Molecular Insights into Human Serum Albumin as a Receptor of Amyloid-β in the Extracellular Region

Abstract

Regulation of amyloid-β (Aβ) aggregation by metal ions and proteins is essential for understanding the pathology of Alzheimer's disease (AD). Human serum albumin (HSA), a regulator of metal and protein transportation, can modulate metal-Aβ interactions and Aβ aggregation in human fluid; however, the molecular mechanisms for such activities remain unclear. Herein, we report the molecular-level complexation between Zn(II), Cu(II), Aβ, and HSA, which is able to alter the aggregation and cytotoxicity of Aβ peptides and induce their cellular transportation. In addition, a single Aβ monomer-bound HSA is observed with the structural change of Aβ from a random coil to an α-helix. Small-angle X-ray scattering (SAXS) studies indicate that Aβ-HSA complexation causes no structural variation of HSA in solution. Conversely, ion mobility mass spectrometry (IM-MS) results present that Aβ prevents the shrinkage of the V-shaped groove of HSA in the gas phase. Consequently, for the first time, HSA is demonstrated to predominantly capture a single Aβ monomer at the groove using the phase transfer of a protein heterodimer from solution to the gas phase. Moreover, HSA sequesters Zn(II) and Cu(II) from Aβ while maintaining Aβ-HSA interaction. Therefore, HSA is capable of controlling metal-free and metal-bound Aβ aggregation and aiding the cellular transportation of Aβ via Aβ-HSA complexation. The overall results and observations regarding HSA, Aβ, and metal ions advance our knowledge of how protein-protein interactions associated with Aβ and metal ions could be linked to AD pathogenesis.

Molecular Role of Ca2+ and Hard Divalent Metal Cations on Accelerated Fibrillation and Interfibrillar Aggregation of α-Synuclein

“…We predicted that this structural change was induced due to the absence of solvent molecules in the gas phase. Because electrostatic interaction becomes influential in the gas phase 50 , 51 , Ca 2+ , which had been bound only to C-terminal region, was additionally attracted to other regions of αSyn in the gas phase, thereby forming structures different from the solution structures.…”

Crosstalk between zinc and free fatty acids in plasma

“…Whilst there is at present no indication that the albumin-mediated Zn-FFA crosstalk is in operation in the brain's extracellular media, both albumin [ 177 , 178 ] and FFAs [ 94 , 95 ] have recently been found to affect Aβ aggregation, in addition to Zn 2+ . There is some exchange between plasma and CSF across the blood-brain barrier, and as a consequence, Aβ is not only present in brain, but also circulates in plasma – overwhelmingly as complex with HSA [ 178 , 179 ]. Significantly, this interaction is not only critical for Aβ clearance, but also inhibits Aβ fibril formation at physiological (μM) concentrations in the brain interstitium [ 180 ].…”

Calprotectin influences the aggregation of metal-free and metal-bound amyloid-β by direct interaction

“…The amount of Aβ fibrillization and the kinetics of Aβ 40 aggregation upon treatment of CP-Ser were investigated as previously described. 23,[85][86][87]…”

“…[8][9][10][11][12][13][14] Since multiple parameters in addition to Aβ have been suggested to be involved in AD pathogenesis, much effort has been expended to investigate the interactions of Aβ with other agents present in the brain that may also be linked to inflammation and metal ion dyshomeostasis. 11,12,[20][21][22][23] Among these candidates is the S100 protein family, members of which exhibit diverse functions, including participation in…”