Cholesterol is eliminated from neurons by oxidization, which generates
oxysterols.
Cholesterol oxidation is mediated by the
enzymes cholesterol 24-hydroxylase (
CYP46A1) and
cholesterol 27-hydroxylase (CYP27A1). Immunocytochemical studies show that
CYP46A1 and CYP27A1 are expressed in neurons and some astrocytes in the normal brain, and CYP27A1 is present in oligodendrocytes. In
Alzheimer's disease (AD),
CYP46A1 shows prominent expression in astrocytes and around
amyloid plaques, whereas CYP27A1 expression decreases in neurons and is not apparent around
amyloid plaques but increases in oligodendrocytes. Although previous studies have examined the effects of synthetic
oxysterols on the processing of
amyloid precursor
protein (APP), the actions of the naturally occurring
oxysterols have yet to be examined. To understand the role of
cholesterol oxidation in AD, we compared the effects of 24(S)- and
27-hydroxycholesterol on the processing of APP and analyzed the cell-specific expression patterns of the two
cholesterol hydroxylases in the human brain. Both
oxysterols inhibited production of Abeta in neurons, but 24(S)-hydroxycholesterol was approximately 1000-fold more potent than
27-hydroxycholesterol. The IC(50) of 24(S)-hydroxycholesterol for inhibiting Abeta secretion was approximately 1 nm. Both
oxysterols induced ABCA1 expression with IC(50) values similar to that for inhibition of A beta secretion, suggesting the involvement of
liver X receptor.
Oxysterols also inhibited
protein kinase C activity and APP secretion following stimulation of
protein kinase C. The selective expression of
CYP46A1 around
neuritic plaques and the potent inhibition of APP processing in neurons by 24(S)-hydroxycholesterol suggests that
CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the
CYP46A1 gene might influence the pathophysiology of this prevalent disease.