The role of apolipoprotein E in neurodegeneration and cardiovascular disease

Abstract

Apolipoprotein E (ApoE) is an abundant plasma protein that interacts with low density lipoprotein receptors and other proteins, participating in the transport of cholesterol and lipids. Research has revealed many other roles for this multifunctional protein. ApoE is polymorphic and exists in three major isoforms: ApoE2, ApoE3 (the most common isoform) and ApoE4, which differ by only one amino acid, at positions 112 and 158. The altered binding to lipids and receptors by ApoE isoforms E2 and E4 results in an elevated risk for neurological, cerebrovascular and cardiovascular pathologies. Most notably, ApoE4 is associated with an elevated risk (relative to E3) for Alzheimer’s disease. The application of mass spectrometry for genotyping and also direct measurement of ApoE protein isoforms is a recent development and is well suited to high-throughput applications. The precise quantification of protein isoforms will allow better characterization of effects resulting from heterozygous APOE genotypes.

Keywords::

• Alzheimer’s disease
• apolipoprotein E
• cardiovascular disease
• mass spectrometry
• stroke

Financial & competing interests disclosure

MF Lopez is supported by ThermoFisher Scientific. MM Ning is supported by the Massachusetts General Hospital. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Apolipoprotein E (ApoE) is a plasma protein that interacts with low-density lipoprotein receptors and other proteins, is crucial in the transport of cholesterol and other lipids and functions in plasma clearance of triglyceride and cholesterol-rich lipoproteins.

• ApoE is polymorphic and exists in three major isoforms ApoE2, ApoE3 (the most common and non pathogenic isoform) and ApoE4, which differ by only one amino acid at positions 112 and 158.

• The altered binding of ApoE isoforms E2 and E4 to lipids and receptors results in an elevated risk for neurodegenerative, cerebrovascular and cardiovascular pathologies.

• The APOE4 genotype is robustly associated with an elevated risk for Alzheimer’s disease, and the ApoE4 protein isoform has altered binding efficiency to Abeta.

• Data from research studies suggest that multiple metabolic pathways are affected by APOE genotype including Alzheimer’s disease, Down syndrome, Parkinson’s disease, immune regulation, inflammation, sepsis, myocardial infarction, atherosclerosis, stroke and preeclampsia.

• Genotyping methods based on PCR amplification following restriction enzyme digestion are routinely applied to detect of APOE variants.

• The application of mass spectrometry for genotyping and also direct measurement of ApoE protein isoforms was recently developed and is well suited to high-throughput applications.

Notes