Apolipoprotein E–Low-density lipoprotein receptor pathway (ApoE-LDLR pathway)

The Apolipoprotein E–Low-density lipoprotein receptor (ApoE-LDLR) pathway is a critical mediator of lipid metabolism and cholesterol homeostasis in both the peripheral circulation and the central nervous system. Apolipoprotein E (ApoE) serves as a high-affinity ligand for the LDL receptor (LDLR), facilitating the cellular uptake and clearance of cholesterol-rich lipoproteins, such as very-low-density lipoprotein (VLDL) remnants and chylomicron remnants [1, 2]. In the liver, this interaction is essential for maintaining systemic cholesterol levels, and its dysfunction leads to conditions like Hyperlipoproteinemia Type III and atherosclerosis [4]. In the brain, the ApoE-LDLR axis is the primary mechanism for lipid redistribution to neurons and plays a significant role in the proteolytic clearance of amyloid-beta peptides, a hallmark of Alzheimer's disease [3]. The ApoE ε4 isoform is the strongest genetic risk factor for late-onset Alzheimer's, partly due to its reduced efficiency in these clearance processes compared to other isoforms. Current therapeutic interventions, such as statins and PCSK9 inhibitors, focus on upregulating LDLR to lower cardiovascular risk, while research continues into modulating this pathway to treat neurodegeneration [5].

Other names

ApoE-LDLR axisApolipoprotein E-LDL receptor interactionLipoprotein clearance pathwayApoE-LDLR signaling pathway

Drugs targeting this pathway primarily increase the surface expression of the Low-density lipoprotein receptor (LDLR) by inhibiting HMG-CoA reductase (statins) or by blocking PCSK9-mediated degradation of the receptor (PCSK9 inhibitors), thereby enhancing the clearance of ApoE- and ApoB-containing lipoproteins from the blood [4, 5].