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Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells.

Prasanthi JR, Huls A, Thomasson S, Thompson A, Schommer E, Ghribi O - Mol Neurodegener (2009)

Bottom Line: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells.We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide.These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA. oghribi@medicine.nodak.edu.

ABSTRACT

Background: Activation of the liver x receptors (LXRs) by exogenous ligands stimulates the degradation of beta-amyloid 1-42 (Abeta42), a peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD). The oxidized cholesterol products (oxysterols), 24-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), are endogenous activators of LXRs. However, the mechanisms by which these oxysterols may modulate Abeta42 levels are not well known.

Results: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells. We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide. Increased Abeta42 levels with 27-OHC are associated with increased levels of beta-amyloid precursor protein (APP) as well as beta-secretase (BACE1), the enzyme that cleaves APP to yield Abeta. Unchanged Abeta42 levels with 24-OHC are associated with increased levels of sAPPalpha, suggesting that 24-OHC favors the processing of APP to the non-amyloidogenic pathway. Interestingly, 24-OHC, but not 27-OHC, increases levels of the ATP-binding cassette transporters, ABCA1 and ABCG1, which regulate cholesterol transport within and between cells.

Conclusion: These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1. Regulation of 24-OHC: 27-OHC ratio could be an important strategy in controlling Abeta42 levels in AD.

No MeSH data available.


Related in: MedlinePlus

Immunofluorescence staining of APP and Aβ increases with 27-OHC. Immunostaining for APP and Aβ showed a decreased immunoreactivity to 6E10 antibody (green) in cells treated with 24-OHC compared treatment with 27-OHC. The immunoreactivity for 6E10 antibody in cells treated with a mixture of 24-OHC + 27-OHC is similar to that observed in control cells. DAPI (blue) was used as a nuclear counterstain. Bar 20 μm.
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Figure 3: Immunofluorescence staining of APP and Aβ increases with 27-OHC. Immunostaining for APP and Aβ showed a decreased immunoreactivity to 6E10 antibody (green) in cells treated with 24-OHC compared treatment with 27-OHC. The immunoreactivity for 6E10 antibody in cells treated with a mixture of 24-OHC + 27-OHC is similar to that observed in control cells. DAPI (blue) was used as a nuclear counterstain. Bar 20 μm.

Mentions: The immunofluorescence imaging (Fig. 3) showed a reduced immunoreactivity to 6E10, an antibody that detects full length APP as well as Aβ, in cells treated with 24-OHC in comparison to control cells. A substantial increase in 6E10 staining was observed in cells with 27-OHC compared to control cells or cells treated with 24-OHC. In cells treated with a mixture of 24-OHC+27-OHC, the intensity of the immunoreactivity to 6E10 antibody appears similar to that in control cells. These results are in accordance with the Western blot data showing increased APP and Aβ42 levels with 27-OHC compared to treatment with 24-OHC.


Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells.

Prasanthi JR, Huls A, Thomasson S, Thompson A, Schommer E, Ghribi O - Mol Neurodegener (2009)

Immunofluorescence staining of APP and Aβ increases with 27-OHC. Immunostaining for APP and Aβ showed a decreased immunoreactivity to 6E10 antibody (green) in cells treated with 24-OHC compared treatment with 27-OHC. The immunoreactivity for 6E10 antibody in cells treated with a mixture of 24-OHC + 27-OHC is similar to that observed in control cells. DAPI (blue) was used as a nuclear counterstain. Bar 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654562&req=5

Figure 3: Immunofluorescence staining of APP and Aβ increases with 27-OHC. Immunostaining for APP and Aβ showed a decreased immunoreactivity to 6E10 antibody (green) in cells treated with 24-OHC compared treatment with 27-OHC. The immunoreactivity for 6E10 antibody in cells treated with a mixture of 24-OHC + 27-OHC is similar to that observed in control cells. DAPI (blue) was used as a nuclear counterstain. Bar 20 μm.
Mentions: The immunofluorescence imaging (Fig. 3) showed a reduced immunoreactivity to 6E10, an antibody that detects full length APP as well as Aβ, in cells treated with 24-OHC in comparison to control cells. A substantial increase in 6E10 staining was observed in cells with 27-OHC compared to control cells or cells treated with 24-OHC. In cells treated with a mixture of 24-OHC+27-OHC, the intensity of the immunoreactivity to 6E10 antibody appears similar to that in control cells. These results are in accordance with the Western blot data showing increased APP and Aβ42 levels with 27-OHC compared to treatment with 24-OHC.

Bottom Line: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells.We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide.These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA. oghribi@medicine.nodak.edu.

ABSTRACT

Background: Activation of the liver x receptors (LXRs) by exogenous ligands stimulates the degradation of beta-amyloid 1-42 (Abeta42), a peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD). The oxidized cholesterol products (oxysterols), 24-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), are endogenous activators of LXRs. However, the mechanisms by which these oxysterols may modulate Abeta42 levels are not well known.

Results: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells. We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide. Increased Abeta42 levels with 27-OHC are associated with increased levels of beta-amyloid precursor protein (APP) as well as beta-secretase (BACE1), the enzyme that cleaves APP to yield Abeta. Unchanged Abeta42 levels with 24-OHC are associated with increased levels of sAPPalpha, suggesting that 24-OHC favors the processing of APP to the non-amyloidogenic pathway. Interestingly, 24-OHC, but not 27-OHC, increases levels of the ATP-binding cassette transporters, ABCA1 and ABCG1, which regulate cholesterol transport within and between cells.

Conclusion: These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1. Regulation of 24-OHC: 27-OHC ratio could be an important strategy in controlling Abeta42 levels in AD.

No MeSH data available.


Related in: MedlinePlus