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The Journal of Neuroscience, February 1, 2006, 26(5):1386-1395; doi:10.1523/JNEUROSCI.3291-05.2006

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Neurobiology of Disease
Alzheimer Precursor Protein Interaction with the Nogo-66 Receptor Reduces Amyloid- Plaque Deposition

James H. Park,¹ David A. Gimbel,¹ Tadzia GrandPre,¹ Jung-Kil Lee,¹ Ji-Eun Kim,¹ Weiwei Li,² Daniel H. S. Lee,² and Stephen M. Strittmatter¹

¹Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, and ²BiogenIdec Inc., 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

Pathophysiologic hypotheses for Alzheimer’s disease (AD) are centered on the role of the amyloid plaque A peptide and the mechanism of its derivation from the amyloid precursor protein (APP). As part of the disease process, an aberrant axonal sprouting response is known to occur near A deposits. A Nogo to Nogo-66 receptor (NgR) pathway contributes to determining the ability of adult CNS axons to extend after traumatic injuries. Here, we consider the potential role of NgR mechanisms in AD. Both Nogo and NgR are mislocalized in AD brain samples. APP physically associates with the NgR. Overexpression of NgR decreases A production in neuroblastoma culture, and targeted disruption of NgR expression increases transgenic mouse brain A levels, A plaque deposition, and dystrophic neurites. Infusion of a soluble NgR fragment reduces A levels, amyloid plaque deposits, and dystrophic neurites in a mouse transgenic AD model. Changes in NgR level produce parallel changes in secreted APP and A, implicating NgR as a blocker of secretase processing of APP. The NgR provides a novel site for modifying the course of AD and highlights the role of axonal dysfunction in the disease.

Key words: Alzheimer’s disease; -amyloid plaque; Nogo; transgenic mice; Nogo-66 receptor; gene targeting; amyloid precursor protein; APP

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Received June 9, 2005; revised Dec. 4, 2005; accepted Dec. 15, 2005.

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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