Apolipoprotein E and cholesterol in aging and disease in the brain

Cholesterol can be detrimental or vital, and must be present in the right place at the right time and in the right amount. This is well known in the heart and the vascular system. However, in the CNS cholesterol is still an enigma, although several of its fundamental functions in the brain have been identified. Brain cholesterol has attracted additional attention owing to its close connection to ApoE, a key polymorphic transporter of extracellular cholesterol in humans. Indeed, both cholesterol and ApoE are so critical to fundamental activities of the brain, that the brain regulates their synthesis autonomously. Yet, similar control mechanisms of ApoE and cholesterol homeostasis may exist on either sides of the blood-brain barrier. One indication is that the APOE ε4 allele is associated with hypercholesterolemia and a proatherogenic profile on the vascular side and with increased risk of Alzheimer's disease on the CNS side. In this review, we draw attention to the association between cholesterol and ApoE in the aging and diseased brain, and to the behavior of the ApoE4 protein at the molecular level. The attempt to correlate in vivo and in vitro observations is challenging but crucial for developing future strategies to address ApoE-related aberrations in cholesterol metabolism selectively in the brain.