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The Journal of Neuroscience, November 26, 2008, 28(48):12798-12807; doi:10.1523/JNEUROSCI.4101-08.2008

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Neurobiology of Disease
Anesthesia-Induced Hyperphosphorylation Detaches 3-Repeat Tau from Microtubules without Affecting Their Stability In Vivo

Emmanuel Planel,¹ Pavan Krishnamurthy,¹ Tomohiro Miyasaka,² Li Liu,¹ Mathieu Herman,¹ Asok Kumar,³ Alexis Bretteville,¹ Helen Y. Figueroa,¹ Wai Haung Yu,¹ Robert A. Whittington,⁴ Peter Davies,⁵ Akihiko Takashima,⁶ Ralph A. Nixon,³ and Karen E. Duff¹

¹Taub Institute for Alzheimer's Disease Research, Department of Pathology, Columbia University Medical Center, New York, New York 10032, ²Faculty of Life and Medical Sciences, Department of Medical Life Systems, Doshisha University, Kyoto 610-0394, Japan, ³Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962, ⁴Department of Anesthesiology, Columbia University, New York, New York 10027, ⁵Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, and ⁶The Institute of Physical and Chemical Research (RIKEN), Brain Science Institute, Laboratory for Alzheimer's Disease, Wako-shi, Saitama, 351-0198, Japan

Correspondence should be addressed to Dr. Karen E. Duff, Columbia University Medical Center, Taub Institute for Alzheimer's Disease Research, Department of Pathology, P&S #12-440, 630 West 168th Street, New York, NY 10032. Email: ked2115{at}columbia.edu

In Alzheimer's disease, tau is hyperphosphorylated, which is thought to detach it from microtubules (MTs), induce MT destabilization, and promote aggregation. Using a previously described in vivo model, we investigated whether hyperphosphorylation impacts tau function in wild-type and transgenic mice. We found that after anesthesia-induced hypothermia, MT-free tau was hyperphosphorylated, which impaired its ability to bind MTs and promote MT assembly. MT-bound tau was more resistant to hyperphosphorylation compared with free tau and tau did not dissociate from MTs in wild-type mice. However, 3-repeat tau detached from MT in the transgenic mice. Surprisingly, dissociation of tau from MTs did not lead to overt depolymerization of tubulin, and there was no collapse, or disturbance of axonal MT networks. These results indicate that, in vivo, a subpopulation of tau bound to MTs does not easily dissociate under conditions that extensively phosphorylate tau. Tau remaining on the MTs under these conditions is sufficient to maintain MT network integrity.

Key words: tau phosphorylation; microtubules; Alzheimer's disease; anesthesia; hypothermia; tubulin

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Received Aug. 27, 2008; accepted Oct. 15, 2008.

Correspondence should be addressed to Dr. Karen E. Duff, Columbia University Medical Center, Taub Institute for Alzheimer's Disease Research, Department of Pathology, P&S #12-440, 630 West 168th Street, New York, NY 10032. Email: ked2115{at}columbia.edu

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