Serotonin Promotes Serum Albumin Interaction with the Monomeric Amyloid β Peptide.

Ekaterina Nemashkalova,Vladimir Uversky,Maria Permyakova,Marina Shevelyova,Sergei Permyakov,Ekaterina Litus,Aliya Nazipova,Alexey Kazakov,Evgenia Deryusheva,Elena Raznikova

doi:10.3390/ijms22115896

Abstract

Prevention of amyloid β peptide (Aβ) deposition via facilitation of Aβ binding to its natural depot, human serum albumin (HSA), is a promising approach to preclude Alzheimer’s disease (AD) onset and progression. Previously, we demonstrated the ability of natural HSA ligands, fatty acids, to improve the affinity of this protein to monomeric Aβ by a factor of 3 (BBRC, 510(2), 248–253). Using plasmon resonance spectroscopy, we show here that another HSA ligand related to AD pathogenesis, serotonin (SRO), increases the affinity of the Aβ monomer to HSA by a factor of 7/17 for Aβ40/Aβ42, respectively. Meanwhile, the structurally homologous SRO precursor, tryptophan (TRP), does not affect HSA’s affinity to monomeric Aβ, despite slowdown of the association and dissociation processes. Crosslinking with glutaraldehyde and dynamic light scattering experiments reveal that, compared with the TRP-induced effects, SRO binding causes more marked changes in the quaternary structure of HSA. Furthermore, molecular docking reveals distinct structural differences between SRO/TRP complexes with HSA. The disintegration of the serotonergic system during AD pathogenesis may contribute to Aβ release from HSA in the central nervous system due to impairment of the SRO-mediated Aβ trapping by HSA.

Highlights

Human serum albumin (HSA; 66.5 kDa) is the most abundant blood and cerebrospinal fluid (CSF) protein and is vital to maintaining the osmotic pressure of blood and the transport of numerous substances, including fatty and amino acids, hormones, metal ions, and over 250 drugs
We show in vitro that SRO is the most potent activator of HSA–amyloid β peptide (Aβ) interaction reported to date, whereas the structurally similar SRO precursor, L-tryptophan (TRP), is inactive in this sense
The HSA–Aβ interaction was studied by the SPR method mainly as described earlier [12]

Summary

Introduction

Human serum albumin (HSA; 66.5 kDa) is the most abundant blood and cerebrospinal fluid (CSF) protein and is vital to maintaining the osmotic pressure of blood and the transport of numerous substances, including fatty and amino acids, hormones, metal ions, and over 250 drugs (reviewed in [1,2]). One of the key participants in progression of Alzheimer’s disease (AD), amyloid peptide (Aβ) [3], is mostly bound to HSA (ca 89% of Aβ in blood plasma [4]). This interaction effectively rescues Aβ from deleterious self-aggregation and cytotoxicity [5,6,7]. The antioxidant and detoxification activities and anti-inflammatory and blood–brain barrier-supporting properties of HSA likely prevent

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Conclusion