Herpes Simplex Virus Glycoprotein D Associated with Aβ_1-42 Tetramers Mediates Neurotoxicity by Perturbing Neuronal...

Alzheimer's disease (AD) is characterized by deleterious amyloid plaques deposited in the brain, formed through the interaction of Amyloid β-peptides (Aβ_1-42) with the cell membrane. Despite promising preclinical results, Aβ_1-42 aggregation inhibitors have not delivered the anticipated benefits in clinical trials for AD. This discrepancy may stem from the fact that the cause of sporadic AD is unknown. Mounting evidence suggests that herpes simplex virus type-1 (HSV-1) may significantly contribute to the onset of AD by facilitating the aggregation of Aβ_1-42 into oligomers, leading to neurotoxicity and neuronal cell loss in the brain. However, the mechanism of neurotoxicity remains elusive. Understanding the relationship between the HSV-1 envelope glycoprotein D (gD) and Aβ_1-42 oligomers and their impact on neuronal membranes, is the most demanding task for unveiling the underlying mechanism. Thus, we performed extensive all-atom molecular dynamics (MD) simulations to thoroughly investigate the molecular mechanism underlying the interaction between the gD protein and Aβ_1-42 oligomers in both aqueous environments and in the presence of lipid bilayers, which mimic the composition of neuronal membranes in vivo. Our simulation study provides valuable insights into the initial stages of this process, in which the Aβ_1-42 tetramer (Aβ_1-42t) associates with gD via hydrogen bonds formed at their interface. Consequently, we observed that Aβ_1-42t-gD, rather than Aβ_1-42t alone, demonstrates significant adsorption to the membrane, driven by robust electrostatic interactions between the charged residues of Aβ_1-42t-gD and the phosphate groups of lipids such as POPC, POPS, POPE, and PSM. This interaction significantly reduces the electrostatic and van der Waals interactions among the lipids, in contrast to Aβ_1-42t binding alone. As a result, disruptions of the lipid membrane integrity are more pronounced upon the Aβ_1-42t-gD binding than the Aβ_1-42t alone. This study provides atomic-level evidence that gD amplifies Aβ_1-42t-membrane interactions, potentially altering membrane phase behavior and contributing to the initial molecular events underlying neuronal dysfunction, thereby suggesting a link between HSV-1 infection and the pathogenesis of AD.