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THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 283, NO. 44, pp. 29639 –29643, October 31, 2008
© 2008 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A.

Structural Classification of Toxic of ␣-synuclein, whereas Huntington and other CAG triplet dis-
eases are typified by the accumulation of polyglutamine-con-
Amyloid Oligomers* taining aggregates. This also includes prion diseases such as
Published, JBC Papers in Press, August 22, 2008, DOI 10.1074/jbc.R800016200 Creutzfeldt-Jakob disease with accumulation of misfolded
Charles G. Glabe1 prion protein, type II diabetes with accumulation of islet amy-
From the Department of Molecular Biology and Biochemistry, loid polypeptide, and amyotrophic lateral sclerosis with aggre-
University of California, Irvine, California 92697
gated superoxide dismutase-1. Like AD, many of these diseases
Amyloid oligomers are believed to play important causal roles have both a sporadic and inherited form, and in many cases, the
in many types of amyloid-related degenerative diseases. Many mutations associated with the familial forms are in the gene
different laboratories have reported amyloid oligomers that dif- encoding the protein that accumulates or in genes directly
fer in size, morphology, toxicity, and method of preparation or related to its production, processing, or accumulation.
purification, raising the question of the structural relationships Although these diseases are associated with different proteins
among these oligomer preparations. The structural plasticity of widely varying normal structure and function, they all
involve the accumulation of abnormal aggregates containing

Downloaded from [Link] at University of Georgia - Athens on June 29, 2009

that has been reported to occur in amyloids formed from the
same protein sequence indicates that it is quite possible that ␤-sheet structure.
different oligomer preparations may represent distinct struc- There is conflicting evidence for the role of macroscopic
tural variants. In view of the difficulty in determining the precise fibrillar amyloid deposits in pathogenesis. It has been reported
structure of amyloids, conformation- and epitope-specific anti- that the extent of amyloid plaque accumulation does not cor-
bodies may provide a facile means of classifying amyloid oli- relate well with AD pathogenesis (4) and that a significant num-
gomer structures. Conformation-dependent antibodies that ber of non-demented individuals have significant amounts of
recognize generic epitopes that are specifically associated with amyloid plaques. In some transgenic animal and cell culture
distinct aggregation states of many different amyloid-forming models, pathological changes are frequently observed prior to
sequences indicate that there are at least two fundamentally dis- the onset of amyloid plaque accumulation (5, 6). It has also been
tinct types of amyloid oligomers: fibrillar and prefibrillar oli- reported that soluble A␤ correlates better with dementia than
gomers. Classification of amyloid oligomers according to their insoluble fibrillar deposits (7, 8), suggesting that oligomeric
underlying structures may be a more useful and rational forms of A␤ may represent the primary toxic species in AD.
approach than relying on differences in size and morphology. Indeed, soluble prefibrillar oligomers have been implicated as
primary causative agents in many different degenerative dis-
eases in which the accumulation of large fibrillar deposits may
A number of age-related degenerative diseases are character- be either inert or protective (reviewed in Refs. 9 and 10). For A␤,
ized by the accumulation of misfolded proteins as amyloid aggregates ranging from dimers up to particles of one million
deposits. Amyloid deposits are typically composed of 6 –10-nm Da or greater have been reported in vitro (11–16). Electron
“cross-␤”-fibrils, in which the polypeptide chain is arranged in microscopy and atomic force microscopy have identified
␤-sheets where the polypeptide is perpendicular to the fibril spherical particles of ⬃3–10 nm that appear at early times of
axis and hydrogen bonding is parallel (1). In AD,2 several types incubation and disappear as mature fibrils appear (16 –18).
of amyloid deposits containing the A␤ peptide accumulate, These spherical oligomers appear to represent intermediates in
including diffuse amyloid deposits, “cored,” “neuritic,” and the pathway of fibril formation because they are transiently
“compact or burned out” senile plaques (2), and cerebrovascu- observed at intermediate times of incubation during fibril for-
lar amyloid deposits. The linkage of familial AD mutations to mation. Soluble A␤ oligomers have been referred to as amor-
the increased production of more highly aggregation-prone phous aggregates, micelles, protofibrils, prefibrillar aggregates,
A␤42 supports a causal role of A␤ aggregation in disease (3), ADDLs, A␤*56, globulomers, amylospheroids, “tA␤” (toxic sol-
but the precise relationships between aggregation state and dis- uble A␤), “paranuclei,” and annular protofibrils (11, 13, 15–17,
ease remain to be established. Many other age-related degener- 19 –26). A similar spectrum of soluble oligomers has been
ative diseases are also characterized by the accumulation of observed for many types of amyloids such as ␣-synuclein (27),
amyloid deposits derived from a variety of other proteins. The islet amyloid (28), and non-disease-associated “neoamyloids”
hallmark lesions of Parkinson disease involve the accumulation (21). Although these oligomers have been formed under differ-
ent conditions and display different toxic activities, sizes, and
morphologies, it is not yet clear whether they represent the
* This work was supported, in part or in whole, by National Institutes of Health
Grants NS31230 and AG00538 and grants from the Cure Alzheimer Fund same or distinct structures.
and the Larry L. Hillblom Foundation. This is the fifth article of eleven in the
Thematic Minireview Series on the Molecular Basis of Alzheimer Disease. Immunological Classification of Amyloid Oligomers
This minireview will be reprinted in the 2008 Minireview Compendium,
which will be available in January, 2009. If the structures of these amyloid oligomers were known, it
1
Consultant for Kinexis, Inc. To whom correspondence should be addressed. would be obvious what their relationships are and how many
E-mail: cglabe@[Link].
2
The abbreviations used are: AD, Alzheimer disease; A␤, amyloid-␤; ADDLs, different and unique structures they represent. Only the struc-
A␤-derived diffusible ligands. tures of a few of the amyloid fibrils are known (29 –33), and

OCTOBER 31, 2008 • VOLUME 283 • NUMBER 44 JOURNAL OF BIOLOGICAL CHEMISTRY 29639
MINIREVIEW: Amyloid Oligomer Structures

amyloid structures that is shared by many different types of amy-

loids. Although fibrils have often been operationally defined as
insoluble material that sediments at 100,000 ⫻ g, the fact that
small soluble oligomers also react with fibril-specific antibodies
indicates that oligomers with the same type of structural orga-
nization as the insoluble fibril also exist (Fig. 1) (37). Although
fibrillar oligomers may sound like an oxymoron, the fact that
fibril assembly is known to be a nucleation-dependent process
indicates that the existence of these small “seed” aggregates, in
which the peptide is organized in the same lattice structure of
the fibrils, is to be expected.

What Are the Generic Epitopes, and Why Are They

Different in Fibrillar and Prefibrillar Oligomers?
It is rather remarkable that the polyclonal immune response
to fibrillar and prefibrillar amyloid antigens is largely independ-

Downloaded from [Link] at University of Georgia - Athens on June 29, 2009

ent of protein sequence and conformation-specific (37). Why
would an antibody raised against aggregates from one sequence
recognize the same aggregation state of another protein
sequence yet be conformationally specific for fibrillar or prefi-
brillar states? The structure of amyloid fibrils and oligomers
FIGURE 1. Schematic representation of the distinct types of amyloid oli-
gomers and fibrils. The aggregation pathway begins with a misfolded amy-
may provide clues for the molecular basis for this peculiar spec-
loidogenic monomer (top) and can diverge into two paths depending on ificity. Most of the fibril structures are relatively simple: paral-
which conformation it adopts. Monomers can aggregate to form prefibrillar lel, in-register, intermolecularly hydrogen-bonded strands.
oligomers that are A11-positive and OC-negative (left pathway). These prefi-
brillar oligomers may then align to form protofibrils (not shown) and undergo This motif gives rise to side chain “steric zippers” composed of
a concerted conformation change “en bloc” to form fibrils. They are termed a single amino acid side chain that runs up and down the sheet
prefibrillar oligomers because they are transient intermediates that ulti-
mately become fibrils. In the other pathway, amyloidogenic monomers (34, 40). These structures were first observed in ␤-helix pro-
aggregate to form a fibrillar conformation or lattice that is OC-positive and teins where a repeating sequence strand is interspersed with a
A11-negative (right pathway). These fibrillar oligomers may represent fibril helical spacer, giving rise to a parallel, in-register ␤-sheet that
nuclei or seeds that are aggregates capable of elongating by recruiting addi-
tional monomers at their ends. Addition of monomers ultimately elongates has stacks of identical amino acid side chains aligned up and
the fibrils to a size that satisfies an arbitrary definition of insolubility and down the sheet (41). Because many amyloid fibril structures
would be recognized as fibrillar under the electron or atomic force micro-
scope, although no conformational difference is apparent by antibody reac- have these side chain zipper tracts and because specific amino
tivity. Fibrils may be distinct from fibrillar oligomers on the basis of their con- acid side chains are widely distributed among amyloid-forming
tent of multiple protofilaments (not shown), but this does not imply that a
fundamental conformation change in their integral peptide-building blocks sequences (42), most fibrils would be expected to share these
is necessary for fibrillar oligomers to convert to fibrils. They may simply coa- steric zippers, and they may constitute the fundamental struc-
lesce or grow by monomer addition to form fibrils. tures recognized as generic epitopes. This hypothesis suggests
that there are many different potential epitopes, at least one per
many of these structures are not known at a resolution suffi-
side chain. If the epitope recognizes two adjacent zippers, the
cient to evaluate how many structural variants exist. These
number of potential epitopes could be exponentially greater.
structural studies have revealed that fibrils are composed of
Whether a given amyloid structure displays a particular steric
parallel, in-register, hydrogen-bonded peptide strands, and a
zipper would depend on the primary sequence and folded
recent x-ray crystallographic analysis of a large number fibrils
structure of the ␤-sheet.
formed by small, 6 –7-residue peptides confirms that parallel
in-register structure is a common motif and provides additional Although steric zippers can explain the widespread generic
details of the fibril structures at atomic resolution (34). nature of the epitopes, they do not explain why the antibodies
In the absence of high resolution oligomer structures, distinguish between fibrillar and prefibrillar amyloid struc-
conformation-dependent antibodies can distinguish different tures. The fact that the recognition of these generic structures
types of amyloid structures. Conformation-dependent antibodies by antibodies is distinct and mutually exclusive suggests that
and antisera that specifically recognize amyloid fibrils (35–38) or the difference is a fundamental difference in the organization of
prefibrillar oligomers (Fig. 1) (39) have been reported. Many of the peptide backbone. One possibility that has been suggested
these antibodies are also interesting because they have the unusual is that prefibrillar oligomers may be ␣-extended sheets (43),
property of recognizing generic epitopes that are associated with whereas fibrillar structures are ␤-sheets. Another possibility is
specific aggregation states regardless of their amino acid sequence. that the difference is due to differences in the twist, tilt, or
The fact that these epitopes are widely distributed yet distinct and hydrogen-bonding pattern of the individual ␤-strands within
non-overlapping between fibrils and prefibrillar oligomers sug- the sheet. Whether these hypothetical inferences are valid must
gests that there is a fundamental structural difference in the orga- await structural characterization of the prefibrillar oligomeric
nization of the polypeptide backbone between these two classes of state.

29640 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 283 • NUMBER 44 • OCTOBER 31, 2008
 MINIREVIEW: Amyloid Oligomer Structures

Does Size Matter? that different amyloid oligomers prepared under different con-
For a long time, the aggregation state of amyloids has been ditions could have subtle differences in structure.
judged by the solubility or the size of the oligomer according to
Structural Basis for the Classification of Amyloid
sedimentation, size exclusion chromatography, and gel electro-
Oligomers
phoresis. Although this has been useful, size measurements
may lack the structural resolution needed to distinguish alter- Which oligomers are fibrillar or prefibrillar, and are there
native conformations and may not reflect the aggregation state any other unique structures? Some data are beginning to
under more physiological circumstances. On Western blots, emerge on which types of oligomers are formed in vivo and in
A␤ aggregates ranging from the size of a dimer all the way up to vitro. ADDLs are formed in vitro by dissolving dry A␤42 in
aggregates ⬎500 kDa that stain with the fibril-specific antibody Me2SO and diluting it in F12 cell culture medium to 100 ␮M,
OC are observed (Fig. 1) (37). In contrast, the prefibrillar oli- followed by incubation at 4 °C for 24 h (20). ADDLs range in
gomer-specific antibody A11 stains bands ranging from size from trimer and tetramer to approximately dodecamer in
approximately tetrameric up to ⬃75 kDa (Fig. 1). Similar results vitro and in vivo (49, 50). Although it is not yet clear whether
were obtained for fibrillar oligomers under nondenaturing con- ADDLs represent fibrillar or prefibrillar oligomers or some
ditions, indicating that the small size of fibrillar oligomers is not other unique type of aggregates, results with conformation-de-
an artifact of SDS-induced dissociation. The size distributions pendent anti-ADDL antibodies are consistent with ADDLs rep-

Downloaded from [Link] at University of Georgia - Athens on June 29, 2009

of soluble fibrillar and prefibrillar A␤ oligomers broadly over- resenting fibril-type oligomers because the antibodies stain
lap, indicating that size is not a good indicator of their immu- plaques (51, 52). ADDLs bind preferentially to synapses on neu-
nologically defined conformation and that distinct oligomeric rons (50, 51), and their level is elevated in AD brain (50) and
conformations of the same size exist. If the oligomer structures cerebrospinal fluid (53).
are intermolecularly hydrogen-bonded extended structures as Prefibrillar oligomers recognized by antibody A11 also occur
in human AD brain, although they are only rarely associated
their ␤-sheet character would indicate, then the difference
with plaque deposits (39). On Western blots, prefibrillar A␤
between a dimer and a trimer or a nonamer and a decamer
oligomers range in size from approximately tetramers to ⬃20-
would be no more significant that adding a single coin to the
mers (37). A␤*56 is a dodecamer that is correlated with cogni-
stack. Of course, size could matter for the activity of small oli-
tive deficits in transgenic animal models, and it is a prefibrillar
gomers in the 10 –100-kDa range and those that are insoluble.
type of oligomer because it stains with antibody A11 on West-
Small oligomers would be expected to have a higher rate of
ern blots (22). Prefibrillar oligomers are also preferentially asso-
diffusion, and if the growing ends of the ␤-sheets are important
ciated with axon terminals in AD and transgenic mouse brains
for pathogenesis, then small size provides a larger number of
(54, 55). Prefibrillar oligomers also bind preferentially to syn-
ends per unit mass of peptide.
apses on human neurons, suggesting that the conformational
differences between fibrillar and prefibrillar oligomers are not
Are There Structural Polymorphisms within a Class of
important for synapse binding (56).
Amyloid Aggregates?
“Globulomers” are prepared in vitro by dissolving A␤42 in
In addition to prefibrillar oligomers and fibrils, structural hexafluoroisopropyl alcohol, drying, resuspending in Me2SO at
variants or polymorphisms appear to exist within a class. This a concentration of 5 mM, and diluting to 400 ␮M in phosphate-
variation may be analogous to the well known phenomenon of buffered saline containing 0.2% SDS. After incubation for 6 h at
strain variation in prions. Prion protein appears to be capable of 37 °C, the solution is diluted 3-fold with water and incubated
forming aggregates that display subtle differences in their pat- for an additional 18 h at 37 °C (23). Globulomers run at
terns of transmissibility and protease resistance (44). Recent ⬃38 – 48 kDa on SDS gels (23). Globulomers bind in a punctate
evidence indicates that structural variants also exist within A␤ distribution to neurons in an age-dependent fashion, and they
fibrils (45) and prefibrillar A␤ oligomers (46). For A␤, distinct alter synaptic activity (57). Anti-globulomer conformation-de-
fibril morphologies have subtle differences in the underlying pendent antibodies do not react with monomeric A␤ but stain
structures determined by solid-state NMR. These distinct vari- fibrillar plaque deposits, suggesting that they are also specific
ants can be propagated by seeding the assembly of monomers for fibril-related epitopes. The reactivity of globulomers with
(45). For prefibrillar A␤ oligomers, a polymorphism at the fibril-specific antibodies suggests that they are fibril-type oli-
N-terminal 6E10 epitope that is displayed at low pH but hidden gomers. The conformation of other types of A␤ oligomers in
or absent at neutral pH was noted (46). Yeast prion strains also not yet known, but it should be relatively easy to determine
display distinct conformations that arise by differences in the their status using the conformation-dependent antibodies that
extent and overlap of the amyloid core region (47). In human are currently available.
prions, variation in fibril structure that is detected by differ- Naturally secreted A␤ oligomers that run predominantly as
ences in antibody binding has been observed to occur in alter- dimers and trimers on SDS gels have been shown to inhibit
nating fashion within a single amyloid fibril (48). In view of the long-term potentiation in vitro, but the conformation of these
potential for structural heterogeneity within a fibril and the low molecular mass oligomers is not yet clear (58 – 60). A␤
difficulty of determining the structure of amyloids, specific monomers and fibrils did not inhibit long-term potentiation in
antibody binding may provide a more facile means of detecting the same paradigm, indicating that the inhibition is conforma-
and characterizing structural polymorphisms. The structural tion-dependent. These low molecular mass oligomers run at a
variability already reported in A␤ and prion structures suggests size that is not recognized by antibody A11, suggesting that they

OCTOBER 31, 2008 • VOLUME 283 • NUMBER 44 JOURNAL OF BIOLOGICAL CHEMISTRY 29641
MINIREVIEW: Amyloid Oligomer Structures

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