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Originally published In Press as doi:10.1074/jbc.M701078200 on June 4, 2007

J. Biol. Chem., Vol. 282, Issue 33, 23818-23828, August 17, 2007
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Accelerating Amyloid-beta Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models*Formula

Irene H. Cheng{ddagger}§, Kimberly Scearce-Levie{ddagger}§, Justin Legleiter{ddagger}§, Jorge J. Palop{ddagger}§, Hilary Gerstein{ddagger}, Nga Bien-Ly{ddagger}, Jukka Puoliväli{ddagger}§1, Sylvain Lesné, Karen H. Ashe, Paul J. Muchowski{ddagger}§||, and Lennart Mucke{ddagger}§2

From the {ddagger}Gladstone Institute of Neurological Disease, San Francisco, California 94158, the Departments of §Neurology and ||Biochemistry and Biophysics, University of California, San Francisco, California 94143, and the Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Many proteins suspected of causing neurodegenerative diseases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid-beta (Abeta) peptides. In vitro, the "Arctic" mutation (AbetaE22G) accelerated Abeta fibrillization but decreased the abundance of nonfibrillar Abeta assemblies, compared with wild-type Abeta. In human amyloid precursor protein (hAPP) transgenic mice carrying mutations adjacent to Abeta that increase Abeta production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar Abeta assembly (Abeta*56). Mice overexpressing Arctic mutant or wild-type Abeta had similar behavioral and neuronal deficits when they were matched for Abeta*56 levels but had vastly different plaque loads. Thus, Abeta*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar Abeta deposits. Therapeutic interventions that reduce Abeta fibrils at the cost of augmenting nonfibrillar Abeta assemblies could be harmful.


Received for publication, February 5, 2007 , and in revised form, May 30, 2007.

* This work was supported in part by National Institutes of Health Grants AG011385, AG022074, and AG023501 (to L. M.), NS33249 (to K. H. A.), and a Facilities Grant (RR 18928-01) from the National Institutes of Health National Center for Research Resources. 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.

Formula The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1, Figs. S1–S4, and Movies S1 and S2.

1 Present address: Cerebricon Ltd., 70211 Kuopio, Finland.

2 To whom correspondence should be addressed: 1650 Owens St., San Francisco, CA 94158. Tel.: 415-734-2504; Fax: 415-355-0131; E-mail: lmucke{at}gladstone.ucsf.edu.


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