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J. Biol. Chem., Vol. 279, Issue 43, 44795-44801, October 22, 2004

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Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

MODULATION BY ZINC^*

Faith M. Harris, Walter J. Brecht, Qin Xu, Robert W. Mahley¶||, and Yadong Huang¶**

From the Gladstone Institutes of Neurological Disease and Cardiovascular Disease and the Departments of ^¶Pathology and ^||Medicine, University of California, San Francisco, California 94141-9100

Although apolipoprotein (apo) E4 is present in amyloid plaques and neurofibrillary tangles, its pathogenic role in Alzheimer's disease (AD) is unclear. Neuronal expression of apoE4 or apoE4 fragments in transgenic mice increases tau phosphorylation. To identify the kinase responsible for the increase, we studied transgenic mice expressing human apoE3 or apoE4 in neurons under the control of the neuron-specific enolase promoter. Brain levels of phosphorylated tau (p-tau) and phosphorylated (active) extracellular signal-regulated kinase (p-Erk) increased with age in both groups but were considerably higher in the apoE4 mice. Other candidate kinases, including glycogen synthase kinase 3 and cyclin-dependent kinase-5 and its activators p25 and p35, were not significantly altered. The increases in p-Erk and p-tau were highest in the hippocampus, intermediate in the cortex, and lowest in the cerebellum. In the hippocampus, p-Erk and p-tau accumulated in the hilus and CA3 region of the dentate gyrus, where high levels of zinc are found along mossy fibers. In Neuro-2a cells stably expressing apoE3 or apoE4, treatment with ZnCl₂ generated 2-fold more p-Erk and 3-fold more p-tau in the apoE4-expressing cells. Phosphorylation of Erk and tau was reduced by preincubation with the Erk pathway inhibitor U0126. Thus, increased tau phosphorylation in apoE4 transgenic mice was associated with Erk activation and could be modified by zinc, suggesting that apoE4 and zinc act in concert to contribute to the pathogenesis of AD.

Received for publication, July 19, 2004 , and in revised form, August 18, 2004.

^* This work was supported in part by National Institutes of Heath Grants P01 AG022074, R01 HL37063, and R21 NS046465. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Gladstone Institute of Neurological Disease, P. O. Box 419100, San Francisco, CA 94141–9100. Tel.: 415-826-7500; Fax: 415-285-5632; E-mail: yhuang{at}gladstone.ucsf.edu.

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