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The Journal of Neuroscience, December 8, 2004, 24(49):11120-11126; doi:10.1523/JNEUROSCI.2860-04.2004

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Neurobiology of Disease
Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade: Implications for Alzheimer's Disease Intervention

Lixia Zhao,^1,3 Bruce Teter,^1,3 Takashi Morihara,^1,3 Giselle P. Lim,^1,3 Surendra S. Ambegaokar,^1,3 Oliver J. Ubeda,^1,3 Sally A. Frautschy,^1,2,3 and Greg M. Cole^1,2,3

Departments of ¹Medicine and ²Neurology, University of California Los Angeles, and ³Geriatric Research Education and Clinical Center and Greater Los Angeles Healthcare System, North Hills, California 91343

Insulin-degrading enzyme (IDE) is one of the proteins that has been demonstrated to play a key role in degrading -amyloid (A) monomer in vitro and in vivo, raising the possibility of upregulating IDE as an approach to reduce A. Little is known, however, about the cellular and molecular regulation of IDE protein. Because one of the main functions of IDE is to degrade insulin, we hypothesized that there is a negative feedback mechanism whereby stimulation of insulin receptor-mediated signaling upregulates IDE to prevent chronic activation of the pathway. We show that treatment of primary hippocampal neurons with insulin increased IDE protein levels by 25%. Insulin treatment also led to phosphatidylinositol-3 (PI3) kinase activation evidenced by Akt phosphorylation, which was blocked by PI3 kinase inhibitors, wortmannin and LY 294002. Inhibition of PI3 kinase abolished the IDE upregulation by insulin, indicating a cause-effect relationship between insulin signaling and IDE upregulation. Further support for this link was provided by the findings that deficient insulin signaling (decreased PI3 kinase subunit P85) was correlated with reduced IDE in Alzheimer's disease (AD) brains and in Tg2576 Swedish amyloid precursor protein transgenic mice fed a safflower oil-enriched ("Bad") diet used to accelerate pathogenesis. Consistent with IDE function in the degradation of A monomer, the IDE decrease in the Bad diet-fed Tg2576 mice was associated with increased A monomer levels. These in vitro and in vivo analyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD.

Key words: insulin; insulin-degrading enzyme; hippocampal neurons; Alzheimer's disease; Tg2576 transgenic mice; PI3 kinase

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Received July 15, 2004; revised October 17, 2004; accepted November 2, 2004.

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