Protein Aggregation Diseases: Toxicity of Soluble Prefibrillar Aggregates and Their Clinical Significance - Protein Misfolding and Cellular Stress in Disease and Aging - page 26

Many studies have highlighted the morphological modifications
occurring in amyloid assemblies made from different disease-
related and disease-unrelated peptides and proteins in the path of
fibrillization from unfolded monomers to aggregation nuclei and
mature fibrils. Several more-or-less defined steps are involved in
such an assembly process ( 27, 28 ). EM and AFM studies have
imaged the initial presence of transient, unstable, roundish or
tubular particles 2.5-5.0 nm in diameter generally enriched in
b-structure often called “amorphous aggregates” or sometimes
“micelles” ( 27-30 ). These species, characterized as protein/
peptide oligomers (see later), frequently associate into bead-like
chains, small annular rings (“doughnuts” or “pores”), or curvy
protofibrils that appear to be precursors of longer protofilaments
and mature fibrils ( 31 ). Other common and highly organised
amyloids appear as large closed rings and ribbons ( 28-32 ). Such
pre-fibrillar assemblies have been reported for many proteins
and peptides associated with disease, including Ab peptides,
a-synuclein, superoxide dismutase, huntingtin, the androgen
receptor, amylin, tranthyretin, serum amyloid A, and others
( 27, 29-32 ). Similar pre-fibrillar assemblies have also been imaged
in the aggregation path of several proteins not associated with
amyloid disease, including HypF-N, an SH3 domain, apomyo-
globin, stefin-B and others ( 28, 33-35 ). Most of these assemblies
are considered intermediates in the path of fibrillization, although
some of them, such as the small annular oligomers, could be
“dead end” products of the process. Finally, soluble oligomers
grown in the fibrillization path of several peptides and proteins
have been repeatedly imaged also in vivo in cultured cells and in
tissues where the monomeric precursors are expressed. These
species are presently considered the main responsible for cell/
tissue impairment (see later).
A better knowledge of the “early aggregates” preceding the
appearance of mature fibrils is considered very important to
understand the nature and origins of the pathological properties
of amyloid structures associated with disease, particularly with
neurodegenerative conditions. However, the intrinsic disordered
nature of these assemblies makes it very difficult to get solid data
on their structural features. A previous study reporting the genera-
tion of a conformational antibody recognising a generic amyloid
fibril epitope highlighted for the first time the presence of shared
conformational features in amyloid fibrils grown from different
peptides and proteins ( 36 ). This information was complemented
and substantiated by a later report describing antibodies able to
recognise specifically amyloid oligomers ( 37 ) and amyloid pores
( 38 ), but not mature fibrils, grown from differing peptides and
proteins. These findings indicate that pre-fibrillar aggregates of
different proteins and peptides share common structural features
that are different from those displayed by the folded monomers