Dissecting the complex molecular interplay of Apolipoprotein E and amyloid-β in diverse environments.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 40 million people worldwide. Several oligomeric forms of the amyloid-β peptide (AβOs) accumulate in the AD brain and cause neurotoxicity, thereby inducing alterations in neuronal signaling pathways, memory impairments, and depressive-like behavior. The amyloid-β peptide forms diverse aggregates, including oligomers and amyloid fibrils, the main component of amyloid plaques, classic neuropathological markers of AD. Despite the direct association between amyloid-β and disease manifestation, most AD patients suffer from a sporadic form of the disease. The apolipoprotein E4 (ApoE ε4) allele is the main risk factor for sporadic AD. ApoE is a glycoprotein that, in humans, has 3 main isoforms, which differ by the mutation of a single amino acid: i) ApoE ε2, of lower incidence in the population; ii) ApoE ε3, predominant in the population; and iii) ApoE ε4, less frequent but associated with AD. Although its first association with the pathology was registered more than 30 years ago, the mechanism by which ApoE ε4 increases the risk for AD is still unknown. Here we aim to evaluate the putative interaction between amyloid-β (Aβ) and apolipoprotein E (ApoE) in the ε3 and ε4 isoforms. First, based on a previous experimental determination, we modeled the ApoE3 and ApoE4 proteins. We also used three Aβ monomeric structures (differed by the lipid/water solution ratios). Then, we performed rigid and flexible molecular docking of ApoE-Aβ complexes. We are analyzing the pH-dependent electrostatic surface of both the proteins and complexes. Further, Coarse-Grained molecular dynamics are underway to identify interaction interfaces and bond stability over time.