(9a) Atomistic-Level Insights into the Interfacial Interactions between Amyloid-Beta and Phospholipid Bilayers for the Treatment of Alzheimer’s Disease

Alzheimer's Disease (AD) is a devastating neurological disease that affects 6.5 million Americans today, and AD diagnoses are projected to more than double by 2050 [1]. A hallmark of AD is the aggregation of misfolded amyloid-β (Aβ) proteins in the brain into Aβ oligomers (AβO), thought to be mediated by interfacial interactions between Aβ and host cell membranes [2]. Experimental data have shown AβO are soluble, neurotoxic, and contribute to cognitive decline in people with AD [3]. New treatment modalities aimed at preventing or reversing Aβ aggregation by controlling these interactions offer promise for combatting AD. Recently, Sosa et al. discovered that lipid vesicles—spherical structures composed of a cell membrane-like phospholipid bilayer, surrounding an aqueous interior—could prevent aggregation of misfolded Aβ and catalyze the breakdown of aggregated Aβ species like AβO [4]. However, the mechanisms behind these promising results remain entirely unclear.

It is hypothesized that the binding energy between AβO and the bilayer must not be too strong such that AβO will be overly stabilized on the surface and unable to undergo conformational changes, but not too weak such that AβO will desorb from the surface without degrading or refolding into a non-neurotoxic form. We explored this hypothesis via molecular dynamics (MD) simulations of the different forms of Aβ (monomers, AβO, and fibrils) adsorbing onto bilayers with lipid compositions mimicking the experiments of Sosa et al. Furthermore, we employed the enhanced sampling method metadynamics combined with temperature-based replica exchange (PTMetaD-WTE; [5]) to ensure robust sampling of the surface-bound conformations of Aβ in the timescales accessible to our simulations. Our results provide new insights into how biological membranes catalyze the degradation of neurotoxic Aβ species in the brain. This knowledge could possibly lead to the design of new and/or improved breakthrough treatments for combatting AD, thereby impacting millions of lives worldwide.

References:

[1] Alzheimer's facts and figures report | Alzheimer's Association. https://www.alz.org/alzheimers- dementia/facts-figures.

[2] Khondker A, et al. “Membrane-accelerated amyloid-β aggregation and formation of cross-β sheets”, Membranes, 2017, 7, 49.

[3] Gibbs E, et al. “A rationally designed humanized antibody selective for amyloid beta oligomers in Alzheimer's Disease”, Sci Rep, 2019, 9, 9870.

[4] Chaparro-Sosa AF, et al. “Mixed phospholipid vesicles catalytically inhibit and reverse amyloid fibril formation”, J Phys Chem Lett, 2020, 11, 7417-7422.

[5] Deighan M, et al. “Efficient simulation of explicitly solvated proteins in the well-tempered ensemble”, J Chem Theory Comput, 2012, 8, 2189-2192.