Daniel H. S. Lee

Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition.

Pathophysiologic hypotheses for Alzheimer’s disease (AD) are centered on the role of the amyloid plaque Aβ 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 Aβ 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 Aβ production in neuroblastoma culture, and targeted disruption of NgR expression increases transgenic mouse brain Aβ levels, Aβ plaque deposition, and dystrophic neurites. Infusion of a soluble NgR fragment reduces Aβ levels, amyloid plaque deposits, and dystrophic neurites in a mouse transgenic AD model. Changes in NgR level produce parallel changes in secreted APPα and Aβ, 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.

Targeting the Nogo Receptor to Treat Central Nervous System Injuries

Axonal damage is a key pathology in many injuries of the central nervous system (CNS), such as spinal cord injury, traumatic brain injury and stroke, as well as in multiple sclerosis. An attractive drug discovery strategy to treat such conditions is to search for agents that promote CNS axonal regeneration. Historically, limited knowledge concerning the basis of poor CNS regeneration has precluded a rational drug discovery approach for promoting axonal regeneration. The recent identification of the Nogo receptor, which interacts with inhibitory myelin protein, established the crucial role of this molecular pathway in mediating the inhibitory effects of CNS myelin. This provides an unprecedented opportunity to manipulate adult CNS axonal regeneration. The development of therapeutics targeting the Nogo receptor has the potential to promote functional recovery and reverse the devastating consequences of CNS injuries.

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

The production and aggregation of cerebral amyloid-β (Aβ) peptide are thought to play a causal role in Alzheimers disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both Aβ and the amyloid precursor protein (APP). The inverse correlation of Aβ levels with NgR levels within the brain may reflect regulation of Aβ production and/or Aβ clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated Aβ clearance in APPswe/PSEN-1ΔE9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15–28 aa of Aβ 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 Aβ plaque load while increasing the relative levels of serum Aβ. These changes in Aβ 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 Aβ residues provides an effective therapeutic approach for AD.

A neutralizing anti-Nogo66 receptor monoclonal antibody reverses inhibition of neurite outgrowth by central nervous system myelin.

The Nogo66 receptor (NgR1) is a neuronal, leucinerich repeat (LRR) protein that binds three central nervous system (CNS) myelin proteins, Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein, and mediates their inhibitory effects on neurite growth. Although the LRR domains on NgR1 are necessary for binding to the myelin proteins, the exact epitope(s) involved in ligand binding is unclear. Here we report the generation and detailed characterization of an anti-NgR1 monoclonal antibody, 7E11. The 7E11 monoclonal antibody blocks Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein binding to NgR1 with IC50 values of 120, 14, and 4.5 nm, respectively, and effectively promotes neurite outgrowth of P3 rat dorsal root ganglia neurons cultured on a CNS myelin substrate. Further, we have defined the molecular epitope of 7E11 to be DNAQLR located in the third LRR domain of rat NgR1. Our data demonstrate that anti-NgR1 antibodies recognizing this epitope, such as 7E11, can neutralize CNS myelin-dependent inhibition of neurite outgrowth. Thus, specific anti-NgR1 antibodies may represent a useful therapeutic approach for promoting CNS repair after injury.