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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

Aβ inhibition of NO signaling is not dependent on TSP1.A Wild type or TSP1−/− primary murine lung endothelial cells were pretreated with 10 µM Aβ followed by 10 µM DEA/NO. Following treatment, cell were lysed and assayed for cGMP production. n = 3, * denotes P<0.05.
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pone-0015686-g005: Aβ inhibition of NO signaling is not dependent on TSP1.A Wild type or TSP1−/− primary murine lung endothelial cells were pretreated with 10 µM Aβ followed by 10 µM DEA/NO. Following treatment, cell were lysed and assayed for cGMP production. n = 3, * denotes P<0.05.

Mentions: TSP1 is known to inhibit NO signaling by suppressing sGC activity through CD47, in the same manner through which we observed Aβ to inhibit NO signaling. To rule out the possibility that the observed Aβ inhibitory activity is due to or influenced by mobilization of endogenous TSP1, we used TSP1 cells to evaluate Aβ inhibition of NO signaling. As shown in Figure 5, in wild type primary murine lung endothelial cells bearing TSP1, the addition of DEA/NO increased intracellular cGMP production, while treatment with Aβ inhibited DEA/NO stimulated cGMP production, as expected. In the corresponding TSP1 cells, a similar pattern was observed in which Aβ inhibited an increase in cGMP levels caused by DEA/NO and thus inhibited sGC activity. Therefore, Aβ inhibition of NO signaling is not an artifact of modulating endogenous TSP1.


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)

Aβ inhibition of NO signaling is not dependent on TSP1.A Wild type or TSP1−/− primary murine lung endothelial cells were pretreated with 10 µM Aβ followed by 10 µM DEA/NO. Following treatment, cell were lysed and assayed for cGMP production. n = 3, * denotes P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0015686-g005: Aβ inhibition of NO signaling is not dependent on TSP1.A Wild type or TSP1−/− primary murine lung endothelial cells were pretreated with 10 µM Aβ followed by 10 µM DEA/NO. Following treatment, cell were lysed and assayed for cGMP production. n = 3, * denotes P<0.05.
Mentions: TSP1 is known to inhibit NO signaling by suppressing sGC activity through CD47, in the same manner through which we observed Aβ to inhibit NO signaling. To rule out the possibility that the observed Aβ inhibitory activity is due to or influenced by mobilization of endogenous TSP1, we used TSP1 cells to evaluate Aβ inhibition of NO signaling. As shown in Figure 5, in wild type primary murine lung endothelial cells bearing TSP1, the addition of DEA/NO increased intracellular cGMP production, while treatment with Aβ inhibited DEA/NO stimulated cGMP production, as expected. In the corresponding TSP1 cells, a similar pattern was observed in which Aβ inhibited an increase in cGMP levels caused by DEA/NO and thus inhibited sGC activity. Therefore, Aβ inhibition of NO signaling is not an artifact of modulating endogenous TSP1.

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