Apolipoprotein E and cholesterol in aging and disease in the brain

Abstract

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.

Links between ApoE, brain cholesterol metabolism, tau and amyloid β-peptide in patients with cognitive impairment

“…As the main extracellular lipids and cholesterol lipid transporter in the brain, ApoE mediates cholesterol exchange between neuronal and non-neuronal cells. ApoE may also play a crucial role in lipid clearance and recycling, particularly after injury [19][20][21]. The mechanisms by which ApoE affects AD in an isoform-specific manner have been extensively studied.…”

“…It was found, for example, that the ApoE4 isoform is less efficient than ApoE3 in facilitating brain function. Supporters of the concept that ApoE has neuroprotective and neurotrophic functions in the normal aging brain argue that ApoE2 and ApoE3 perform these functions more efficiently than does ApoE4 [19][20][21]. Neurodegeneration in AD may result from impaired delivery of cholesterol from astrocytes to neurons.…”

Cholesterol overload induces apoptosis in SH-SY5Y human neuroblastoma cells through the up regulation of flotillin-2 in the lipid raft and the activation of BDNF/Trkb signaling

“…To cross the BBB, cholesterol needs to be hydroxylated to 24-hydroxycholesterol (24-OHC) by 24-hydroxylase (Cyp46) to maintain a balance between the cholesterol and its metabolites, and hence to avoid the accumulation of brain cholesterol (Shobab et al, 2005). It has been shown that the BBB can be damaged by long-term hypercholesterolemia and aging, which results in the entry of circulating cholesterol into the brain and causes impairment of cholesterol metabolism (de Chaves and Narayanaswami, 2008;Takechi et al, 2013). Additionally, when the function of the converting enzyme is impaired due to oxidative stress, brain cholesterol may also accumulate (Ohyama et al, 2006).…”

Age-Related Binding of Proximal Region of ApoE Promoter to Nuclear Proteins of Mouse Cerebral Cortex

“…It is abundant in the brain and increases 250-to 350-fold in response to peripheral nerve injury in a rat model [18]. It may protect against motor and cognitive defects due to acute head injury or stroke [4,5]. ApoE is important for maintaining brain homeostasis during aging because its altered expression and genotypic variants are associated with agerelated disorders [7,12,16,21,32].…”

“…ApoE is important for maintaining brain homeostasis during aging because its altered expression and genotypic variants are associated with agerelated disorders [7,12,16,21,32]. Moreover, mice deficient of apoE develop severe spatial learning and memory abnormalities [4]. Due to importance of apoE in brain function and aging, it is important to study the effect of age on the binding of different regulatory elements present in the promoter region of ApoE with nuclear proteins.…”