ApoE Lipidation as a Therapeutic Target in Alzheimer's Disease

Abstract

Apolipoprotein E (APOE) is the major cholesterol carrier in the brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance and degradation of amyloid β (Aβ) and neuroinflammation. In humans, the APOE gene has three common allelic variants, termed E2, E3, and E4. APOE4 is considered the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOE2 is neuroprotective. To perform its normal functions, apoE must be secreted and properly lipidated, a process influenced by the structural differences associated with apoE isoforms. Here we highlight the importance of lipidated apoE as well as the APOE-lipidation targeted therapeutic approaches that have the potential to correct or prevent neurodegeneration. Many of these approaches have been validated using diverse cellular and animal models. Overall, there is great potential to improve the lipidated state of apoE with the goal of ameliorating APOE-associated central nervous system impairments.

Keywords: apolipoprotein E; cholesterol; lipid homeostasis; neurodegeneration.

Figure 1

apoE and cholesterol transport and efflux. (A) In astrocytes, cholesterol synthesis is regulated by the liver X receptors (LXRs) and the retinoid X receptor (RXR). The LXR/RXR heterodimer interacts with sequence-specific DNA elements positioned close to enhancers or promoters of their target genes, including the ABCA1, ABCG1, and APOE, thus acting directly to upregulate their transcription. (B) apoE initiates the formation of high-density lipoprotein (HDL)-like particles by accepting cholesterol and phospholipids through the ABCA1 and ABCG1 transporters. (C) apoE-containing lipoproteins and lipid complexes interact with cell surface heparin sulfate proteoglycans and cell membrane associated receptors, including the LDL receptor and the LDL receptor-related protein 1 (LRP) in neurons. This interaction promotes cellular uptake and redistribution of cholesterol to maintain proper cellular function, including neuronal growth, repair and remodeling of membranes, organelle biogenesis, and synaptogenesis.

Figure 2

Recalibrating apoE functions by increasing lipidation. Therapeutic strategies to improve the lipidated state of apoE include the use of: (1) Small molecules that enhance ABCA1 activity, (2) Liver X receptor (LXR) and retinoid X receptor (RXR) agonists to increase the expression of ABCA1, ABCG1 and APOE, (3) regulation of micro-RNAs to increase ABCA1 expression, (4) small molecules as apoE4 structure correctors, (5) anti-apoE4 immunotherapy targeting non-lipidated apoE, and (6) recalibrating apoE function by using AAV-APOE2 biologic therapy.