Alzheimer's disease: unraveling APOE4 binding to amyloid-beta peptide and lipids with molecular dynamics and quantum mechanics

The apolipoprotein E (APOE) involved in lipid metabolism participates in the clearance and deposition of the amyloid-beta peptide of the Alzheimer's disease (AD). The isoform APOE4 with the ARG112 mutation is the main genetic risk for the late-onset AD. Herein, using both molecular dynamics and quantum mechanics, the binding mechanisms of APOE4 leading to the AD are unraveled and now available for drug design. The binding affinities of APOE4 compared to the normal APOE3 are computed for the four cases: the bare APOE, APOE bound to the amyloid-beta peptide, APOE bound to a lipid nanoparticle mimicking the lipid effects and APOE bound to both amyloid-beta peptide and lipid nanoparticle. When APOE4 is bound to the amyloid-beta peptide, its structure becomes misfolded. Its binding free energy is higher than that of APOE3 in complex with the amyloid-beta peptide. Salt bridges for the APOE correct folding are missing in APOE4, resulting in an increased deposition of the amyloid-beta peptide, compared to APOE3, which can lead to the AD. When both amyloid-beta peptide and lipid nanoparticle are bound to APOE4, there is a detrimental cooperativity between the two misfolding effects, and amyloid-beta peptide deposition is even more significant. Immunotherapies with anti-APOE4 antibodies are promising for drug design against APOE4, but only non-lipidated APOE4 can be targeted. Gene editing is an interesting research alternative, because the genes APO epsilon(4)and APO epsilon(3)differ by only one nucleotide.

Automated summary

The study unravels the binding mechanisms of APOE4 associated with Alzheimer's disease, showing that when bound to the amyloid-beta peptide, APOE4 undergoes misfolding and increased deposition, potentially leading to the disease. Immunotherapies targeting APOE4 are promising for drug design, but the focus should be on non-lipidated APOE4.