Subcutaneous Nogo receptor removes brain amyloid-β and improves spatial memory in Alzheimer's transgenic mice

The production and aggregation of cerebral amyloid-beta (A beta) 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 A beta and the amyloid precursor protein ( APP). The inverse correlation of A beta levels with NgR levels within the brain may reflect regulation of A beta production and/ or A beta clearance. Here, we assess the potential therapeutic benefit of peripheral NgR- mediated A beta clearance in APPswe/ PSEN-1 Delta E9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15 - 28 aa of A beta 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 A beta plaque load while increasing the relative levels of serum A beta. These changes in A beta 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 A beta residues provides an effective therapeutic approach for AD.