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.