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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 dependent on CD47.A Wild type or CD47−/− primary murine lung endothelial cells were pretreated with 10 µM Aβ followed by 10 µM DEA/NO. B Wild type Jurkat cells were incubated with 10 µM CD47 antisense morpholino or 10 µM of a 5 base mismatched CD47 control morpholino for 48 hrs. Following CD47 knockdown, cells were pretreated with 10 µM Aβ followed by 1 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-g004: Aβ inhibition of NO signaling is dependent on CD47.A Wild type or CD47−/− primary murine lung endothelial cells were pretreated with 10 µM Aβ followed by 10 µM DEA/NO. B Wild type Jurkat cells were incubated with 10 µM CD47 antisense morpholino or 10 µM of a 5 base mismatched CD47 control morpholino for 48 hrs. Following CD47 knockdown, cells were pretreated with 10 µM Aβ followed by 1 µM DEA/NO. Following treatment, cell were lysed and assayed for cGMP production. n = 3, * denotes P<0.05.

Mentions: Although ligation of CD36 is sufficient to inhibit cGMP signaling, this inhibition is lost in cells lacking CD47 [25]. Therefore, CD47 is necessary for CD36-mediated inhibition of cGMP signaling. In contrast, TSP1 inhibition of cGMP signaling via of its high affinity binding to CD47 does not require CD36 [39]. This suggests that modulation of cGMP signaling by CD36 ligands is mediated by cross-talk with CD47. Consistent with the BAEC data described above, wild-type murine vascular cells expressing CD47 and treated with 10 µM DEA/NO showed a 4-fold increase in intracellular cGMP production that was inhibited by the addition of Aβ (Fig. 4A). In contrast, Aβ failed to suppress the increase in the cGMP production induced by DEA/NO in murine CD47−/− lung endothelial cells. Conversely, suppressing CD47 expression in Jurkat T-cells using a CD47-specific morpholino abolished the effect of Aβ on NO-stimulated cGMP accumulation (Fig. 4B). Thus, two independent approaches confirm that CD47 is necessary for Aβ to suppress NO signaling.


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 dependent on CD47.A Wild type or CD47−/− primary murine lung endothelial cells were pretreated with 10 µM Aβ followed by 10 µM DEA/NO. B Wild type Jurkat cells were incubated with 10 µM CD47 antisense morpholino or 10 µM of a 5 base mismatched CD47 control morpholino for 48 hrs. Following CD47 knockdown, cells were pretreated with 10 µM Aβ followed by 1 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-g004: Aβ inhibition of NO signaling is dependent on CD47.A Wild type or CD47−/− primary murine lung endothelial cells were pretreated with 10 µM Aβ followed by 10 µM DEA/NO. B Wild type Jurkat cells were incubated with 10 µM CD47 antisense morpholino or 10 µM of a 5 base mismatched CD47 control morpholino for 48 hrs. Following CD47 knockdown, cells were pretreated with 10 µM Aβ followed by 1 µM DEA/NO. Following treatment, cell were lysed and assayed for cGMP production. n = 3, * denotes P<0.05.
Mentions: Although ligation of CD36 is sufficient to inhibit cGMP signaling, this inhibition is lost in cells lacking CD47 [25]. Therefore, CD47 is necessary for CD36-mediated inhibition of cGMP signaling. In contrast, TSP1 inhibition of cGMP signaling via of its high affinity binding to CD47 does not require CD36 [39]. This suggests that modulation of cGMP signaling by CD36 ligands is mediated by cross-talk with CD47. Consistent with the BAEC data described above, wild-type murine vascular cells expressing CD47 and treated with 10 µM DEA/NO showed a 4-fold increase in intracellular cGMP production that was inhibited by the addition of Aβ (Fig. 4A). In contrast, Aβ failed to suppress the increase in the cGMP production induced by DEA/NO in murine CD47−/− lung endothelial cells. Conversely, suppressing CD47 expression in Jurkat T-cells using a CD47-specific morpholino abolished the effect of Aβ on NO-stimulated cGMP accumulation (Fig. 4B). Thus, two independent approaches confirm that CD47 is necessary for Aβ to suppress NO signaling.

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