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J. Biol. Chem., Vol. 280, Issue 17, 17458-17463, April 29, 2005

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Autoantibodies to Redox-modified Oligomeric A Are Attenuated in the Plasma of Alzheimer's Disease Patients^*

Robert D. Moir, Katya A. Tseitlin, Stephanie Soscia, Bradley T. Hyman, Michael C. Irizarry, and Rudolph E Tanzi¶

From the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease and the Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129-4404

Accumulation of A protein in -amyloid deposits is a hallmark event in Alzheimer's disease (AD). Recent findings suggest anti-A autoantibodies may have a role in AD pathology. However, a consensus has yet to emerge as to whether endogenous anti-A autoantibodies are elevated, depressed, or unchanged in AD patients. Whereas experiments to date have used synthetic unmodified monomeric A (A_mon) to test autoimmunity, up to 40% of the A pool inB AD brain consists of low molecular weight oligomeric cross-linked -amyloid protein species (CAPS). Recent studies also suggest that CAPS may be the primary neurotoxic agent in AD. In the present study, AD and nondemented control plasma were analyzed for immunoreactivity to CAPS and A_mon. Plasma of both nondemented and AD patients were found to contain autoantibodies specific for soluble CAPS. Nondemented control and AD plasmas demonstrated similar immunoreactivity to A_mon. In contrast, anti-CAPS antibodies in AD plasma were found to be significantly reduced compared with nondemented controls (p = 0.018). Furthermore, age at onset for AD correlated significantly (p = 0.041) with plasma immunoreactivity to CAPS. These data suggest that autoantibodies to CAPS are depleted in AD patients and raise the prospect that immunization with anti-CAPS antibodies might provide therapeutic benefit for AD.

Received for publication, December 16, 2004 , and in revised form, February 18, 2005.

^* This work was supported by the American Federation of Aging Research and Alzheimer's Disease Association. R. E. T. is a board member, consultant to, and shareholder in Prana Biotechnology and Neurogenetics. R. D. M. is a shareholder in Prana Biotechnology. 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.

^¶ An Ellison Medical Foundation Scholar. To whom correspondence should be addressed: Genetics and Aging Research Unit, Massachusetts General Hospital East, Bldg. 114, 16th St., Charlestown, MA 02129-4404. Tel.: 617-726-6845; Fax: 617-724-1823; E-mail: tanzi{at}helix.mgh.harvard.edu.

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