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Amyloid-β inhibits No-cGMP signaling in a CD36- and CD47-dependent manner.

Miller TW, Isenberg JS, Shih HB, Wang Y, Roberts DD - PLoS ONE (2010)

Bottom Line: In contrast, amyloid-β did not compete with the known ligand SIRPα for binding to CD47.These data suggest that amyloid-β interaction with CD36 induces a CD47-dependent signal that inhibits soluble guanylate cyclase activation.Combined with the pleiotropic effects of inhibiting free fatty acid transport via CD36, these data provides a molecular mechanism through which amyloid-β can contribute to the nitric oxide signaling deficiencies associated with Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Amyloid-β interacts with two cell surface receptors, CD36 and CD47, through which the matricellular protein thrombospondin-1 inhibits soluble guanylate cyclase activation. Here we examine whether amyloid-β shares this inhibitory activity. Amyloid-β inhibited both drug and nitric oxide-mediated activation of soluble guanylate cyclase in several cell types. Known cGMP-dependent functional responses to nitric oxide in platelets and vascular smooth muscle cells were correspondingly inhibited by amyloid-β. Functional interaction of amyloid-β with the scavenger receptor CD36 was indicated by inhibition of free fatty acid uptake via this receptor. Both soluble oligomer and fibrillar forms of amyloid-β were active. In contrast, amyloid-β did not compete with the known ligand SIRPα for binding to CD47. However, both receptors were necessary for amyloid-β to inhibit cGMP accumulation. These data suggest that amyloid-β interaction with CD36 induces a CD47-dependent signal that inhibits soluble guanylate cyclase activation. Combined with the pleiotropic effects of inhibiting free fatty acid transport via CD36, these data provides a molecular mechanism through which amyloid-β can contribute to the nitric oxide signaling deficiencies associated with Alzheimer's disease.

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Related in: MedlinePlus

Proposed model of Aβ inhibition of cGMP production.Aβ binds directly to CD36 to inhibit uptake of free fatty acids. In the presence of CD47, CD36 engagement transduces an inhibitory signal to sGC, limiting its activation and production of cGMP.
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pone-0015686-g006: Proposed model of Aβ inhibition of cGMP production.Aβ binds directly to CD36 to inhibit uptake of free fatty acids. In the presence of CD47, CD36 engagement transduces an inhibitory signal to sGC, limiting its activation and production of cGMP.

Mentions: The activity of Aβ to inhibit NO/cGMP signaling in vascular and T cells suggests that pathological accumulation of Aβ can play a key role in limiting the NO signaling pathway (7). Previously, various downstream targets of NO have been shown to be inhibited by Aβ (18, 19). Here, we provide a link between Aβ and NO signaling by showing that all the downstream inhibitory responses could result from suppression of sGC activity by Aβ (Figure 6). We further report that Aβ offsets increases in cGMP levels caused by both NO donors and synthetic sGC activators, indicating that Aβ can inhibit sGC independent of its NO-binding heme prosthetic group. This is important because others have shown that sGC can be inhibited by oxidizing the Fe2+ in this heme.


Amyloid-β inhibits No-cGMP signaling in a CD36- and CD47-dependent manner.

Miller TW, Isenberg JS, Shih HB, Wang Y, Roberts DD - PLoS ONE (2010)

Proposed model of Aβ inhibition of cGMP production.Aβ binds directly to CD36 to inhibit uptake of free fatty acids. In the presence of CD47, CD36 engagement transduces an inhibitory signal to sGC, limiting its activation and production of cGMP.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3008726&req=5

pone-0015686-g006: Proposed model of Aβ inhibition of cGMP production.Aβ binds directly to CD36 to inhibit uptake of free fatty acids. In the presence of CD47, CD36 engagement transduces an inhibitory signal to sGC, limiting its activation and production of cGMP.
Mentions: The activity of Aβ to inhibit NO/cGMP signaling in vascular and T cells suggests that pathological accumulation of Aβ can play a key role in limiting the NO signaling pathway (7). Previously, various downstream targets of NO have been shown to be inhibited by Aβ (18, 19). Here, we provide a link between Aβ and NO signaling by showing that all the downstream inhibitory responses could result from suppression of sGC activity by Aβ (Figure 6). We further report that Aβ offsets increases in cGMP levels caused by both NO donors and synthetic sGC activators, indicating that Aβ can inhibit sGC independent of its NO-binding heme prosthetic group. This is important because others have shown that sGC can be inhibited by oxidizing the Fe2+ in this heme.

Bottom Line: In contrast, amyloid-β did not compete with the known ligand SIRPα for binding to CD47.These data suggest that amyloid-β interaction with CD36 induces a CD47-dependent signal that inhibits soluble guanylate cyclase activation.Combined with the pleiotropic effects of inhibiting free fatty acid transport via CD36, these data provides a molecular mechanism through which amyloid-β can contribute to the nitric oxide signaling deficiencies associated with Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Amyloid-β interacts with two cell surface receptors, CD36 and CD47, through which the matricellular protein thrombospondin-1 inhibits soluble guanylate cyclase activation. Here we examine whether amyloid-β shares this inhibitory activity. Amyloid-β inhibited both drug and nitric oxide-mediated activation of soluble guanylate cyclase in several cell types. Known cGMP-dependent functional responses to nitric oxide in platelets and vascular smooth muscle cells were correspondingly inhibited by amyloid-β. Functional interaction of amyloid-β with the scavenger receptor CD36 was indicated by inhibition of free fatty acid uptake via this receptor. Both soluble oligomer and fibrillar forms of amyloid-β were active. In contrast, amyloid-β did not compete with the known ligand SIRPα for binding to CD47. However, both receptors were necessary for amyloid-β to inhibit cGMP accumulation. These data suggest that amyloid-β interaction with CD36 induces a CD47-dependent signal that inhibits soluble guanylate cyclase activation. Combined with the pleiotropic effects of inhibiting free fatty acid transport via CD36, these data provides a molecular mechanism through which amyloid-β can contribute to the nitric oxide signaling deficiencies associated with Alzheimer's disease.

Show MeSH
Related in: MedlinePlus