Subcutaneous Nogo Receptor Removes Brain Amyloid-β and Improves Spatial Memory in Alzheimer's Transgenic Mice

Abstract

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

Effects of curcumin on hippocampal expression of NgR and axonal regeneration in Aβ-induced cognitive disorder rats

“…Excessive expression of NgR has been shown to prevent α-and β-secretase from cleaving amyloid precursor protein (APP), which reduces the production of Aβ (Park, 2006b). Aβ/APP metabolism is a complex multi-step process involving a variety of proteins.…”

Blocking Nogo Receptor 1 Promotes Functional Regeneration after Spinal Cord Injury

“…Beyond its suggested role in SCI, NgR1 has been discussed to be involved in neurodegenerative diseases and to possess multiple physiological functions [48][49][50][51][52], for example including regulation of macrophage movement in inflammatory responses [31]. With respect to its involvement in neurodegenerative diseases it was demonstrated that NgR1 directly interacts with Aβ and APP.…”

“…With respect to its involvement in neurodegenerative diseases it was demonstrated that NgR1 directly interacts with Aβ and APP. Overexpression of NgR reduces plaque load, and also treatment of APPswe/PSEN-1ΔE9 transgenic mice with the decoy receptor NgR(310)ecto-Fc is able to reduce plaque load and leads to improved spatial memory in these animals [48,49]. In addition, NgR1 may be directly involved in plasticity and synaptic functioning [53,54] and a slower acquisition of a spatial learning and memory task has recently been described for NgR1 (-/-) mice [55].…”

Keystone Symposium, Neurodegenerative Diseases: New Molecular Mechanisms 17–22 February 2009

“…As Strittmatter outlined in his Keystone presentation, the laboratory had previously shown that the Nogo receptor, known for limiting axon regeneration and repair, binds to the AβPP and to Aβ, but not necessarily oligomers [3,4]. To find proteins that specifically bind to oligomeric species of the peptide, which are now widely believed to be the most toxic Aβ entities, Juha Lauren and colleagues in the laboratory used biotinlabeled oligomers (prepared as per the ADDL method of Bill Klein's group) [5] to screen COS-7 cells expressing a mouse adult brain cDNA library.…”