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The Journal of Neuroscience, March 21, 2007, 27(12):3090-3097; doi:10.1523/JNEUROSCI.4854-06.2007

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Neurobiology of Disease
Anesthesia Leads to Tau Hyperphosphorylation through Inhibition of Phosphatase Activity by Hypothermia

Emmanuel Planel,¹ Karl E. G. Richter,² Charles E. Nolan,² James E. Finley,² Li Liu,¹ Yi Wen,¹ Pavan Krishnamurthy,¹ Mathieu Herman,¹ Lili Wang,¹ Joel B. Schachter,² Robert B. Nelson,² Lit-Fui Lau,² and Karen E. Duff¹

¹Columbia University Medical Center, Department of Pathology, Taub Institute for Alzheimer's Disease Research, New York, New York 10032, and ²CNS Discovery, Pfizer Global Research and Development, Groton, Connecticut 06340

Correspondence should be addressed to Dr. Emmanuel Planel, Columbia University Medical Center, Department of Pathology, Taub Institute for Alzheimer's Disease Research, Black Building #5-513, 650 West 168th Street, New York, NY 10032. Email: emmanuel{at}planel.org

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 Aß (ß-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.

Key words: Alzheimer's disease; anesthesia; tau; phosphorylation; hypothermia; amyloid-ß

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Received Nov. 7, 2007; revised Jan. 30, 2007; accepted Feb. 8, 2007.

Correspondence should be addressed to Dr. Emmanuel Planel, Columbia University Medical Center, Department of Pathology, Taub Institute for Alzheimer's Disease Research, Black Building #5-513, 650 West 168th Street, New York, NY 10032. Email: emmanuel{at}planel.org

This article has been cited by other articles:

				E. Planel, A. Bretteville, L. Liu, L. Virag, A. L. Du, W. H. Yu, D. W. Dickson, R. A. Whittington, and K. E. Duff Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia FASEB J, August 1, 2009; 23(8): 2595 - 2604. [Abstract] [Full Text] [PDF]

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				E. Planel, P. Krishnamurthy, T. Miyasaka, L. Liu, M. Herman, A. Kumar, A. Bretteville, H. Y. Figueroa, W. Haung Yu, R. A. Whittington, et al. Anesthesia-Induced Hyperphosphorylation Detaches 3-Repeat Tau from Microtubules without Affecting Their Stability In Vivo J. Neurosci., November 26, 2008; 28(48): 12798 - 12807. [Abstract] [Full Text] [PDF]

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				E. Planel, Y. Tatebayashi, T. Miyasaka, L. Liu, L. Wang, M. Herman, W. H. Yu, J. A. Luchsinger, B. Wadzinski, K. E. Duff, et al. Insulin Dysfunction Induces In Vivo Tau Hyperphosphorylation through Distinct Mechanisms J. Neurosci., December 12, 2007; 27(50): 13635 - 13648. [Abstract] [Full Text] [PDF]

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