Fig. 3

A Revised Cholesterol Hypothesis of AD. There are abnormal alterations in brain cholesterol metabolism, including the decrease of de novo cholesterol synthesis, and/or cholesterol trafficking (transportation, uptake, and intracellular transportation), and/or cholesterol catabolism in aging humans and animals, SAMP8 mice, diabetic mice, FAD (5xFAD and APP/PS-1) animals, AD patients, genetic forms of AD animals and patients (ApoE4 allele, mutation of NPC1 or NPC2, polymorphism of ABC and LDL receptor family), suggesting the brain cholesterol insufficiency/loss. To some extent, we found that these different kinds of AD models and patients include major risk factors for AD, such as Aβ, genetic factors, aging, diabetes-related risk factors, chronic hypoxia, oxidative stress, chronic inflammation, and metabolic syndrome, etc. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD in these different kinds of AD models and patients, suggesting a possible causative link between brain cholesterol loss and AD. Importantly, the brain cholesterol loss might lead to the membrane lipid raft disorganization and decrease of intracellular compartments, resulting in the pathological impairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the onset and progression of AD