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J. Biol. Chem., Vol. 282, Issue 13, 9952-9961, March 30, 2007

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Inhibition of Familial Cerebral Amyloid Angiopathy Mutant Amyloid -Protein Fibril Assembly by Myelin Basic Protein^*

Michael D. Hoos, Mahiuddin Ahmed, Steven O. Smith, and William E. Van Nostrand¹

From the Department of Medicine and the Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794-8153

Deposition of fibrillar amyloid -protein (A) in the brain is a prominent pathological feature of Alzheimer disease and related disorders, including familial forms of cerebral amyloid angiopathy (CAA). Mutant forms of A, including Dutch- and Iowa-type A, which are responsible for familial CAA, deposit primarily as fibrillar amyloid along the cerebral vasculature and are either absent or present only as diffuse non-fibrillar plaques in the brain parenchyma. Despite the lack of parenchymal fibril formation in vivo, these CAA mutant A peptides exhibit a markedly increased rate and extent of fibril formation in vitro compared with wild-type A. Based on these conflicting observations, we sought to determine whether brain parenchymal factors that selectively interact with and modulate CAA mutant A fibril assembly exist. Using a combination of immunoaffinity chromatography and mass spectrometry, we identified myelin basic protein (MBP) as a prominent brain parenchymal factor that preferentially binds to CAA mutant A compared with wild-type A. Surface plasmon resonance measurements confirmed that MBP bound more tightly to Dutch/Iowa CAA double mutant A than to wild-type A. Using a combination of biochemical and ultrastructural techniques, we found that MBP inhibited the fibril assembly of CAA mutant A. Together, these findings suggest a possible role for MBP in regulating parenchymal fibrillar A deposition in familial CAA.

Received for publication, April 11, 2006 , and in revised form, January 16, 2007.

^* This work was supported by National Institutes of Health Grant NS35781 and Alzheimer's Association Grant IIRG-06-26805. 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, HSC T-15/083, Stony Brook University, Stony Brook, NY 11794-8153. Tel.: 631-444-1661; Fax: 631-444-2560; E-mail: William.VanNostrand{at}stonybrook.edu.

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