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

Background: Activation of the liver x receptors (LXRs) by exogenous ligands stimulates the degradation of beta-amyloid 1-42 (A beta 42), 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 A beta 42 levels are not well known. Results: We determined the effect of 24-OHC and/or 27-OHC on A beta generation in SH-SY5Y cells. We found that while 27-OHC increases levels of A beta 42, 24-OHC did not affect levels of this peptide. Increased A beta 42 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 A beta. Unchanged A beta 42 levels with 24-OHC are associated with increased levels of sAPP alpha, 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 A beta 42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of A beta 42 by upregulating APP and BACE1. Regulation of 24-OHC: 27-OHC ratio could be an important strategy in controlling A beta 42 levels in AD.