Binding of Human Proteins to Amyloid‑β Protofibrils

The
progressive neurodegeneration in Alzheimer’s disease
is believed to be linked to the presence of prefibrillar aggregates
of the amyloid-β (Aβ) peptide in the brain. The exact
role of these aggregates in the disease pathology is, however, still
an open question. Any mechanism by which oligomeric Aβ may cause
damage to neuronal cells must, in one way or another, involve interactions
with other molecules. Here, we identify proteins in human serum and
cerebrospinal fluid that bind to stable protofibrils formed by an
engineered variant of Aβ42 (Aβ42CC). We find that the protofibrils attract a substantial number of
protein binding partners. Many of the 101 identified proteins are
involved in lipid transport and metabolism, the complement system,
or in hemostasis. Binding of representative proteins from all of these
groups with micromolar affinity was confirmed using surface plasmon
resonance. In addition, binding of apolipoprotein E to the protofibrils
with nanomolar affinity was demonstrated. We also find that aggregation
of Aβ enhances protein binding, as lower amounts of proteins
bind monomeric Aβ. Proteins that bind to Aβ protofibrils
might contribute to biological effects in which these aggregates are
involved. Our results therefore suggest that an improved understanding
of the mechanisms by which Aβ causes cytotoxicity and neurodegeneration
might be gained from studies carried out in biologically relevant
matrices in which Aβ-binding proteins are present.