Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer's transgenic mice.
The production and aggregation of cerebral amyloid-beta (Abeta) 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 Abeta and the amyloid precursor protein (APP). The inverse correlation of Abeta levels with NgR levels within the brain may reflect regulation of Abeta production and/or Abeta clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated Abeta clearance in APPswe/PSEN-1deltaE9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of Abeta 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 Abeta plaque load while increasing the relative levels of serum Abeta. These changes in Abeta 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 Abeta residues provides an effective therapeutic approach for AD.
Park
James H
JH
Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Widi
Gabriel A
GA
Gimbel
David A
DA
Harel
Noam Y
NY
Lee
Daniel H S
DH
Strittmatter
Stephen M
SM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D019556:COS Cells; D002522:Chlorocebus aethiops; D058851:GPI-Linked Proteins; D006801:Humans; D007279:Injections, Subcutaneous; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D000070816:Nogo Receptor 1; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D011956:Receptors, Cell Surface / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D013037:Spatial Behavior / Q000502:physiology*
D016229:Amyloid beta-Peptides; D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface