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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 APP and BACE1. Representative Western blots (a) and densitometric (b) analysis demonstrating increased levels of APP with 27-OHC. No changes were found in levels of APP with 24-OHC or 24-OHC+ 27-OHC treatment. BACE1 levels were unchanged with 24-OHC treatment but significantly increased with 27-OHC or a mixture of 24-OHC + 27-OHC. *p < 0.05, **p < 0.01 (One way ANOVA followed by Dunnett's multiple comparison test).
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Figure 2: 27-OHC, but not 24-OHC, increases levels of APP and BACE1. Representative Western blots (a) and densitometric (b) analysis demonstrating increased levels of APP with 27-OHC. No changes were found in levels of APP with 24-OHC or 24-OHC+ 27-OHC treatment. BACE1 levels were unchanged with 24-OHC treatment but significantly increased with 27-OHC or a mixture of 24-OHC + 27-OHC. *p < 0.05, **p < 0.01 (One way ANOVA followed by Dunnett's multiple comparison test).

Mentions: In order to determine potential mechanisms involved in 27-OHC-induced increase in Aβ42 levels, we examined first the effects of 24-OHC and 27-OHC on levels of APP and BACE1. We chose to carry out our experiments with a concentration of 10 μM 24-OHC or 27-OHC. At 10 μM/mL concentration, 24-hydroxycholesterol has been shown to increase APP gene expression in human neuronal cells [13] and 27-hydroxycholesterol has been shown to inhibit neutral sphingomyelinase in human endothelial cells [14]. Western blot (Fig. 2a) and densitometric (Fig. 2b) analyses show the effect of 24-OHC, 27-OHC, or a mixture of 24-OHC + 27-OHC on levels of APP and BACE1. There was a significant increase in APP levels following treatment with 27-OHC. Treatment with 24-OHC or with a mixture of 24-OHC + 27-OHC did not statistically increase APP levels. Increase in APP levels with 27-OHC was associated with an increase in BACE1 levels. Treatment with 24-OHC did not significantly alter BACE1 levels. The mixture of 24-OHC + 27-OHC increased BACE1 levels significantly, indicating that 24-OHC does not reverse the effects of 27-OHC on BACE1 levels. These results suggest that 27-OHC-induced increase in levels of APP and BACE1 favors the amyloidogenic pathway that leads to increased Aβ42 production.


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 APP and BACE1. Representative Western blots (a) and densitometric (b) analysis demonstrating increased levels of APP with 27-OHC. No changes were found in levels of APP with 24-OHC or 24-OHC+ 27-OHC treatment. BACE1 levels were unchanged with 24-OHC treatment but significantly increased with 27-OHC or a mixture of 24-OHC + 27-OHC. *p < 0.05, **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 2: 27-OHC, but not 24-OHC, increases levels of APP and BACE1. Representative Western blots (a) and densitometric (b) analysis demonstrating increased levels of APP with 27-OHC. No changes were found in levels of APP with 24-OHC or 24-OHC+ 27-OHC treatment. BACE1 levels were unchanged with 24-OHC treatment but significantly increased with 27-OHC or a mixture of 24-OHC + 27-OHC. *p < 0.05, **p < 0.01 (One way ANOVA followed by Dunnett's multiple comparison test).
Mentions: In order to determine potential mechanisms involved in 27-OHC-induced increase in Aβ42 levels, we examined first the effects of 24-OHC and 27-OHC on levels of APP and BACE1. We chose to carry out our experiments with a concentration of 10 μM 24-OHC or 27-OHC. At 10 μM/mL concentration, 24-hydroxycholesterol has been shown to increase APP gene expression in human neuronal cells [13] and 27-hydroxycholesterol has been shown to inhibit neutral sphingomyelinase in human endothelial cells [14]. Western blot (Fig. 2a) and densitometric (Fig. 2b) analyses show the effect of 24-OHC, 27-OHC, or a mixture of 24-OHC + 27-OHC on levels of APP and BACE1. There was a significant increase in APP levels following treatment with 27-OHC. Treatment with 24-OHC or with a mixture of 24-OHC + 27-OHC did not statistically increase APP levels. Increase in APP levels with 27-OHC was associated with an increase in BACE1 levels. Treatment with 24-OHC did not significantly alter BACE1 levels. The mixture of 24-OHC + 27-OHC increased BACE1 levels significantly, indicating that 24-OHC does not reverse the effects of 27-OHC on BACE1 levels. These results suggest that 27-OHC-induced increase in levels of APP and BACE1 favors the amyloidogenic pathway that leads to increased Aβ42 production.

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