Alzheimer Precursor Protein Interaction with the Nogo-66 Receptor Reduces Amyloid-β Plaque Deposition

Park, James H.; Gimbel, David A.; GrandPré, Tadzia; Lee, Jung-Kil; Kim, Jieun; Li, Weiwei; Lee, Daniel H. S.; Strittmatter, Stephen M.

doi:10.1523/jneurosci.3291-05.2006

Cited by 125 publications

(140 citation statements)

References 38 publications

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“…AP-A␤ and AP-Nogo proteins were produced as described previously (Fournier et al, 2001;Park et al, 2006). To generate AP-A␤ mutant constructs, A␤ fragments were amplified, ligated into the pAP5tag vector (GenHunter, Nashville, TN), and sequenced.…”

Section: Methodsmentioning

confidence: 99%

“…To administer rat NgR(310)ecto-Fc protein, APPswe/PSEN-1⌬E9 mice (Park et al, 2006) from The Jackson Laboratory (Bar Harbor, ME) were anesthetized with isoflurane and oxygen, and an Alzet (Cupertino, CA) osmotic pump 2004 was subcutaneously inserted over the scapula and allowed to rest between fascia. The 200 l pump delivered 0.25 l/h for 28 d of a 1.2 g/l solution of rat NgR(310)Ecto-Fc or rat IgG in PBS.…”

Section: Methodsmentioning

confidence: 99%

“…In this role, it serves as a receptor for three myelin inhibitor proteins, Nogo, MAG, and OMgp, signaling to activate Rho GTPase in axons (Fournier et al, 2001(Fournier et al, , 2003Liu et al, 2002;Wang et al, 2002;McGee and Strittmatter, 2003). Recently, we found that brain NgR interacts with APP through its A␤ domain (Park et al, 2006). Moreover, increased levels of brain NgR result in reduced A␤ load, whereas loss of endogenous NgR elevates A␤.…”

Section: Introductionmentioning

confidence: 99%

“…Parallel changes in A␤ and secreted APP␣ plus APP␤ suggest that at least a portion of the in vivo effects of brain NgR on A␤ levels is mediated by blockade of ␣/␤-secretase activity. However, the high affinity of NgR for A␤ and the presence of NgR in plaques imply that NgR might also regulate the clearance of A␤ (Park et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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

Park

Widi²,

Gimbel³

et al. 2006

J. Neurosci.

100

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Park

Widi²,

Gimbel³

et al. 2006

J. Neurosci.

100

View full text Add to dashboard Cite

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“…It has been shown previously that ligands of this receptor complex, reticulons 1-4, influence the level of BACE1-mediated A␤ generation (62). It has further been shown that both p75 itself and the Nogo receptor, another protein harboring leucine-rich-repeat domains, affect APP processing (63)(64)(65). However, whereas there is an inverse relationship between Nogo receptor and secreted A␤ levels, LINGO-1 appears to promote A␤ secretion.…”

Section: Coomassiementioning

confidence: 98%

The in Vivo Brain Interactome of the Amyloid Precursor Protein

Bai

Markham

Chen

et al. 2008

Molecular & Cellular Proteomics

156

153

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Despite intense research efforts, the physiological function and molecular environment of the amyloid precursor protein has remained enigmatic. Here we describe the application of time-controlled transcardiac perfusion cross-linking, a method for the in vivo mapping of protein interactions in intact tissue, to study the interactome of the amyloid precursor protein (APP). To gain insights into the specificity of reported protein interactions the study was extended to the mammalian amyloid precursor-like proteins (APLP1 and APLP2). Alzheimer disease (AD) 1 is the most prevalent neurodegenerative disorder worldwide. A defining pathological hallmark of AD is the deposition of plaques, largely consisting of the 40 -42-amino acid amyloid ␤-peptide (A␤). A␤ is generated by the consecutive cleavage of the amyloid precursor protein (APP) by two proteases, ␤-secretase and ␥-secretase (1). Less than 10% of all AD cases are inherited. All mutations known to date that lead to early onset familial forms of AD occur either in APP itself or in protein components of the ␥-secretase complex (2). Although a large body of literature exists that establishes the importance of a few key proteins for AD, our understanding of the cellular context in which these proteins operate is sketchy at best. It has, for example, long been hypothesized that APP represents a transmembrane receptor. However, despite the presence of a large and structurally complex extracellular domain within this protein, to this date no extracellular APP ligand has been firmly established as a physiological interactor. The significance of a recently reported in vitro interaction between F-spondin and a recombinant APP construct consisting of a conserved central extracellular domain of APP fused to GST remains to be established (3). Early studies suggested binding of APP to the intracellular GTP-binding protein G o (4). Various other intracellular interactions of APP, in particular with proteins (FE65, mDab1, X11␣, and Shc) that bear phosphotyrosine interaction domains, have been reported (5-7). Most of these phosphotyrosine interaction domain-mediated interactions involve an NPXY motif present in the C-terminal domain of APP but are, somewhat surprisingly, observed to be independent of the phosphorylation status of the tyrosine within this motif (8). Following phosphorylation of FE65, a trimeric complex consisting of the APP intracellular domain (AICD), FE65 and the From the

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