High-affinity multivalent interactions between apolipoprotein E and the oligomers of amyloid-β

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Apolipoprotein E (apoE) isoforms are critical in Alzheimer's disease (AD) pathogenesis.
• The precise molecular mechanisms of apoE and amyloid-beta (Aβ) interactions remain incompletely understood.
• Understanding these interactions is key to developing AD therapeutics.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying apoE isoform interactions with Aβ peptides.
• To compare the effects of different apoE domains (N-terminal fragment (NTF), C-terminal fragment (CTF), and full-length) on Aβ aggregation and interaction kinetics.
• To investigate the binding affinity and dynamics of apoE-Aβ interactions.

Main Methods:

• Investigated Aβ1-42 aggregation kinetics in the presence of varying apoE forms (lipid-free and lipidated).
• Utilized intermolecular Förster resonance energy transfer (FRET) analysis to measure apoE-Aβ interactions over time.
• Employed competitive binding assays with labelled and unlabelled apoE fragments and full-length apoE.

Main Results:

• Substoichiometric concentrations of apoE (NTF, CTF, full-length) significantly delayed Aβ1-42 aggregation.
• FRET analysis revealed time-dependent apoE-Aβ interactions, suggesting binding to Aβ intermediates rather than monomers.
• Full-length apoE exhibited higher binding affinity to Aβ than its fragments, with apoE4 showing stronger interaction than apoE3.

Conclusions:

• ApoE interacts with oligomeric Aβ intermediates, not monomers, influencing Aβ aggregation kinetics.
• All three domains of apoE contribute to Aβ binding, with multivalent interactions likely mediating high-affinity binding of full-length apoE.
• ApoE4's stronger interaction with Aβ compared to apoE3 may contribute to its increased risk for Alzheimer's disease.