Apolipoprotein E (APOE), a classical lipid-binding protein, binds cholesterol or other lipids to form lipoprotein particles that mediate lipid transport in the central nervous system and peripheral tissues. Increasing evidence suggests that APOE gene polymorphisms are closely associated with Alzheimer's disease (AD), vascular atherosclerosis, and human lifespan regulation.
Related Products
APOE Gene and Risk of AD
The human APOE gene is located on chromosome 19 and exists as three polymorphic alleles, ε2, ε3, and ε4, which encode the three APOE proteins, APOE2, APOE3, and APOE4. In 1996, Stritmatter and Roses found that carriers of the APOE ε4 gene were more likely to develop AD, and genome-wide association studies confirmed that the APOE ε4 allele was the strongest risk factor for late-onset AD (onset of the disease at age 65 years or older), whereas the APOE ε2 allele was protective against AD.
Fig.1 Structural components of APOE isoforms (Flowers S. A., Rebeck G. W. 2020).
In addition, the proportion of APOE genotypes carried also affects the likelihood of developing AD, with one APOE ε4 allele increasing the risk of AD by 3-4 times and two APOE ε4 alleles (hereafter referred to as the APOE4 gene) increasing the risk of the disease by 9-15 times. Numerous studies have found that APOE not only regulates the expression levels of brain β-amyloid plaques, tau proteins, and TDP43 proteins in AD patients but also affects normal brain function.
Physiological Characteristics of APOE
The human APOE protein has a size of 34 kDa and is composed of 299 amino acids. Upon release from cells, the cell surface ATP-binding cassette transporters (ABCA1 and ABCG1) transport cholesterol and phospholipids. APOE binds to these, forming lipoprotein particles, which then bind to cell surface receptors, redistributing cholesterol and other phospholipids to neurons. The LDL receptor family (LDLR and LRP1) are the main receptors for APOE, participating in APOE-mediated lipid metabolism.
APOE mutations are encoded by three corresponding alleles, and amino acid polymorphisms among these alleles alter the structure and function of APOE. This leads to differences in the affinity of APOE variants for APOE receptors, resulting in variations in lipid clearance efficiency, and inconsistent associations with disease occurrence.
Furthermore, APOE also regulates different pathways in the brain to varying degrees, including lipid transport, synaptic integrity and plasticity, glucose metabolism, and vascular function.
APOE Clearance of Aβ
The clearance pathways of Aβ include clearance through the blood-brain barrier, cellular phagocytosis and degradation, enzymatic degradation, clearance through cerebrospinal fluid flow, circulation to the periphery, and lymphatic system. Aβ clearance is related to the genotype and lipidation status of APOE, where APOE2 and APOE3 have Aβ clearance abilities, while APOE4 can exacerbate Aβ deposition, especially in the early stages. APOE2-Aβ and APOE3-Aβ complexes can be cleared through VLDLR and LRP1 on the blood-brain barrier, while the clearance of APOE4-Aβ is through LRP1 to VLDLR. Since the internalization of APOE4-Aβ mediated by VLDLR is slower than that by LRP1, the clearance of APOE4-Aβ is slower than that of APOE2 and APOE3. Additionally, the efficiency of APOE4 in promoting Aβ transport across the vascular wall is lower than that of APOE2, and the process of peripheral cell clearance of Aβ related to the blood-brain barrier is impaired when APOE derived from astrocytes is present.
Phagocytosis and degradation mediated by receptors on glial cells are important pathways for Aβ clearance. The clearance of Aβ by astrocytes is partially dependent on APOE genotype and APOE receptors, with APOE4 capable of inhibiting cellular phagocytosis. Furthermore, APOE-mediated cholesterol efflux can promote Aβ transport to lysosomes, simultaneously enhancing the efficiency of microglial cell degradation of extracellular Aβ. APOE also plays a role in other Aβ clearance pathways, including peripheral vascular efflux and the enzymatic hydrolysis of Aβ.
APOE and Tau Protein, α-Synuclein Protein, and TDP43 Protein
APOE can regulate tau-mediated neurodegeneration and microglial self-homeostasis, synaptic integrity, lipid transport, glucose metabolism, and brain vascular function. The effect of APOE on tau protein depends on the presence or absence of β-amyloid plaques.
Furthermore, it is currently unclear whether APOE4 acts on α-synuclein protein through an Aβ-dependent mechanism, similar to the amyloid cascade hypothesis for tau protein, or independent of Aβ. In Alzheimer's disease (AD), there may be a direct link between APOE4 and TDP43, which could be independent of Aβ.
Treatments for Target APOE
In the field of AD, treatments targeting APOE mainly focus on the following aspects.
Increase APOE Levels and Their Lipidation
APOE4 in the brain has a lower and more stable level of lipidation than APOE2 and APOE3, so increasing the binding of APOE4 to lipids in the brain may accelerate the clearance of Aβ. Bexarotene enhances the lipidation of APOE and increases the expression level of APOE by inducing the expression of the ABCA1 and ABCG1 genes, which can rapidly reduce the Aβ plaque load and improve cognitive ability in the brain of AD mice.
Block the Interaction between APOE and Aβ
Anti-APOE monoclonal antibody (HJ6.3) significantly reduced insoluble Aβ levels, Aβ plaque burden, and APOE levels in the brains of APP/PS1 transgenic memory-deficient mice. Interfering with the binding of APOE and Aβ using Aβ12-28P, a synthetic peptide that binds to APOE, reduces soluble and insoluble Aβ levels and Aβ plaque burden in memory-deficient mice, and reduces APOE deposition in Aβ plaques.
APOE Analogs
APOE analogs (the N-terminal fragment of APOE, including its receptor-binding motif) have been shown to improve Aβ levels and Aβ plaque burden, tau hyperphosphorylation, and neuroinflammation in various Alzheimer's disease mouse models, but have not yet entered human clinical trials.
Gene therapy
The application of CRISPR-Cas9 editing technology for editing the transformed APOE allele has been successful at the cell culture level but remains to be validated in mouse knockout experiments. However, it has become possible to apply gene therapy to express APOE ε2 and increase APOE ε2 expression levels in APOE ε4 carriers (or even APOE ε3 purists).
References
- Namboori P. K.; et al. The ApoE gene of Alzheimer's disease (AD)[J]. Functional & integrative genomics, 2011, 11: 519-522.
- Flowers S. A.; Rebeck G. W. APOE in the normal brain. Neurobiology of Disease. 2020, 136: 104724.
.
