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J. Biol. Chem., Vol. 282, Issue 46, 33305-33312, November 16, 2007

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Soluble A Inhibits Specific Signal Transduction Cascades Common to the Insulin Receptor Pathway^*

From the Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115

Numerous studies have now shown that the amyloid -protein (A), the principal component of cerebral plaques in Alzheimer disease, rapidly and potently inhibits certain forms of synaptic plasticity. The amyloid (or A) hypothesis proposes that the continuous disruption of normal synaptic physiology by A contributes to the development of Alzheimer disease. However, there is little consensus about how A mediates this inhibition at the molecular level. Using mouse primary hippocampal neurons, we observed that a brief treatment with cell-derived, soluble, human A disrupted the activation of three kinases (Erk/MAPK, CaMKII, and the phosphatidylinositol 3-kinase-activated protein Akt/protein kinase B) that are required for long term potentiation, whereas two other kinases (protein kinase A and protein kinase C) were stimulated normally. An antagonist of the insulin receptor family of tyrosine kinases was found to mimic the pattern of A-mediated kinase inhibition. We then found that soluble A binds to the insulin receptor and interferes with its insulin-induced autophosphorylation. Taken together, these data demonstrate that physiologically relevant levels of naturally secreted A interfere with insulin receptor function in hippocampal neurons and prevent the rapid activation of specific kinases required for long term potentiation.

Received for publication, November 7, 2006 , and in revised form, September 5, 2007.

^* This work was supported by National Institutes of Health Grants AG027443 (to D. J. S.) and T32 NS07484-04 and Massachusetts Alzheimer's Disease Research Center (to M. T.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 617-525-5200; Fax: 617-525-5305; E-mail: dselkoe{at}rics.bwh.harvard.edu.

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