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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

27-OHC, but not 24-OHC, increases levels of secreted Aβ42. While treatment with 5, 10 and 25 μM 24-OHC did not alter Aβ42 levels (a), treatment with 5, 10 and 25 μM 27-OHC significantly increased levels of Aβ42 compared to levels in medium of untreated cells (b). There was no difference in Aβ42 levels between untreated cells and cells treated with a mixture of 24-OHC + 27-OHC (c). **p < 0.01 (One way ANOVA followed by Dunnett's multiple comparison test).
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Figure 1: 27-OHC, but not 24-OHC, increases levels of secreted Aβ42. While treatment with 5, 10 and 25 μM 24-OHC did not alter Aβ42 levels (a), treatment with 5, 10 and 25 μM 27-OHC significantly increased levels of Aβ42 compared to levels in medium of untreated cells (b). There was no difference in Aβ42 levels between untreated cells and cells treated with a mixture of 24-OHC + 27-OHC (c). **p < 0.01 (One way ANOVA followed by Dunnett's multiple comparison test).

Mentions: Human neuroblastoma SH-SY5Y cells were treated with 5, 10 and 25 μM of 24-OHC, 27-OHC, or a mixture of 24-OHC and 27-OHC, and Aβ42 levels were determined with ELISA. ELISA measurements showed that treatment with 5, 10 or 25 μM 24-OHC did not induce significant changes in secreted Aβ42 levels compared to levels in medium of untreated cells (Fig. 1a). Conversely to 24-OHC, treatment with 5, 10 or 25 μM 27-OHC led to a substantial increase in Aβ42 levels (Fig. 1b). Treatment with a mixture of 24-OHC + 27-OHC did not induce significant changes in the levels of Aβ42 compared to levels from untreated cells or cells treated with 27-OHC (Fig. 1c). These results suggest that, although it doesn't reduce Aβ42 levels per se, 24-OHC, when added to 27-OHC, prevents the 27-OHC-induced significant increase in Aβ42 levels.


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)

27-OHC, but not 24-OHC, increases levels of secreted Aβ42. While treatment with 5, 10 and 25 μM 24-OHC did not alter Aβ42 levels (a), treatment with 5, 10 and 25 μM 27-OHC significantly increased levels of Aβ42 compared to levels in medium of untreated cells (b). There was no difference in Aβ42 levels between untreated cells and cells treated with a mixture of 24-OHC + 27-OHC (c). **p < 0.01 (One way ANOVA followed by Dunnett's multiple comparison test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: 27-OHC, but not 24-OHC, increases levels of secreted Aβ42. While treatment with 5, 10 and 25 μM 24-OHC did not alter Aβ42 levels (a), treatment with 5, 10 and 25 μM 27-OHC significantly increased levels of Aβ42 compared to levels in medium of untreated cells (b). There was no difference in Aβ42 levels between untreated cells and cells treated with a mixture of 24-OHC + 27-OHC (c). **p < 0.01 (One way ANOVA followed by Dunnett's multiple comparison test).
Mentions: Human neuroblastoma SH-SY5Y cells were treated with 5, 10 and 25 μM of 24-OHC, 27-OHC, or a mixture of 24-OHC and 27-OHC, and Aβ42 levels were determined with ELISA. ELISA measurements showed that treatment with 5, 10 or 25 μM 24-OHC did not induce significant changes in secreted Aβ42 levels compared to levels in medium of untreated cells (Fig. 1a). Conversely to 24-OHC, treatment with 5, 10 or 25 μM 27-OHC led to a substantial increase in Aβ42 levels (Fig. 1b). Treatment with a mixture of 24-OHC + 27-OHC did not induce significant changes in the levels of Aβ42 compared to levels from untreated cells or cells treated with 27-OHC (Fig. 1c). These results suggest that, although it doesn't reduce Aβ42 levels per se, 24-OHC, when added to 27-OHC, prevents the 27-OHC-induced significant increase in Aβ42 levels.

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