Cholesterol metabolism and oxidative stress in Alzheimer's disease

Cholesterol has a prominent role in cell structure and function, in the brain, including signal transduction, neurotransmitter release, synaptogenesis, and membrane trafficking. Perturbation of cholesterol trafficking in the brain is potentially linked to the pathogenesis of Alzheimer's disease (AD). Cholesterol is unable to pass the blood-brain barrier, and its level in the brain depends exclusively on de novo synthesis and elimination, which rely on local transcription of ApoE and cassette transporters (ABCA1, ABCG1, and ABCG4) involved in the lipid transfer across membranes. These pathways are controlled by oxysterols. In order to maintain homeostasis, cholesterol is converted into 24-hydroxycholesterol by the neuronal specific cholesterol 24-hydroxylase, which is located in the endoplasmic reticulum. The putative role of upregulated oxidative stress in AD has raised interest in nonenzymatic oxysterols, which are generated by free radical species, such as those arising from the superoxide/hydrogen peroxide/hydroxyl radical system and by non-radical highly reactive oxygen species such as singlet oxygen, HOCl, and ozone. The analysis of oxysterols is a valuable tool to noninvasively investigating the role of cholesterol metabolism in the pathogenesis of neurodegeneration.