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The Journal of Neuroscience, December 20, 2006, 26(51):13279-13286; doi:10.1523/JNEUROSCI.4504-06.2006

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Neurobiology of Disease
Subcutaneous Nogo Receptor Removes Brain Amyloid-ß and Improves Spatial Memory in Alzheimer's Transgenic Mice

James H. Park,¹ Gabriel A. Widi,¹ David A. Gimbel,¹ Noam Y. Harel,¹ Daniel H. S. Lee,² and Stephen M. Strittmatter¹

¹Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, and ²Biogen Idec, Cambridge, Massachusetts 02140

Correspondence should be addressed to Stephen M. Strittmatter, Department of Neurology, Yale University School of Medicine, P.O. Box 208018, New Haven, CT 06510. Email: stephen.strittmatter{at}yale.edu

The production and aggregation of cerebral amyloid-ß (Aß) peptide are thought to play a causal role in Alzheimer's disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both Aß and the amyloid precursor protein (APP). The inverse correlation of Aß levels with NgR levels within the brain may reflect regulation of Aß production and/or Aß clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated Aß clearance in APPswe/PSEN-1E9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15–28 aa of Aß associate with specific surface-accessible patches on the leucine-rich repeat concave side of the solenoid structure of NgR. In transgenic mice, subcutaneous NgR(310)ecto-Fc treatment reduces brain Aß plaque load while increasing the relative levels of serum Aß. These changes in Aß are correlated with improved spatial memory in the radial arm water maze. The benefits of peripheral NgR administration are evident when therapy is initiated after disease onset. Thus, the peripheral association of NgR(310)ecto-Fc with central Aß residues provides an effective therapeutic approach for AD.

Key words: Alzheimer's disease; ß-amyloid; Nogo-66 receptor; axon; therapy; radial arm water maze; degeneration; amyloid precursor protein

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Received Aug. 10, 2006; accepted Nov. 12, 2006.

Correspondence should be addressed to Stephen M. Strittmatter, Department of Neurology, Yale University School of Medicine, P.O. Box 208018, New Haven, CT 06510. Email: stephen.strittmatter{at}yale.edu

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