(197m) Elucidating the Molecular Mechanisms By Which Amyloid-Beta Suppresses HSV-1 Infection in the Brain

Amyloid-beta (Aβ) is derived from the neuronal transmembrane protein Amyloid Precursor Protein, following its cleavage by a series of secretases. Self-aggregation of the resulting Aβ peptides into oligomers and plaques has been strongly implicated in mediating neurodegeneration and Alzheimer’s disease¹. However, recent studies have elucidated many beneficial functions of Aβ, including its ability to repair holes in the blood-brain barrier, regulate synaptic properties of neurons, adopt antimicrobial peptide-like behaviors, and even exhibit antiviral behaviors towards foreign pathogens in the brain. In the latter case, for example, Aβ has been shown to sequester and remove herpes simplex virus (HSV-1)—which affects 67% of the human population—from the brain, via direct interactions with the virus’ surface glycoproteins². Yet, the full picture of how Aβ mediates these antiviral behaviors with respect to HSV-1, and other viral pathogens in the brain, remains unclear.

The structure of Aβ has been observed to vary between a mostly unstructured coil in solution, to a helical form after coming into contact with a cellular membrane, to a neurotoxic beta sheet-like structure after the process of self-aggregation has begun. Moreover, Aβ commonly exists as both a 40- and 42-residue peptide, the latter of which is considered to be the more neurotoxic form³, but also the form with the more potent antiviral capabilities. As such, we hypothesized that the 42-residue Aβ peptide that resides in an unstructured or helical form would exhibit the strongest antiviral behavior, binding to HSV-1 glycoproteins in a way that directly interferes with their ability to bind to host cell receptors. To test this idea, we performed molecular dynamics (MD) simulations, in triplicate using the GROMACS engine, of Aβ in the six configurations (40- and 42-residue peptide in a coil, helical, or beta-sheet form), interacting with all four HSV-1 glycoproteins. Our results confirm that specific forms of Aβ bind more strongly to HSV-1 glycoproteins than other forms, and that the most strongly-binding forms of Aβ interact with regions of HSV-1 glycoproteins that are crucial for host cell receptor binding. Overall, insights gained from these simulations may be used to guide the future design of novel drugs to prevent and/or treat HSV-1 infection in the brain. More broadly, this work provides a deeper understanding of the innate therapeutic properties of Aβ in the brain and may help to elucidate the true role of Aβ in other contexts like Alzheimer’s disease.

References:

[1] Chen et. al, Amyloid beta: structure, biology and structure-based therapeutic development. APS, 38(9):1205-1235. (2017).

[2] Bourgade K et. al, Anti-Viral Properties of Amyloid-β Peptides. Journal of Alzheimer’s Disease Reports, (6):599-606. (2022).

[3] Olubiyi et. al, Structures of the amyloid β-peptides Aβ1-40 and Aβ1-42 as influenced by pH and a d-peptide. J. P. Chem. B, 116(10):3280–3291. (2012).