1 research outputs found
In Vitro and Mechanistic Studies of an Antiamyloidogenic Self-Assembled Cyclic d,l‑α-Peptide Architecture
Misfolding
of the Aβ protein and its subsequent aggregation
into toxic oligomers are related to Alzheimer’s disease. Although
peptides of various sequences can self-assemble into amyloid structures,
these structures share common three-dimensional features that may
promote their cross-reaction. Given the significant similarities between
amyloids and the architecture of self-assembled cyclic d,l-α-peptide, we hypothesized that the latter may bind
and stabilize a nontoxic form of Aβ, thereby preventing its
aggregation into toxic forms. By screening a focused library of six-residue
cyclic d,l-α-peptides and optimizing the activity
of a lead peptide, we found one cyclic d,l-α-peptide
(<b>CP-2</b>) that interacts strongly with Aβ and inhibits
its aggregation. In transmission electron microscopy, optimized thioflavin
T and cell survival assays, <b>CP-2</b> inhibits the formation
of Aβ aggregates, entirely disassembles preformed aggregated
and fibrillar Aβ, and protects rat pheochromocytoma PC12 cells
from Aβ toxicity, without inducing any toxicity by itself. Using
various immunoassays, circular dichroism spectroscopy, photoinduced
cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE,
and NMR, we probed the mechanisms underlying <b>CP-2</b>’s
antiamyloidogenic activity. NMR spectroscopy indicates that <b>CP-2</b> interacts with Aβ through its self-assembled conformation
and induces weak secondary structure in Aβ. Upon coincubation, <b>CP-2</b> changes the aggregation pathway of Aβ and alters
its oligomer distribution by stabilizing small oligomers (1–3
mers). Our results support studies suggesting that toxic early oligomeric
states of Aβ may be composed of antiparallel β-peptide
structures and that the interaction of Aβ with <b>CP-2</b> promotes formation of more benign parallel β-structures. Further
studies will show whether these kinds of abiotic cyclic d,l-α-peptides are also beneficial as an intervention
in related in vivo models