Apolipoprotein E in Alzheimer's disease: molecular insights and therapeutic opportunities

Abstract

Apolipoprotein E (APOE- gene; apoE- protein) is the strongest genetic modulator of late-onset Alzheimer's disease (AD), with its three major isoforms conferring risk for disease ε2 < ε3 < ε4. Emerging protective gene variants, such as APOE Christchurch and the COLBOS variant of REELIN, an alternative target of certain apoE receptors, offer novel insights into resilience against AD. In recent years, the role of apoE has been shown to extend beyond its primary function in lipid transport, influencing multiple biological processes, including amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, autophagy, cerebrovascular integrity and protection from lipid peroxidation and the resulting ferroptotic cell death. While the detrimental influence of apoE ε4 on these and other processes has been well described, the molecular mechanisms underpinning this disadvantage require further enunciation, particularly to realize therapeutic opportunities related to apoE. This review explores the multifaceted roles of apoE in AD pathogenesis, emphasizing recent discoveries and translational approaches to target apoE-mediated pathways. These findings underscore the potential for apoE-based therapeutic strategies to prevent or mitigate AD in genetically at-risk populations.

Keywords: APOER2; Alzheimer’s disease; ApoE Christchurch; Apolipoprotein E; Apolipoprotein E receptors; Autophagy; Ferroptosis; Lipid peroxidation; Neurodegeneration; Neuroinflammation.

Fig. 1

ApoE domain structure and associated variants. Domain organization of the human apoE protein is highlighted including amino acid changes associated with the AD risk isoform apoE4, the protective isoform apoE2 and 3 additional protective variants: the Christchurch variant, the Jacksonville variant and the Arg251Val variant

Fig. 2

Structural organization of apoE receptors. LDLR, VLDLR, APOER2 and LRP1 share similar structure that includes an extracellular ligand binding domain, EGF-precursor homology domain, an O-linked sugar domain, a transmembrane domain, and an intracellular cytoplasmic domain that contains an NPxY motif

Fig. 3

ApoE biology in the brain. ApoE is mainly expressed by astrocytes in the brain. Upon expression, apoE is lipidated mainly by the ABCA1 transporter, which is located at the plasma membrane of astrocytes and ABCG1, which is present on the plasma membrane of astrocytes and neurons. Secreted apoE binds to different receptors expressed on neurons (and other cells) that are involved in endocytosis (LDLR, LRP1, HSPG) or signaling (apoER2, VLDLR) and affects endosomal trafficking and receptor recycling to the plasma membrane. ApoE is also required for the transport of excess oxidized fatty acids that are generated during neuronal activity to astrocytes, which are either stored in lipid droplets or used for energy production via β-oxidation

Fig. 4

Mechanism of ferroptosis. Schematic description of the ferroptosis pathway highlighting the defense mechanisms mediated by the selenium-dependent protein glutathione peroxidase 4 (GPX4) requiring glutathione (GSH) for activity and ferroptosis suppressor protein 1 (FSP1) requiring NADPH for activity. Iron is required for ferroptosis and can be delivered via transferrin receptor 1 (TfR1) uptake or via autophagic degradation of the iron storage protein ferritin. ApoER2 is linked with selenium uptake and regulation of autophagy. Ferroptosis can be induced by various small molecule inhibitors (highlighted in red) and can be inhibited by radical trapping agents and iron chelators (highlighted in green)

Fig. 5

ApoE biology, intersection with disease and therapeutic approaches