in APP-overexpressing cells (4). Accordingly, compounds able to inhibit or prevent the expression of PP2A by pharmacological (5) or genetic means (6) should be tested to confirm the previous results on APP metabolism, or to determine other side effects for anesthesia.


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    . Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci. 2007 Mar 21;27(12):3090-7. PubMed.

    . Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer's disease. J Neurosci. 2004 Mar 10;24(10):2401-11. PubMed.

    . Alzheimer's disease and post-operative cognitive dysfunction. Exp Gerontol. 2006 Apr;41(4):346-59. PubMed.

    . Phosphorylation of tau, Abeta-formation, and apoptosis after in vivo inhibition of PP-1 and PP-2A. Neurobiol Aging. 1998 Jan-Feb;19(1):3-13. PubMed.

    . Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem. 2001 Oct 12;276(41):38193-200. Epub 2001 Jul 25 PubMed.

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