Abstract
Impairment in cholesterol metabolism is associated with many neurodegenerative disorders including Alzheimer's disease (AD). However, the lipid alterations underlying neurodegeneration and the connection between altered cholesterol levels and AD remains not fully understood. We recently showed that cholesterol accumulation in hippocampal neurons, induced by silencing Cyp46a1 gene expression, leads to neurodegeneration with a progressive neuronal loss associated with AD-like phenotype in wild-type mice. We used a targeted and non-targeted lipidomics approach by liquid chromatography coupled to high-resolution mass spectrometry to further characterize lipid modifications associated to neurodegeneration and cholesterol accumulation induced by CYP46A1 inhibition. Hippocampus lipidome of normal mice was profiled 4 weeks after cholesterol accumulation due to Cyp46a1 gene expression down-regulation at the onset of neurodegeneration. We showed that major membrane lipids, sphingolipids and specific enzymes involved in phosphatidylcholine and sphingolipid metabolism, were rapidly increased in the hippocampus of AAV-shCYP46A1 injected mice. This lipid accumulation was associated with alterations in the lysosomal cargoe, accumulation of phagolysosomes and impairment of endosome-lysosome trafficking. Altogether, we demonstrated that inhibition of cholesterol 24-hydroxylase, key enzyme of cholesterol metabolism leads to a complex dysregulation of lipid homeostasis. Our results contribute to dissect the potential role of lipids in severe neurodegenerative diseases like AD.
Highlights
Mammalian brain, most cholesterol-rich organ contains 10-fold more cholesterol than any other organ (Dietschy and Turley, 2004; Bjorkhem, 2006; Bjorkhem et al, 2010)
No change in other sterols or oxidative product of cholesterol, such as desmosterol or 5α,6α-epoxycholesterol was observed (Supplementary Figure 1). These results indicate that the injection of AAV-shCYP46A1 induced a strong reduction of cholesterol-24(S)-hydroxylase activity leading to a decreased production of 24-(S) hydroxycholesterol and to an accumulation of cholesterol
Impairment in cholesterol metabolism is involved in many neurodegenerative diseases including Alzheimer’s disease (AD) (Anstey et al, 2008)
Summary
Most cholesterol-rich organ contains 10-fold more cholesterol than any other organ (Dietschy and Turley, 2004; Bjorkhem, 2006; Bjorkhem et al, 2010). One of the mechanisms for cholesterol clearance from the brain is its conversion into an hydroxylated metabolite, the 24(S)-hydroxycholesterol (24-OHC), which is able to cross the BBB and enter the circulation to the liver to be further metabolized to bile acids (Lund et al, 2003; Bjorkhem, 2006; Russell et al, 2009) This conversion is catalyzed by an enzyme cytochrome P450, the cholesterol 24-hydroxylase, called CYP46A1, mainly expressed by neuronal cells (Lutjohann et al, 1996; Lund et al, 1999). This conversion represents one of the most important mechanisms for cholesterol clearance from the brain (Bjorkhem, 2006; Russell et al, 2009)
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