MINIREVIEW SERIES

Amyloid oligomers
Tamotsu Zako
RIKEN Institute, Japan

Amyloid diseases are a group of degenerative disor-
ders, such as Alzheimer’s, Huntington’s, Parkinson’s
and Prion diseases and amyotrophic lateral sclerosis
(ALS). They are characterized by tissue damage caused
by toxic aggregates of misfolded proteins called
amyloid. To date, more than 20 different proteins or
peptides are known to form fibrillar amyloid aggre-
gates associated with human pathologies.
Accumulating evidence indicates that amyloid oligo-
mers (which are oligomeric but soluble states of amy-
loidogenic proteins), rather than insoluble amyloid
fibrils, play important roles in various types of amy-
loid-related degenerative diseases. It has also been sug-
gested that soluble oligomers from different proteins
share common structural properties and cellular toxi-
city mechanisms. This minireview series deals with the
structural and biochemical characteristics of various
amyloid oligomers and their possible roles in the path-
ogenesis of the diseases. Recent advances in imaging
techniques to understand amyloid oligomer formation
are also described. In the first minireview by Sakono &
Zako, structures and toxicity mechanisms of soluble
amyloid-beta (Ab) oligomers, which are thought to
cause Alzheimer’s disease (AD), are described. At pres-
ent, many types of Ab oligomers of different sizes and
shapes have been reported, which account for their
biological and structural diversity, and for the com-
plexity of AD pathology. Recent studies on Ab oligo-
mer formation, using single molecule observation
techniques, are also described. The single molecule
approach overcomes the limitations of resolution and
sample heterogeneity, and will be a powerful tool to
analyze amyloid oligomer formation and elucidate the
formation mechanism at the molecular level. These
authors also discuss possible formation mechanisms of
extracellular and intracellular Ab oligomers.
In the second minireview by Taguchi & Kawai-
Noma, the biological roles of prion oligomers are
described. Prions are infectious proteins, by which self-
propagating amyloid conformations of proteins are
transmitted. Recent advances in techniques capable of
investigating the dynamics of protein molecules in
living cells, such as single-cell imaging systems, are also
described. These techniques provide novel insights into
the molecular mechanism of prion propagation and
transmission. Using yeast Sup35 as a model prion pro-
tein, they suggest that oligomeric species of prion pro-
teins dispersed in the cytoplasm are critical for the
transmission of prion phenotypes.
The next two minireviews focus on various fluorescent
techniques in amyloid aggregation studies. The third
minireview, by Kitamura & Kubota, discusses and
exemplifies the merits and drawbacks of various spectro-
scopic analyses, such as fluorescence recovery after
photobleaching (FRAP), fluorescence loss in photo-
bleaching (FLIP), fluorescence correlation spectroscopy
(FCS) and fluorescence resonance energy transfer
(FRET) analysis on the studies on aggregates and
soluble oligomers of misfolded proteins. In particular,
they focus on the formation of toxic aggregates made up
from polyQ-expanded proteins (e.g. involved in Hun-
tington’s disease and in ataxias) and from superoxide
dismutase 1 (SOD1) mutants involved in the pathogene-
sis of ALS. They suggest that protein aggregates of
misfolded proteins are dynamic structures that interact
with other proteins such as molecular chaperones, and
discuss how these oligomers are toxic to cells.
In the final minireview, by Lindgren & Hammar-
ström, recent optical spectroscopic studies of amyloid
protein misfolding, oligomerization and amyloid fibril
growth are reviewed. In particular, detection of oligo-
meric states and prefibrillar states of amyloidogenic
proteins using novel small molecular probes, named
‘luminescent conjugate polymers’ (LCPs), is described.
In amyloid research, LCPs that have polythiophene
backbones have been used. Optical spectroscopy using
these novel molecular probes has shown that the inter-
mediate oligomeric state can be captured and studied
in vitro. Molecular probes and optical spectroscopy are
now entering a phase that enables in vivo interrogation
of the role of oligomers in amyloid diseases. Such tech-
niques used in parallel with in vitro experiments, will
probably relate structure to pathogenesis in the near
future.

Tamotsu Zako is a senior research scientist at RIKEN Institute, Japan. He received his PhD at The University of Tokyo, Japan,
and studied at Waseda University and Tokyo University of Agriculture and Technology as a postdoctoral fellow. He was a
recipient of a Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science (JSPS). His
main research interests include the investigation of the mechanism of molecular chaperones in protein folding, the character-
ization of aggregated states of amyloidogenic proteins and their relation to protein-misfolding diseases such as Alzheimer’s
disease.

doi:10.1111/j.1742-4658.2010.07567.x

FEBS Journal 277 (2010) 1347 ª 2010 The Author Journal compilation ª 2010 FEBS 1347