Reduction of Liver X Receptor β expression in primary rat neurons by antisense oligodeoxynucleotides decreases secreted amyloid β levels

•LXRβ inactivation with specific antisense oligodeoxynucleotides (As-ODN) significantly reduced secreted Aβ40 in primary rat neurons.•Inactivating LXRβ by As-ODN significantly decreased the neuronal cholesterol levels.•LXRβ As-ODN decreased APP751+770, ADAM10 and BACE1 expressions in primary rat neurons.•LXRβ As-ODN down-regulated gene expression of ABCA1, CYP46 and HMGCR in primary rat neurons.•LXRβ may play a role in maintaining cholesterol homeostasis and physiological levels of Aβ in neurons.

Ligand-activated Liver X Receptor (LXR) is known to increase cholesterol efflux from cells and reduce the production of amyloid β (Aβ) from amyloid-beta precursor protein (APP). However, little is known about the effects of LXRβ, one subtype of LXR, on endogenous Aβ. In this study, we show that LXRβ inactivation with specific antisense oligodeoxynucleotides (As-ODN) significantly reduced secreted Aβ and decreased mRNA levels of APP751+770, and α-, β-secretase (ADAM10, BACE1) in primary rat neurons. We also show that As-ODN down-regulated the LXR responsive genes ABCA1 and HMG-CoA reductase (HMGCR). These changes are associated with decreased cellular cholesterol levels. The effect of LXRβ inactivation on Aβ levels is likely due to the alteration of cholesterol production and APP processing. Thus, our data suggest that LXRβ has an important function in cholesterol homeostasis and endogenous Aβ maintenance in neurons.