Anesthesia and AD: Phospho-Tau Surges in Sleeping Mice

Anesthesia dulls the senses by design, but for elderly people the after-effects might be more than they bargained for. Months of confusion and even permanent cognitive decline can occur after surgery under general anesthesia. Some epidemiological studies have suggested that anesthesia in elderly patients is a risk factor for developing AD. Other studies have suggested that some commonly used inhaled anesthetics might exacerbate amyloid pathology by promoting the oligomerization of amyloid-β (Aβ) peptides (Eckenhoff et al., 2004; Bianchi et al., 2007), or their production and toxicity to cells (see ARF related news story).

Now, tau is getting dragged into the act, too, with new work showing that, in mice, several anesthetics cause rapid and dramatic increases in tau phosphorylation. Emmanuel Planel and Karen Duff at Columbia University Medical Center in New York, demonstrate that the spike in phospho-tau is not caused by the anesthetics themselves, but instead occurs in response to a rapid and prolonged anesthetic-induced lowering of body temperature, which decreases the activity of the protein phosphatase 2A (PP2A), a major tau phosphatase in brain. Joining Planel as coauthors on the March 21 publication in the Journal of Neuroscience are Lit-Fui Lau and colleagues at Pfizer Global Research and Development in Groton, Connecticut.

In the study, the researchers treated mice with any of three anesthetics—intraperitoneal chloral hydrate, pentobarbital, or inhaled isoflurane—and looked at tau by Western blot 1 hour later. In each case, they saw massively increased phosphorylation at every one of the eight phosphoepitopes they checked, including pathological epitopes associated with paired helical filament formation. Anesthesia was accompanied by a dramatic drop in core body temperature to as low as 26-27 degrees centigrade, and phosphorylation at the AT8 epitope went up as body temperature dropped. When the scientists kept anesthetized animals in heated chambers to prevent the drop, the hyperphosphorylation disappeared.

Under these acute treatment conditions, the researchers did not see changes in amyloid precursor protein metabolism or Aβ levels. This is in contrast to experiments in cell culture, where isoflurane enhanced Aβ accumulation and apoptosis in human neuroglioma cells (Xie et al., 2006).

It is not news that lowering body temperature jacks up tau phosphorylation. Planel and colleagues previously showed a reversible hyperphosphorylation of tau epitopes by hypothermia in mice with impaired glucose metabolism (Planel et al., 2004), and studies from Thomas Arendt and colleagues at Leipzig University, Germany, found the same in hibernating ground squirrels (Arendt et al., 2003). In both cases, the phosphorylation rapidly reverses when the animals warm up to normal body temperature, and indeed the current work shows the same result.

However, no one knows what effect anesthesia and hypothermia might have when the brain is already afflicted with a tauopathy or AD. “We must redo these experiments in tau transgenic mice, or in a mouse model of AD. If we see more accumulation of tangles, it will be further evidence that anesthesia can have pathological effects,” Planel told ARF.

The results also carry a warning for researchers studying mouse models of AD that fluctuations in body temperature during experiments may produce artifacts of tau phosphorylation. The authors cite one study that showed APP transgenic mice are more prone to hypothermia than normal mice (Huitron-Resendiz et al., 2002), and another that found the standard procedure for the Morris water maze leaves mice hypothermic (Iivonen et al., 2003). “The main implication of this work is that people should be very careful when they analyze their mice,” Planel said. “These are not subtle changes. We found that a 3-4-degree drop in temperature can increase AT8 phosphorylation by 400-500 percent.”

How does hypothermia affect tau? Planel’s previous work showed that lowering body temperature decreases the activity of the protein phosphatase 2A (PP2A). In agreement with this, the scientists now found that when they reduced the assay temperature from 37 to 26 degrees, PP2A in brain extracts from anesthetized mice were inhibited by 40 percent. PP2A is the main enzyme responsible for dephosphorylating tau in the brain, and low PP2A activity has been implicated in AD pathology (reviewed in Tian and Wang, 2002).

Finally, the authors call for a re-examination of epidemiological studies looking at the association between anesthesia and AD. Where data are available about how changes in body temperature were managed, looking at the outcome in cases where anesthesia resulted in documented hypothermia may give a different picture of the anesthesia-AD link.—Pat McCaffrey

Comments

    • User Profile Image Zhongcong Xie
      Massachusetts General Hospital/Harvard Medical School
    • Posted:

    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.

    References:

    Eckenhoff RG, Johansson JS, Wei H, Carnini A, Kang B, Wei W, Pidikiti R, Keller JM, Eckenhoff MF. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology. 2004 Sep;101(3):703-9. PubMed.

    Xie Z, Dong Y, Maeda U, Moir R, Inouye SK, Culley DJ, Crosby G, Tanzi RE. 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.

    Xie Z, Dong Y, Maeda U, Moir RD, Xia W, Culley DJ, Crosby G, Tanzi RE. 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.

    View all comments by Zhongcong Xie

  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.

    References:

    Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998 Mar 21;351(9106):857-61. PubMed.

    Planel E, Richter KE, Nolan CE, Finley JE, Liu L, Wen Y, Krishnamurthy P, Herman M, Wang L, Schachter JB, Nelson RB, Lau LF, Duff KE. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci. 2007 Mar 21;27(12):3090-7. PubMed.

    Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A. 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.

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

    Arendt T, Holzer M, Fruth R, Brückner MK, Gärtner U. 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.

    Kins S, Crameri A, Evans DR, Hemmings BA, Nitsch RM, Gotz J. 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.

    View all comments by Jesus Avila

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References

News Citations

  1. Do Inhaled Anesthetics Contribute to AD?

Paper Citations

  1. Eckenhoff RG, Johansson JS, Wei H, Carnini A, Kang B, Wei W, Pidikiti R, Keller JM, Eckenhoff MF. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology. 2004 Sep;101(3):703-9. PubMed.
  2. Bianchi SL, Tran T, Liu C, Lin S, Li Y, Keller JM, Eckenhoff RG, Eckenhoff MF. Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics. Neurobiol Aging. 2008 Jul;29(7):1002-10. PubMed.
  3. Xie Z, Dong Y, Maeda U, Alfille P, Culley DJ, Crosby G, Tanzi RE. The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels. Anesthesiology. 2006 May;104(5):988-94. PubMed.
  4. Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A. 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.
  5. Arendt T, Stieler J, Strijkstra AM, Hut RA, Rüdiger J, Van der Zee EA, Harkany T, Holzer M, Härtig W. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci. 2003 Aug 6;23(18):6972-81. PubMed.
  6. Huitrón-Reséndiz S, Sánchez-Alavez M, Gallegos R, Berg G, Crawford E, Giacchino JL, Games D, Henriksen SJ, Criado JR. Age-independent and age-related deficits in visuospatial learning, sleep-wake states, thermoregulation and motor activity in PDAPP mice. Brain Res. 2002 Feb 22;928(1-2):126-37. PubMed.
  7. Iivonen H, Nurminen L, Harri M, Tanila H, Puoliväli J. Hypothermia in mice tested in Morris water maze. Behav Brain Res. 2003 May 15;141(2):207-13. PubMed.
  8. Tian Q, Wang J. Role of serine/threonine protein phosphatase in Alzheimer's disease. Neurosignals. 2002 Sep-Oct;11(5):262-9. PubMed.

Further Reading

Papers

  1. Carnini A, Eckenhoff MF, Eckenhoff RG. Interactions of volatile anesthetics with neurodegenerative-disease-associated proteins. Anesthesiol Clin. 2006 Jun;24(2):381-405. PubMed.
  2. Härtig W, Stieler J, Boerema AS, Wolf J, Schmidt U, Weissfuss J, Bullmann T, Strijkstra AM, Arendt T. Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons - implications for Alzheimer's disease. Eur J Neurosci. 2007 Jan;25(1):69-80. PubMed.

Primary Papers

  1. Planel E, Richter KE, Nolan CE, Finley JE, Liu L, Wen Y, Krishnamurthy P, Herman M, Wang L, Schachter JB, Nelson RB, Lau LF, Duff KE. 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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