pathway. In all proteins known to form
amyloid Fbrils, there is a conversion of
-structure. Amyloid Fbrils are ab-
normal, insoluble, and generally protease-
resistant structures. They were Frst rec-
ognized by their staining properties. The
tect amyloid is staining by Congo Red,
which exhibits a green birefringence. Amy-
loid Fbrils are generally 60 to 100
diameter and of variable length. X-ray
diffraction data on Fbrils, solid-state NMR
studies, cryoelectron microscopy, and in-
frared ±ourier transform experiments have
shown that amyloid Fbrils are made of two
-sheet Flaments wound around
one another. They have a characteristic
repeat structure, the individual
strands being oriented perpendicular to
the long axis of the Fbril.
Recently, progress has been made in
the knowledge of the mechanisms in-
volved in the formation of amyloid Fbrils.
Oligomeric preFbrillar intermediates have
been extensively characterized with re-
evolution. A well-documented example is
provided by the studies on transthyretin.
The biological role of this protein is the
transport of thyroxin by direct binding
and the transport of retinol via the retinol
binding protein. The wild-type protein is
very stable at neutral pH. In certain in-
dividuals, however, it is converted into
amyloid Fbrils, and this is associated
with the disease, senile systemic amy-
loidosis. Several variants are associated
with familial polyneuropathies.
biophysical studies have identiFed condi-
tions leading to amyloid formation. The
three-dimensional structure of the pro-
tein is known. The wild-type protein is
a tetramer at pH ranging between 5 and 7;
the tetramer dissociates into a monomer
when the pH decreases. The dissociation
is the rate-limiting step of the process.
The monomer exhibits an altered tertiary
structure, which aggregates in amyloid
Schematic representation of the formation of amyloid Fbrils from a
partially folded intermediate.