APOE

ApoE, or apolipoprotein E, is a multifunctional protein that plays a central role in lipid transport and cholesterol metabolism. It is a component of various lipoprotein particles and is essential for the distribution and clearance of lipids in both peripheral tissues and the brain. In the liver and macrophages it is produced and released into circulation; in the brain, astrocytes secrete ApoE which participates in lipid delivery to neurons and in membrane maintenance and repair.

The APOE gene is located on chromosome 19q13.2-13.3. Three common protein isoforms arise from two single-nucleotide polymorphisms, producing ApoE2, ApoE3, and ApoE4. They differ at amino acids 112 and 158: ApoE2 has Cys at both positions, ApoE3 has Cys112 and Arg158, and ApoE4 has Arg112 and Arg158. These substitutions alter lipid-binding properties and interactions with LDL receptor family members, influencing lipoprotein clearance and distribution.

Functionally, ApoE acts as a ligand for LDL receptor family members (such as LDLR and LRP1), facilitating endocytosis of chylomicron and VLDL remnants and the regulation of plasma lipid levels. In the CNS, ApoE is the main apolipoprotein for lipid transport between glial cells and neurons, supporting membrane synthesis, synaptic remodeling, and repair after injury. The lipidation state of ApoE and its isoform composition affect these processes and receptor interactions.

Clinical significance includes the APOE genotype as a major genetic factor in sporadic Alzheimer's disease risk and age at onset, with ApoE4 increasing risk and ApoE2 potentially reducing it. ApoE also modulates cardiovascular risk through its effects on lipoprotein metabolism. Ongoing research explores isoform-specific therapies and strategies to modify ApoE function.

---