Serotonin Promotes Serum Albumin Interaction with the Monomeric Amyloid β Peptide

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.

Ibuprofen Favors Binding of Amyloid-β Peptide to Its Depot, Serum Albumin

“…Unexpectedly, K d for HSA–Aβ 40 /Aβ 42 complexes are 2–3 orders of magnitude lower compared to those reported earlier under identical solution conditions [ 13 ]. This inconsistency can be resolved considering that we washed the non-covalently bound Aβ molecules from the chip surface using two additional solutions, aside from the 2% SDS solution used earlier [ 13 ], thereby ensuring a more monomeric state of Aβ.…”

“…The interaction between fatty-acid-free HSA and Aβ at 25 °C was studied by surface plasmon resonance (SPR) spectroscopy mainly as described earlier [ 12 , 13 ]. The recombinant human Aβ 40 /Aβ 42 or Flemish variant of Aβ 40 [ 41 ], Aβ 40 (A21G), was immobilized on the surface of the SPR sensor chip by amine coupling.…”

“…This inconsistency can be resolved considering that we washed the non-covalently bound Aβ molecules from the chip surface using two additional solutions, aside from the 2% SDS solution used earlier [ 13 ], thereby ensuring a more monomeric state of Aβ. Notably, despite the differences in the absolute values of the K d estimates obtained here and in the previous works [ 12 , 13 ], the general regularities remain the same: HSA’s affinities to Aβ 40 and Aβ 42 are nearly equal, whereas the A21G mutation increases HSA’s affinity to Aβ 40 by a factor of 2.5–10 [ 12 ] or 1.5–4 ( Table 1 ).…”

“…Human Aβ 40 /Aβ 42 /Aβ 40 (A21G) were expressed in E. coli and purified as described earlier [ 12 , 13 ] with the following modifications. The cells were disintegrated by wet grinding using a Retsch ® Mixer Mill MM 400 (glass beads with diameter of 0.5–0.75 mm, grinding time 1 min, 7 cycles).…”

“…The Aβ-buffering role of HSA could be exploited for AD therapy by directed improvement of HSA’s affinity to Aβ, as exemplified by the addition of certain low-molecular-weight ligands of HSA: arachidonic/linoleic acid or serotonin (the maximal effect is a 17-fold increase in HSA’s affinity to Aβ [ 12 , 13 ]). Other HSA ligands typically act in the opposite direction, as shown for tolbutamide [ 7 ], cholesterol, palmitic acid, and warfarin [ 14 ].…”