Alzheimer's disease: brain desmosterol levels

Abstract

Desmosterol is a C27 sterol intermediate in cholesterol synthesis generated during the metabolic pathway that transforms lanosterol into cholesterol. It has become of particular interest in the pathogenesis of Alzheimer's disease (AD) because of the report that the activity of the gene coding for the enzyme DHCR24, which metabolizes desmosterol to cholesterol, is selectively reduced in the affected areas of the brain. Any change in the pattern of C27 sterol intermediates in cholesterol synthesis merits investigation with respect to the pathogenesis of AD, since neurosteroids such as progesterone can modulate the tissue levels. We therefore analyzed the C27 sterol composition using a metabolomics approach that preserves the proportion of the different sterol intermediates. In AD, the proportion of desmosterol was found to be less than that of age-matched controls. The findings do not directly support the focus on Seladin-1, although they could reflect different stages of a slowly progressive disease.

Fig. 1

Role of 24-dehydrocholesterol reductase (DHCR24) in the transformation of lanosterol to cholesterol. Beginning with lanosterol, two groups of sterol intermediates progress toward cholesterol, those with an unsaturation at C24 = C5 and those where the reduction occurs early in the pathway. Desmosterol is considered to be the preferred substrate, see [26], from which this illustration has been taken with permission.

Fig. 2

LC-MS analysis of C27 sterol intermediates in cholesterol synthesis. Reverse-phase (C18) chromatography separates isomers of C27 sterol intermediates of cholesterol as zymosterol, desmosterol, 8-dehydrocholesterol, and 7-dehydrocholesterol based on the different sites of the unsaturation in the molecule. Because it is established that levels of both 8- and 7-dehydrocholesterol are increased in the plasma of individuals with Smith-Lemli-Opitz syndrome, see [21], and desmosterol is undetectable, this plasma is a very useful reference for establishing relative retention times. Loss of the 3-OH group (M-17), common to cholesterol and the sterol intermediates, that occurs with an APCI detector provides fragments, 369 m/z and 367, respectively, in high abundance that permits detection at the nanogram level.

Fig. 3

C27 sterol intermediates in the sterol extract of brain tissue from AD and non-AD age-matched controls. Using an internal standard of deuterated (373 m/z) desmosterol (D) the location of endogenous desmosterol, 367 m/z [1], can always be ascertained regardless of slight changes that may occur in the retention time. We chose for NMR analysis samples with barely detectable desmosterol to highlight the difference between AD and non-AD patients. 8-Dehydro-cholesterol was the predominant C27 sterol intermediate found in all specimens.

Fig. 4

Determinants of 8-dehydrocholesterol levels in tissues. Evidence for active cholesterol synthesis is the finding of relatively high levels of sterol intermediates in tissues. Other than the endogenous rate of cholesterol synthesis, the other determinants of the tissue level of 8-dehydrocholesterol are the relative activities of sterol delta 5 desaturase (SΔ5DS), delta 8-delta 7 isomerase (SΔ8Δ7iso), and 7-dehydrocholesterol 7 reductase (7DHCR7).