Multipronged Regulatory Functions of Serum Albumin in Early Stages of Amyloid-β Aggregation

Abstract

Human serum albumin (HSA) is a major interacting-partner of Alzheimer’s amyloid-β (Aβ) peptide in the plasma and has emerged as a promising therapeutic target. HSA inhibits Aβ fibrillization, but the underlying molecular mechanism is not well elucidated. In this work, we investigated the role of HSA in the early stages of Aβ aggregation by simulating the binding process of multiple Aβ monomers and protofibrils to HSA with extensive molecular dynamics simulations. HSA could simultaneously trap multiple Aβ monomers and accommodate the formation of nonfibrillar Aβ oligomers after binding. In particular, domains I and III show stronger binding capacities and hold preferable interaction sites for oligomers. Consequently, HSA prevents the formation of fibrillar oligomers in water, thus interfering with the nucleation process. On the other aspect, when protofibrils are preformed, HSA tends to block the β-strand spanning the central hydrophobic core located at the protofibril end, preventing the addition of monomers to protofibrils. Furthermore, Aβ protofibril structures are severely disrupted both globally and locally. Thus, further growth of protofibrils to fibrils is impeded by HSA. Our results collectively indicate that HSA performs multipronged regulatory functions in the early stages of Aβ aggregation. Our work advances the understanding of the amyloid inhibition of Aβ by HSA and provides theoretical guidance for developing rational therapies of Alzheimer’s disease.

Testing the link between isoaspartate and Alzheimer's disease etiology

“…Being a major carrier protein, HSA is one of the most potent Aβ sequestering agents, binding 90% to 95% of the Aβ in blood plasma [25]. Model organism studies indicated that serum albumin inhibits Aβ aggregation [26,27] and fibrillation [28][29][30] by binding Aβ monomers and oligomers, while human studies have revealed the association of low HSA levels with cognitive impairment [31,32] as well as AD [33,34]. A recent rather large study (n = 396) demonstrated that the HSA level is inversely associated as a continuous variable with Aβ deposition and Aβ positivity in older adults [35].…”

Controllable membrane damage by tunable peptide aggregation with albumin

“…Albumin, as a flexible hydrophobic protein, aggregates with amyloid‐forming proteins, prolonging the lag phase 22–24 . The unstable and soluble monomers present in the lag phase are able to integrate into the cell membrane and become more toxic 30 .…”

“…Albumin is an abundant protein in the human body, flexible, and mostly hydrophobic; thus, it has a high nonspecific binding capacity 21 . It is known that albumin impedes the fibrillization of amyloids and increases the soluble misfolded oligomers of higher toxicity 22–24 . Akin to amyloid, co‐aggregation with albumin creates a soluble oligomeric form of [II] that is more toxic than its fibril form.…”

First Immunoassay for Measuring Isoaspartate in Human Serum Albumin

“…As elevated isoAsp levels in blood are associated with AD [8], an ELISA with 1A3 mAb could be used as an auxiliary tool in AD diagnostics. The fact that the targeted isoAsp residue resides in the HSA domain responsible for Aß binding and disrupting the structural transformation of Aß42 protofibrils to fibrils [28], potentially links deamidation at this site this to disease etiology. Although significant amount of preclinical and clinical research needs to be done for the assay validation, adding this analysis to already formidable arsenal of AD diagnostics tools will not incur much inconvenience and additional expense.…”

“…The 1A3 sensorgrams demonstrates a clear-cut concentration-response relationship with smooth and consistent curves indicative of good interactions (Figure 3a). The calculated K D value of 2.1 × 10 −8 M means an above-average (≈10 −6 M [28]) binding affinity.…”