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The Journal of Neuroscience, December 12, 2007, 27(50):13635-13648; doi:10.1523/JNEUROSCI.3949-07.2007

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Neurobiology of Disease
Insulin Dysfunction Induces In Vivo Tau Hyperphosphorylation through Distinct Mechanisms

Emmanuel Planel,^1,4 Yoshitaka Tatebayashi,^1,2 Tomohiro Miyasaka,^1,3 Li Liu,⁴ Lili Wang,⁴ Mathieu Herman,⁴ W. Haung Yu,⁴ Jose A. Luchsinger,⁵ Brian Wadzinski,⁶ Karen E. Duff,⁴ and Akihiko Takashima¹

¹Laboratory for Alzheimer's Disease, Brain Science Institute, The Institute of Physical and Chemical Research, Saitama 351-0198, Japan, ²Depression Project, Mood Disorder Research Team, Tokyo Institute of Psychiatry, Tokyo 156-8585, Japan, ³Department of Neuropathology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan, ⁴Department of Pathology, Taub Institute for Alzheimer's Disease Research, Columbia University Medical Center, ⁵Columbia University, New York, New York 10032, and ⁶Vanderbilt University Medical Center, Nashville, Tennessee 37232

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

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of the disease. The large majority of AD cases is late onset and sporadic in origin, with aging as the most important risk factor. Insulin resistance, impaired glucose tolerance, and diabetes mellitus (DM) are other common syndromes in the elderly also strongly age dependent, and there is evidence supporting a link between insulin dysfunction and AD. To investigate the possibility that insulin dysfunction might promote tau pathology, we induced insulin deficiency and caused DM in mice with streptozotocin (STZ). A mild hyperphosphorylation of tau could be detected 10, 20, and 30 d after STZ injection, and a massive hyperphosphorylation of tau was observed after 40 d. The robust hyperphosphorylation of tau was localized in the axons and neuropil, and prevented tau binding to microtubules. Neither mild nor massive tau phosphorylation induced tau aggregation. Body temperature of the STZ-treated mice did not differ from control animals during 30 d, but dropped significantly thereafter. No change in β-amyloid (Aβ) precursor protein (APP), APP C-terminal fragments, or Aβ levels were observed in STZ-treated mice; however, cellular protein phosphatase 2A activity was significantly decreased. Together, these data indicate that insulin dysfunction induced abnormal tau hyperphosphorylation through two distinct mechanisms: one was consequent to hypothermia; the other was temperature-independent, inherent to insulin depletion, and probably caused by inhibition of phosphatase activity.

Key words: Alzheimer's disease; tau hyperphosphorylation; β-amyloid precursor protein; insulin deficiency; streptozotocin; diabetes mellitus; hypothermia; kinase; serine/threonine protein phosphatase; PP2A; GSK-3; cdk5; JNK; MAPK; CaMKII

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Received March 15, 2007; revised Oct. 17, 2007; accepted Oct. 18, 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:

				B. Kim, C. Backus, S. Oh, J. M. Hayes, and E. L. Feldman Increased Tau Phosphorylation and Cleavage in Mouse Models of Type 1 and Type 2 Diabetes Endocrinology, December 1, 2009; 150(12): 5294 - 5301. [Abstract] [Full Text] [PDF]

				R. Puri, T. Suzuki, K. Yamakawa, and S. Ganesh Hyperphosphorylation and Aggregation of Tau in Laforin-deficient Mice, an Animal Model for Lafora Disease J. Biol. Chem., August 21, 2009; 284(34): 22657 - 22663. [Abstract] [Full Text] [PDF]

				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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