Differential Expression of Cholesterol Hydroxylases in Alzheimer's Disease

Abstract

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 A␤ in neurons, but 24(S)-hydroxycholesterol was ϳ1000-fold more potent than 27-hydroxycholesterol. The IC 50 of 24(S)-hydroxycholesterol for inhibiting A␤ secretion was ϳ1 nM. Both oxysterols induced ABCA1 expression with IC 50 values similar to that for inhibition of A␤ 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.

Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain

“…There appears to be a link between CYP46A1 and AD; the CYP46A1 expression pattern in the brain and levels of 24OH-CH in the serum and cerebrospinal f luid are different in healthy people and those affected by AD (13)(14)(15)(16)(17). The association between polymorphisms in the CYP46A1 gene and susceptibility to AD was also demonstrated in a number of studies (www.alzforum.org).…”

“…Evidence has also been obtained in cultured cells and mice that supports a role for side-chain oxysterols, including 24OH-CH, as endogenous ligands for liver X receptors, that regulate the expression of genes involved in fatty acid and cholesterol metabolism (7). 24OH-CH was also shown to inhibit the formation of amyloid ␤-peptides, a hallmark of AD, in cell cultures (14,18). Additionally, 24OH-CH is thought to induce apolipoprotein E-mediated cholesterol eff lux from astrocytes and thus to affect the progression of neurodegenerative diseases, including AD (19).…”

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

“…In intact cells and in vitro, 24SOH can down-regulate sterol synthesis (15,16). When provided to neurons, 24SOH decreases the secretion of Aβ (17). 24SOH levels were decreased in brain samples from patients with AD (18).…”

Neuronal cholesterol esterification by ACAT1 in Alzheimer's disease

“…Various oxysterols, including 24SOH, can downregulate sterol synthesis in intact cells and in vitro (61,62), and can bind and activate the LXRs (52,63). When provided to neurons, 24SOH decreases the secretion of Abeta (64). 24SOH levels were decreased in brain samples from late stage AD patients (65), suggesting a relationship between 24SOH and AD.…”