MINIREVIEW
Amyloid oligomers: formation and toxicity of Ab oligomers
Masafumi Sakono
1,2
and Tamotsu Zako
1
1 Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan
2 PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan
Introduction
Alzheimer’s disease (AD) is an age-related, progressive
degenerative disorder characterized by the loss of
synapses and neurons from the brain, and by the accu-
mulation of extracellular protein-containing deposits
(referred to as ‘senile plaques’) and neurofibrillary
tangles [1]. Amyloid b-peptide (Ab; 39–43 amino acids
in length) is the principal component of plaques. Ab is
produced by the proteolytic cleavage of the parental
amyloid precursor protein (APP) that localizes to the
plasma membrane, trans-Golgi network, endoplasmic
reticulum (ER) and endosomal, lysosomal and mito-
chondrial membranes. Synthetic Ab spontaneously
aggregates into b-sheet-rich fibrils, resembling those
in plaques. As insoluble fibrillar aggregates are neuro-
toxic in vivo and in vitro, it has long been hypothesized
that fibrils cause neurodegeneration in AD [2].
However, debate over this ‘amyloid cascade hypothe-
sis’ remains contentious.
The number of senile plaques in a particular region
of the AD brain correlates poorly with the local extent
of neuron death or synaptic loss, or with cognitive
impairment [3]. However, recent studies show a robust

suggests that prefibrillar soluble Ab oligomers induce AD-related synaptic
dysfunction. The size of Ab oligomers is distributed over a wide molecular
weight range (from < 10 kDa to > 100 kDa), with structural polymor-
phism in Ab oligomers of similar sizes. Recent studies have demonstrated
that Ab can accumulate in living cells, as well as in extracellular spaces.
This review summarizes current research on Ab oligomers, focusing on
their structures and toxicity mechanism. We also discuss possible formation
mechanisms of intracellular and extracellular Ab oligomers.
Abbreviations
AD, Alzheimer’s disease; ADDL, Ab-derived diffusible ligand; APP, amyloid precursor protein; Ab, amyloid-b peptide; ER, endoplasmic
reticulum; FCS, fluorescence correlation spectroscopy; HD, Huntington’s disease; LTP, long-term potentiation; MW, molecular weight;
NGF, nerve growth factor; NMDAR, N-methyl-
D-aspartate (NMDA)-type glutamate receptor; PD, Parkinson’s disease; polyQ, polyglutamine;
PrP
C,
cellular prion protein.
1348 FEBS Journal 277 (2010) 1348–1358 ª 2010 The Authors Journal compilation ª 2010 FEBS
inhibit many critical neuronal activities, including
long-term potentiation (LTP), a classic model for syn-
aptic plasticity and memory loss in vivo and in culture
[12–15]. These studies strongly support the idea that
soluble Ab oligomers are the causative agents of AD;
however, the biological and structural characteristics
of Ab oligomers and their formation mechanism
remain unclear.
Structure and size of soluble Ab
oligomers
Many types of natural and synthetic Ab oligomers of
different sizes and shapes have been reported, which
accounts for their biological and structural diversity

memory impairment. These oligomers could be classified
as low-MW (< 50 kDa) oligomers. However, natural
Ab oligomers with a wide-ranging MW distribution
(from < 10 kDa to > 100 kDa) have been found in
the AD brain [22], suggesting that Ab oligomers of
various sizes are associated with the disease.
There are also many reports of toxic oligomers from
synthetic Ab. Synthetic Ab forms fibrillar aggregates
that have properties similar to those found in AD
plaques in the brain. In vitro studies using synthetic
Ab are useful to complement efforts to determine the
disease mechanism. Snyder et al. [23] detected the for-
mation of soluble Ab assemblies, rather than fibrils,
using an analytical ultracentrifugation technique, and
Lambert et al. [12] reported the formation of small Ab
globular oligomers (5 nm in diameter) in Hams-F12
medium, which were referred to as Ab-derived
diffusible ligands (ADDLs). Importantly, ADDLs
strongly bound to the dendritic arbors of cultured
neurons, caused neuronal cell death and blocked LTP.
The finding of ADDL in soluble brain extracts from
the human AD brain using ADDL-specific antibody
supports the idea that the existence of ADDLs in the
human AD brain causes disease [24].
The formation of annular Ab oligomers, with an outer
diameter of 8–12 nm and an inner diameter of 2.0–
2.5 nm (150–250 kDa), has also been reported [25,26].
As these annular Ab oligomers could be preferentially
formed from mutant Ab (such as those carrying the
Arctic mutation), and because the amyloid ‘pore’ resem-

ever, because the fibrillar oligomers are recognized by
the fibril-specific antibody, but not by A11, they at
M. Sakono and T. Zako Formation of toxic Ab oligomers
FEBS Journal 277 (2010) 1348–1358 ª 2010 The Authors Journal compilation ª 2010 FEBS 1349
least possess the structural characteristics of fibrils.
Thus, it is plausible that the fibrillar oligomer might
represent fibril nuclei to which the monomers can
attach before elongation [10]. Ab oligomers formed at
a low pH, but not those formed at a neutral pH, are
recognized by the 6E10 antibody [29]. These results
strongly suggest the existence of a structural polymor-
phism of A b oligomers.
There have been several other attempts to examine
Ab oligomer structures to elucidate the mechanism of
formation of Ab oligomers. Studies using atomic force
microscopy and scanning tunneling microscopy showed
that the structures of dimers, tetramers and other low-
MW Ab oligomers were consistent with the model of
the Ab monomers as b-hairpins [30,31]. These low-
MW Ab oligomers are relatively compact, being
1–3 nm in height and 5–10 nm in width ⁄ length, and
could be the fundamental building blocks of larger
oligomers and protofibrils.
Bernstein et al. [18] developed a new method, called
electrospray-ionization ion-mobility mass spectrometry,
to obtain oligomer size distributions and the qualita-
tive structure of each oligomer. Electrospray ionization
allows a fixed population of different Ab oligomer
states in solution to be isolated from one another, and
their size and shape could be determined using ion-

single molecule level have been performed. Dukes
et al. [32] and Ding et al. [33] recently reported
oligomer size determination with single molecule
spectroscopy using fluorescently labeled Ab.By
directly counting the photobleaching steps in the
fluorescence of each oligomer on a cover-glass sur-
face, the number of monomer molecules in individual
oligomers could be determined, enabling the determi-
nation of more precise oligomer size distributions.
For example, an Ab
40
sample incubated at a neutral
pH was shown to be a mixture of monomers,
dimers, trimers and tetramers, and the presence of
zinc ion in the sample buffer increased the number
of tetramers [33]. Although application of this
method is limited to small oligomers, the single mol-
ecule approach overcomes the limitations of resolu-
tion and sample heterogeneity.
Analyses of the size of the Ab oligomer in solution
at the single molecule level have also been performed
using fluorescence correlation spectroscopy (FCS),
which detects the fluorescence of dye-labeled molecules
in a very small confocal volume excited by a sharply
focused laser beam [34]; FCS enables estimation of the
size distribution of an oligomeric species in solution
over a wide range of sizes (from monomers to large
soluble particles) with a good time resolution ( 1
min). From the fluorescence intensity fluctuations, one
can calculate the number of molecules in the confocal

to stable oligomers that show no monomer dissocia-
tion [35]. It would be interesting to apply this method
to examine the time-course of the stability of Ab
oligomers.
Formation of toxic Ab oligomers M. Sakono and T. Zako
1350 FEBS Journal 277 (2010) 1348–1358 ª 2010 The Authors Journal compilation ª 2010 FEBS
Although these in vitro studies provide insight into
how Ab monomers assemble into oligomeric com-
plexes, further characterizations, by such as visualiza-
tion of Ab oligomer at the molecular level in living
cells and animal models, may be required to elucidate
the mechanism of formation of Ab oligomers.
Possible mechanism of soluble
oligomer formation and toxicity
The mechanism of formation of soluble Ab oligomer
in vivo remains unclear. Glabe et al. [10] proposed that
multiple Ab oligomer conformations were produced
via different pathways, indicating the complexity of
the oligomer formation mechanism. The mechanisms
of formation may also differ for extracellular and
intracellular oligomers. In this section, we discuss pos-
sible formation mechanisms of extracellular and intra-
cellular Ab oligomers, and also discuss how these Ab
oligomers can cause cell death or neuronal impairment
(Figs 1 and 2).
Extracellular soluble Ab oligomer formation and
its toxicity
A recent study by Yamamoto et al. [36] showed the
formation of toxic Ab oligomers in the presence of
GM1 ganglioside. This Ab oligomer was spherical,

The GM1-induced Ab oligomer induces neuronal
cell death mediated by nerve growth factor (NGF)
receptors, suggesting that binding of the Ab oligomer
to the NGF receptor is important for the toxicity
mechanism [36] (Fig. 1). Potent alternation of NGF-
mediated signaling by ADDL supports this concept
[40]. Moreover, previous studies suggested that apopto-
tic cell death occurs through the interaction of Ab with
low-affinity NGF receptor [pan neurotrophin receptor
(p75NTR)] and the activation of downstream signaling
molecules, such as c-Jun N-terminal kinase (reviewed
in ref. [41]). However, it has also been demonstrated
that p75NTR promotes neuronal survival and differen-
tiation, indicating that p75NTR might have diverse
functions in both cell death and cell survival [42].
Consistent with this notion, there are also conflicting
reports showing that p75NTR is protective against
Ab toxicity [43,44]. These results imply that the
NGF-mediated toxicity mechanism is complicated.
Other reports on neuronal receptor-mediated toxicity
mechanisms (reviewed in ref. [9]) have shown that
ADDL binding to an N-methyl-d-aspartate (NMDA)-
type glutamate receptor (NMDAR) causes abnormal
calcium homeostasis, leading to increased oxidative
stress and synapse loss [45,46]. ADDL can also induce
the loss of insulin receptors from the neuronal surface
[47,48] and impair LTP-associated kinase activity [49].
However, such insulin receptor impairment is inhibited
by extracellular insulin, suggesting that insulin plays
an important role in oligomer-induced cell death.

proteins or channels may cause modification of the
P ⁄ Q current. By contrast, another study showed that
the cell membrane could be destabilized by the Ab oli-
gomer [52]. The membrane pores formed by the Ab
oligomer would allow the abnormal flow of ions, such
as Ca
2+
, suggesting another plausible mechanism for
Ab oligomer toxicity [53,54]. Recent observations by
Lauren et al. [55] indicate that cellular prion protein
(PrP
C
) can act as an Ab oligomer receptor with a
nanomolar affinity, mediating synaptic dysfunction.
Although misfolded prion protein (PrP
Sc
) is thought to
cause prion disease, the interaction between the Ab oli-
gomer and the prion does not require the infectious
PrP
Sc
conformation. This interaction may disrupt the
interaction between PrP
C
and a co-receptor, such as
NMDAR, impairing the neuron signal-transduction
pathways. This discovery by Lauren et al. also suggests
that AD is linked with other neurodegenerative
diseases.
Recently, interactions between Ab and a-synuclein

along the secretory pathway. Identification of the
intracellular protein, endoplasmic reticulum associated
binding protein (ERAB), which binds to Ab,
also strongly suggests the existence of intracellular Ab
[60].
In addition to Ab being produced intracellularly,
previously secreted Ab that forms the extracellular Ab
pool can be taken up by cells and internalized into
intracellular pools through various receptors and trans-
porters, such as the nicotinic acetylcholine receptor,
low-density lipoprotein receptor, formyl peptide recep-
tor-like protein 1, NMDAR and the scavenger recep-
tor for advanced glycation end-products [6] (Fig. 2).
These receptor-associated Ab complexes could be
internalized into endosomes. Recent findings also sup-
port the idea that Ab is present within the cytosolic
compartment. Intracellular accumulation of Ab in the
multivesicular body is linked to cytosolic proteasome
inhibition [61]. Furthermore, in vivo and in vitro pro-
teasome inhibition also leads to higher Ab levels
[62,63]. As the proteasome is primarily located within
the cytosol, these findings strongly suggest that Ab is
also located within the cytosolic compartment. Extra-
cellular Ab can enter the cytosolic compartment and
inhibit the proteasome activity of cultured neuronal
cells [62]. Clifford et al.
[64] showed that fluorescently
labeled Ab which is injected into the tail of mice with
a defective blood–brain barrier (which is common in
AD patients) accumulates in the perinuclear cytosol of

the cytosolic molecular chaperone protein, prefoldin,
in vitro [68]. In general, molecular chaperones stabilize
and mediate the folding of unfolded proteins. Molecu-
lar chaperones play essential roles in many cellular
processes, such as protein folding, targeting, transpor-
tation, degradation and signal transductions [69].
Prefoldin reportedly captures and delivers denatured
protein to another cytosolic chaperone, chaperonin
[70–73]. Our results also suggested that the interaction
between prefoldin and A b oligomers prevents further
aggregation and stabilizes the oligomer structure
(Fig. 2).
Molecular chaperones are potent suppressors of pro-
tein aggregation, leading to neurodegenerative disor-
ders such as AD, PD and Huntington’s disease (HD)
[74–76]. Various molecular chaperones are upregulated
in patients and co-localize with aggregated proteins in
plaques ⁄ inclusion bodies. These molecular chaperones
prevent aggregation in vivo and in vitro; for example,
the cytosolic chaperonin CCT can inhibit aggregation
of the polyglutamine (polyQ) expansion protein, which
causes HD in vivo and in vitro [77–79]. Reduced CCT
levels also enhance the aggregation and toxicity of pol-
yQ in neuronal cells, strongly supporting the idea that
molecular chaperones can be a defense against the
aggregation of misfolded protein. Importantly, how-
ever, our findings also suggest the possibility that the
suppression of protein aggregation may cause the for-
mation of toxic oligomeric species, which is consistent
with previous results showing that toxic nonfibrillar

focused especially on the proteolysis system in AD
brains, are necessary to understand AD pathology in
relation to intracellular soluble Ab oligomers.
Concluding remarks
It has long been argued that insoluble Ab fibrillar
aggregates found in extracellular amyloid plaques initi-
ate the neurodegenerative cascades of AD. However,
recent emerging results indicate that prefibrillar soluble
Ab oligomers are the key intermediates in AD-related
synaptic dysfunction. Various amyloidogenic proteins
can form toxic soluble oligomers, suggesting that solu-
ble oligomers are the general key factors in various
diseases such as AD, PD, HD and other amyloidosis
[5,28,83]. Although much research effort is being direc-
ted towards characterizing oligomer states, their con-
formations and formation mechanisms remain unclear.
Recent evidence suggests that the size of Ab oligomers
is distributed in a wide MW range (from < 10 kDa to
> 100 kDa), and that there is structural polymor-
phism of Ab oligomers, even for those of a similar
size. The biochemical properties of these oligomers in
relation to disease pathology also seem to differ
depending on their sizes and structures.
Formation of toxic Ab oligomers M. Sakono and T. Zako
1354 FEBS Journal 277 (2010) 1348–1358 ª 2010 The Authors Journal compilation ª 2010 FEBS
Ab can form various distinct oligomeric states via
various pathways. The formation and toxicity mecha-
nisms of extracellular and intracellular Ab oligomers
can also be different from one another. Regardless of
the complexity of the oligomer-formation mechanism,

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