aguzzi2010.pdf

Inappropriate aggregation of proteins is normally
prevented by complex cellular quality control mecha-
nisms.However, under certain circumstances, an unusual
subset of proteins is able to aggregate within or around
cells. Although the amino-acid sequences of this class of
proteinsarediverse,theyallseemtoadoptasimilar,insol-
uble, highly ordered structure when aggregated known as
the cross-β spine1
(FIG. 1a). The histology of the resulting
protein deposits was appreciated more than 150years ago
and was termed amyloid2
(FIG. 1b). Although it is possible
to predict the approximate tendency of proteins to form
amyloid on the basis of their sequence3
, amyloid forma-
tion is far from a simple function of protein sequences
and secondary structures. It is becoming increasingly
apparent that amyloid-forming proteins exist in a com-
plex dynamic equilibrium between soluble monomeric or
oligomeric states and various insoluble states of higher-
order aggregation. The formation of these aggregates
depends on the protein concentration, complex inter-
actions with other proteins and the specific cellular envi-
ronment. A more thorough understanding of the factors
that influence this equilibrium is crucial for determining
howproteinaggregationdisordersariseandfordeveloping
effective therapies against them.
From protein aggregation to pathology
Aggregation and accumulation of amyloid-forming
proteins can lead to a wide range of protein aggregation
diseases known as amyloidoses. These diseases include
systemic amyloidoses in which deposits may occur in
any part of the body, such as AL amyloidosis due to the
accumulation of immunoglobulin light chain amyloid
fibrils; amyloid A (AA) or reactive systemic amyloid-
osis resulting from deposits of catabolic products of the
serum amyloid A protein (SAA); and ATTR duetotrans-
thyretin (TTR) accumulation. There are also amyloidoses
in which a single organ is affected — possibly including
pancreatic accumulation of islet amyloid polypeptide in
type 2 diabetes4
.
Many protein aggregation diseases affect the nervous
system. Interestingly, certain proteins specifically aggre-
gate and are toxic in the central nervous system (CNS)
despite the fact that they are ubiquitously expressed.
These neurodegenerative diseases include disorders in
which the pathological proteins may accumulate within
the nucleus, as is the case with polyglutamine expansion
diseases(suchasHuntington’sdiseaseandspinocerebellar
ataxias), disorders characterized by cytoplasmic inclu-
sions (such as α-synuclein in Parkinson’s disease), as well
as disorders in which pathological proteins accumulate
extracellularly (for example in prion diseases) or both
intracellularly and extracellularly (for example, tau and
amyloid-β (Aβ) in Alzheimer’s disease).
It is becoming clear that amyloid formation is not
always pathological, but rather might have a nor-
mal physiological function5
. However, not all patho-
logical protein aggregates necessarily form amyloids.
Nevertheless, the definition of amyloid is broadening
Institute of Neuropathology,
University Hospital of Zürich,
Schmelzbergstrasse 12,
CH‑8091 Zürich, Switzerland.
Correspondence to A.A.
e‑mail:
adriano.aguzzi@usz.ch
doi:10.1038/nrd3050
Protein aggregation diseases:
pathogenicity and therapeutic
perspectives
Adriano Aguzzi and Tracy O’Connor
Abstract | A growing number of diseases seem to be associated with inappropriate
deposition of protein aggregates. Some of these diseases — such as Alzheimer’s disease and
systemic amyloidoses — have been recognized for a long time. However, it is now clear
that ordered aggregation of pathogenic proteins does not only occur in the extracellular
space, but in the cytoplasm and nucleus as well, indicating that many other diseases may also
qualify as amyloidoses. The common structural and pathogenic features of these diverse
protein aggregation diseases is only now being fully understood, and may provide novel
opportunities for overarching therapeutic approaches such as depleting the monomeric
precursor protein, inhibiting aggregation, enhancing aggregate clearance or blocking
common aggregation-induced cellular toxicity pathways.
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© 20 Macmillan Publishers Limited. All rights reserved
10

Nature Reviews | Drug Discovery
a b
100 µm
β1
β1
Odd
end
L17
V40
K28
D23
Odd end
Fibril axis
β2
β2
to encompass a wider range of diseases6
. originally,
the term was used exclusively to describe extracellu-
lar amyloid deposits that stain with histological dyes
such as Congo red. Now, it is recognized that many
cytoplasmic7
and even intranuclear inclusions8
, which
do not necessarily stain with these dyes, are composed
of ordered fibrillar structures similar to those of clas-
sical amyloids. Furthermore, some of these dyes seem
to bind to aggregated intermediates of amyloid-forming
proteins in addition to mature amyloid fibrils (for exam-
ple, thioflavin appears to bind to Aβ oligomers)9–11
.
Interestingly, staining with Congo red and thioflavin S
has been reported intracellularly in some cases12,13
.
Thus, the current classification of amyloids is far from
clearly defined.
In this Review, we summarize various therapeutic
approaches aimed at preventing or reversing patho-
logical protein aggregation (TABLE 1). our discussion is
focused around two neurodegenerative diseases: prion
disease and Alzheimer’s disease. However, a number
of extracerebral amyloidoses are also benefiting from
therapeutic advances. Several systemic amyloidoses
are becoming manageable chronic diseases rather than
definite death sentences.
Alzheimer’s disease
Alzheimer’s disease, the most common neurodegenera-
tive disorder, is currently the focus of some of the most
exciting and rapidly progressing research on amyloid
therapeutics. Alzheimer’s disease pathology is character-
ized by the formation of two types of protein aggregates
in the brain: amyloid plaques (FIG. 2a) — which form an
extracellular lesion composed of the Aβ peptide; and
intracellular neurofibrillary tangles (FIG. 2b) — which
are composed of hyperphosphorylated filaments of the
microtubule-associated protein tau. Genetic evidence
implicates deregulated Aβ homeostasis as an early event
in Alzheimer’s disease pathology14
. Indeed as all familial
Alzheimer’s disease mutations lead to increased produc-
tion of this peptide or preferential production of a more
fibrillogenic Aβ isoform (Aβ42)15
. For this reason, most
Alzheimer’s disease therapeutics have targeted the Aβ
peptide, although tau-targeted therapies are also being
pursued16,17
.
Targeting Aβ production: the secretase inhibitors. one
widely pursued method of combating protein aggrega-
tion diseases is to inhibit the production of the mono-
meric form of the protein with the aim of reducing the
amount of protein available to aggregate. In the case
of Alzheimer’s disease, the amyloidogenic Aβ frag-
ment associated with amyloid plaques is derived from
proteolytic processing of a longer, non-aggregating
precursor protein — amyloid precursor protein (APP)
(FIG. 3). Therefore, pharmacological inhibition of the
enzymes responsible for Aβ formation (γ-secretase and
β-secretase) is a prime strategy for blocking Aβ produc-
tion. The γ-secretase complex consists of four proteins18
,
the catalytic activity of which is thought to be mediated
by the presenilin 1 (PS1) and PS2 proteins. The func-
tional assembly of these proteins has the unusual ability
to target a stretch of APP that is entirely buried within
Figure 1 | common features of protein aggregation and amyloids. a | Ribbon diagrams of the three-dimensional
structure of amyloid-β (Aβ42) (residues 17–40). Amyloid-forming proteins such as Aβ are all thought to form similar tertiary
structures when aggregated, known as a cross-β spine or amyloid162
. The cross-β spine consists of an ordered arrangement
of β-sheets (thick coloured arrows). b | Congo red-stained sections of human kidney affected by amyloidosis. The cross-β
spine structure is able to intercalate with molecules of the azo-dye Congo red and cause them to emit a characteristic
apple-green birefringence upon exposure to polarized light163
. This unique feature of amyloids has historically been used
to identify them histologically.
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Blood–brain barrier
A protective wall of capillary
epithelium separating
the brain parenchyma
from the bloodstream that
is impenetrable to most
circulating substances.
the lipid bilayer of the plasma membrane. The γ-secretase
complex is responsible for the carboxy-terminal cleavage
of APP to produce Aβ40 or Aβ42.
Potent small-molecule inhibitors of γ-secretase can
dramatically reduce Aβ40 and Aβ42 production19–22
. The
primary caveat to targeting γ-secretase for Alzheimer’s
disease therapeutics is that APP is not the only substrate
of γ-secretase. The most notable alternative cleavage
substrate is the Notch receptor23,24
. Cleavage of Notch
by γ-secretase is crucial for normal development, as
shown by the fact that Ps1–/–
mice suffer from embryonic
lethality owing to deficient Notch cleavage25,26
. Although
this does not necessarily disqualify γ-secretase as a drug
target, Notch seems to mediate differentiation of sev-
eral cell types throughout adulthood (for example, gut
epithelium and T cells). The unfortunate consequence
of this is that potent γ-secretase inhibitors have serious
gastrointestinal and immunological side effects27
.
As a result of this drawback, the field has shifted
towards the development of γ-secretase modulators.
These compounds either selectively inhibit γ-secretase
cleavage of APP, leaving Notch cleavage unaffected, or
alter γ-secretase cleavage of APP to favour Aβ40 pro-
duction rather than Aβ42. The longer, less abundant
42 amino-acid isoform of Aβ, Aβ42, seems to be more
closely associated with the development of amyloid
pathology than its counterpart, Aβ40. Studies have
shown that dominantly-inherited PS1 mutations, which
cause Alzheimer’s disease with 100% penetrance, lead to a
shift in γ-secretase cleavage of APP in favour of the Aβ42
isoform28–33
. Drugs that modulate γ-secretase activity in
this manner include non-steroidal anti-inflammatory
drugs (NSAIDs) such as ibuprofen34
and compounds
that interact with the ATP-binding motif of PS1 near the
γ-secretase active site35
.
one such γ-secretase-modulating compound, the
NSAID (R)-flurbiprofen (also known as tarenflurbil),
effectively reduced amyloid plaque formation36
and res-
cued memory deficits37
in APP-transgenic mice. It also
yielded encouraging results in early human trials38,39
.
However, (R)-flurbiprofen failed to significantly enhance
cognitive performance of patients with Alzheimer’s
disease in Phase III clinical trials and has recently been
abandoned as a potential therapy40
. The compound-
screening approach may identify additional promising
small-molecule γ-secretase modulators, and other com-
pounds may be more successful than (R)-flurbiprofen in
human trials (for example, semagacestat from Lilly and
elan is currently in Phase III trials41
), researchers may
also decide to capitalize on recent results demonstrating
the existence of endogenous γ-secretase activity modi-
fiers that are APP-specific42
and the observation that
some components of the γ-secretase complex have tissue-
specific isoforms, which may provide a novel means of
achieving brain-specific γ-secretase inhibition43
.
The amino-terminal cleavage of APP to form both
Aβ40 and Aβ42 results from β-secretase activity. After
the discovery that β-secretase cleavage of APP seemed
to be due to the activity of a single aspartic protease,
β-secretase 1 (BACe1; also known as memapsin 2 and
ASP2), there was much interest in the possibility of
targeting β-secretase for the treatment of Alzheimer’s
disease44–48
. Deletion of this enzyme does not have
an overt effect on phenotype in mice, suggesting that
BACe1 inhibitors, unlike γ-secretase inhibitors, might
lack serious target-related side effects49
. Inhibition of
BACe1 activity can block the production of Aβ, prevent
the development of amyloid pathology in the brain and
rescue Alzheimer’s disease-related memory deficits in
mice50–53
.
However, nearly a decade has passed since the initial
identification of BACe1 as the β-secretase, and
researchers continue to struggle with the development
of effective BACe1 inhibitors that are active in the CNS.
The large BACe1 active site requires the identification of
large compounds for potent BACe1 inhibition that also
readily penetrate the blood–brain barrier (BBB)54
and
are reasonably stable. unfortunately, the slow progress
of the BACe1 inhibitor field is a testament to the fact
that such molecules are relatively rare. Furthermore,
it is becoming increasingly apparent that BACe1
has alternative cleavage substrates and may have
Table 1 | Summary of therapeutic strategies for protein aggregation diseases
Approach Therapy expected effect current status refs
Inhibition of
amyloidformation
γ-Secretase
inhibitors and
modulators
Reduced carboxy-terminal cleavage
of APP to form Aβ40 or Aβ42
Phase II and III clinical
trials
39
β-Secretase
inhibitors
Reduced amino-terminal cleavage
of APP to form Aβ40 and Aβ42
Phase I clinical trials 63
Promotion of
amyloid clearance
Aβ
immunotherapy
Enhanced clearance of Aβ-containing
aggregates
trials
17,82,83
Prion
immunotherapy
Enhanced clearance of PrPSc
-containing
aggregates; prevention of the invasion
of prions into neurons
Preclinical 117,118,
120–127
Inhibition
of amyloid
aggregation
Scyllo-inositol Prevention of the formation of
higher-order aggregates
Phase II clinical trials 168
Tafamidis Stabilization of the native state of
transthyretin
trials
145
Aβ, amyloid-β; APP, amyloid precursor protein; PrPSc
, prion protein with abnormal conformation.
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a
b
200 µm
200 µm
Passive transfer
A process by which a host
acquires exogenous antibodies
and hence immunity to an
immunogen without generating
an active immune response.
subtle physiological roles in humans (for example, in
peripheral nerve myelination and synaptic transmis-
sion)55–64
. Nevertheless, some BACe1 inhibitors have
progressed to early clinical trials65
. As with γ-secretase
inhibition, problems with developing small-molecule
BACe1 inhibitiors may ultimately be circumvented by
indirect approaches to BACe1 inhibition — for example,
by modulating regulatory mechanisms that control
BACe1 expression66–72
or by taking advantage of the
fact that BACe1 activity is optimal in acidic cellular
compartments73
. Despite the various drawbacks to the
approach of secretase inhibition, γ-secretase inhibi-
tors, γ-secretase modulators and β-secretase inhibitors
continue to be actively pursued as drug targets for
Alzheimer’s disease therapy in the hope that the eventual
benefits might outweigh the risks.
Mobilizing the immune system: Aβ immunotherapy. An
alternative approach to protein aggregation therapeutics
is to enhance the degradation of the aggregating protein
or the aggregates themselves. Manipulating the immune
system for the purpose of enhancing Aβ clearance has
been pursued as a therapeutic approach for Alzheimer’s
disease since the turn of the millennium. This was when
several studies reported dramatically reduced Aβ levels
and plaque pathology and/or cognitive improvements
upon active immunization of APP-transgenic mice with
full-length Aβ peptide74–76
, Aβ peptide fragments77
and
passive transfer of Aβ-specific antibodies78–81
. Based on
these studies and encouraging results from Phase I trials,
active Aβ immunotherapy in humans subsequently
progressed to a widely publicized Phase II clinical trial
in 2001. unfortunately, this trial was halted in January
2002 owing to the development of sterile meningoen-
cephalitis in some patients82
.
Nonetheless, a follow-up study on a small subset of
patients from the Phase II immunotherapy trial sug-
gested that individuals that had generated high Aβ anti-
body titres exhibited a decreased rate of cognitive decline
compared with placebo-treated individuals83
. However,
theseresultsarecontroversialandfollow-upanalyseshave
questioned the validity of this positive interpretation.
As a complementary strategy, second-generation
Aβ immunotherapies are attempting passive transfer
approaches. A monoclonal Aβ antibody from Pfizer
is currently in Phase II clinical trials. Additionally,
bapineuzumab from elan–wyeth caused a significant
delay in cognitive decline, at least in a subset of indi-
viduals17
. Therefore, the outlook on Aβ immunotherapy
remains hopeful.
Interestingly, preliminary studies have shown that
intravenous treatment with human immunoglobu-
lins, an approved treatment for immune deficiencies
and autoimmune disorders, also seems to be effective
in reducing Aβ levels and cognitive decline in patients
with Alzheimer’s disease84,85
. Although the mechanism
of action remains unclear, these studies raise the interest-
ing question of whether immunotherapy for Alzheimer’s
disease needs to be directed against the Aβ peptide, or
whether general immunomodulation (possibly through
Fcγ-mediated engulfment of amyloid deposits by micro-
glia, or through poorly understood modulation of cere-
bral cytokine signalling)86
might be sufficient to enhance
the clearance and degradation of pathological peptides
in the brain. If so, this finding would have important
implications for the treatment of other protein aggrega-
tion diseases.
Figure 2 | characteristics of Alzheimer’s disease. a | A human cortical section from
a patient affected by Alzheimer’s disease, stained with an amyloid-β (Aβ)-specific
antibody. One of the classical hallmarks of Alzheimer’s disease histopathology is the
appearance of extracellular lesions known as senile or amyloid plaques, which are
primarily composed of the Aβ peptide. b | A human cortical section from a patient
affected by Alzheimer’s disease, stained with a phospho-tau-specific antibody.
The second histopathological hallmark of Alzheimer’s disease is the presence of
intraneuronal lesions known as neurofibrillary tangles (indicated by an arrow),
which are composed of abnormal, hyperphosphorylated filaments of the microtubule-
associated protein tau.
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b Non-amyloidogenic
a Amyloidogenic
γ
γ
α
β
Endosome
Cytoplasm
Nucleus
Endosome
APP
APP
APP
APPsα
C83
AICD
p3
APPsβ C99
Aβ42
Aβ40
Curiously, despite the initial success of Aβ immuno-
therapeutic methods, the mechanisms by which these
antibodies function to clear amyloid and/or to elicit cog-
nitive improvement remains an area of intensive debate.
Three scenarios have been envisaged87
. First, immuno-
therapy might enhance microglial phagocytic activity,
which could be directed against the soluble monomeric
and/or oligomeric forms of the amyloid-forming protein.
This would reduce the amount of protein that is avail-
able to aggregate. Alternatively, microglia might directly
disassemble the insoluble deposits, as microscopic analy-
sis suggests that Aβ antibody administration promotes
microglial uptake of insoluble deposits78
. However,
the stability of deposits in the brain argues against this
hypothesis81,88
. Second, the ‘peripheral sink hypoth-
esis’ postulates that antibodies mediate their effects by
sequestering amyloid-forming proteins in the periphery
(based on the theory that peripheral plasma proteins are
in equilibrium with CNS amyloid-forming proteins )79,80
.
In this scenario, antibodies may bind to amyloid-forming
proteins and act as a physical barrier, preventing amyloid-
formingproteinfromcrossingtheBBB,orantibodiesmay
stimulate immune-mediated uptake of amyloid-forming
proteins. In either case, the proposed net result is efflux of
protein out of the CNS into the periphery, where the pro-
tein is presumably degraded by circulating macrophages.
Third, antibodies might inhibit the aggregation process
by preventing the recruitment of monomeric species to
aggregated moieties, either by binding to the monomers
or the aggregates themselves. evidence that Aβ antibod-
ies, which bind amyloid plaques, are the same antibodies
that effectively ameliorate plaque pathology78
supports
this hypothesis89
.
Regardlessoftheexactimmunotherapeuticmechanism
ofaction,thenetresultislikelytobeenhancedclearanceof
amyloid-forming proteins, as non-aggregated and aggre-
gated states are in equilibrium and soluble forms of the
protein are more accessible to clearance and degrada-
tion mechanisms than insoluble forms. Several of these
mechanisms probably act simultaneously, with the rela-
tive contribution of each to net reduction in aggregation
depending upon the specific properties of the amyloid-
forming protein being targeted, the stage of disease pro-
gression and the antibody being used.
All aggregates are not created equal: toxic oligomers
and neurodegeneration. An important assumption
underlying therapeutic strategies aimed at reducing
protein aggregation is that protein aggregates are toxic
to cells. But is this the case? It has long been known that
the number of amyloid plaques in Alzheimer’s diseased
brains correlates poorly with the degree of dementia90
.
Figure 3 | Amyloid-β formation. Amyloid precursor protein (APP) undergoes a series of proteolytic cleavages in neurons
to form the amyloid-β (Aβ) peptide that is associated with senile plaques in Alzheimer’s disease. In the amyloidogenic
pathway (a), internalized APP is initially cleaved at its amino terminus by endocytic β-secretase (β) to form secreted APPsβ
and C99. C99 then becomes a substrate for intramembraneous cleavage by the γ-secretase complex, leading to the
release of Aβ40 (or Aβ42 at low frequency) and the APP intracellular domain (AICD), which may regulate gene expression.
In a competing, non-amyloidogenic pathway (b), α-secretase cleaves cell surface APP to liberate secreted APPsα and C83.
C83 is then cleaved by γ-secretase to form the soluble p3 peptide and the AICD. The majority of Aβ and N-terminal APP
cleavage fragments are eliminated from the neuron by the secretory pathway.
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Long-term depression
An enduring weakening of
synaptic strength that is
thought to interact with
long-term potentiation (LTP)
in the cellular mechanisms of
learning and memory. Unlike
LTP, which is produced by brief
high-frequency stimulation,
LTD can be produced by
long-term, low-frequency
stimulation.
More refined measurements that take into account levels
of total Aβ aggregates (or amyloid load, of which plaques
are only a subset) seem to be better predictors of cog-
nitive performance. one theory that has emerged to
explain this observation is that the large, insoluble
lesions observed upon histological examination are
benign ‘tombstones’ and that the pathological media-
tors are highly toxic oligomeric intermediates, which
exist in a kinetic state that is between the monomeric
and the insoluble, aggregated state. oligomers derived
from cultured cells consist primarily of Aβ dimers and
trimers91,92
, whereas oligomers isolated from brain tissue
consist of a mixture of dimers, trimers and higher-order
aggregates93,94
. Interestingly, a reduction in higher-order
Aβ aggregates (and not Aβ trimers) was co-incident with
cognitive improvement in APP-transgenic mice receiv-
ing scyllo-inositol (eLND005) treatment95
. A large body
of evidence has accumulated over the past decade estab-
lishing a role for Aβ oligomers in synaptic dysfunction
and neurotoxicity (reviewed in REFS 96,97). In addition,
more recent studies have further implicated this Aβ spe-
cies in other aspects of Alzheimer’s disease pathogenesis,
including tau phosphorylation98
, long-term depression 99
,
retrograde trafficking of brain-derived neurotrophic fac-
tor100
and insulin signalling101,102
. with regards to thera-
peutics, it is hoped that traditional approaches will clear
oligomeric species with as much (or more) efficacy as
they clear mature amyloid fibrils.
However, the theory of toxic oligomers has other
interesting implications for therapeutics. For example, it
implies that therapies do not have to clear protein aggre-
gates to be beneficial. Indeed, studies in APP-transgenic
mice indicate that certain Aβ immunotherapies lead to
cognitive improvement without any detectable clearance
of Aβ81
. In the future, conformation-specific antibodies
that recognize and neutralize the action of these toxic
species in addition to promoting Aβ clearance could be
the most effective type of antibodies in eliciting cognitive
improvement in Alzheimer’s disease. Interestingly, some
of these antibodies recognize a common motif in diverse
protein aggregates103
, and so could be broadly useful for
the treatment of many aggregation disorders.
Inside or out? The role of intracellular Aβ in amyloid
pathology. As with any new discovery, the idea of toxic
oligomershasultimatelyraisedasmanyquestionsasithas
answered. For example, how and where do Aβ oligomers
induce neurotoxicity? Amyloid plaques seem to be extra-
cellular lesions; however, if soluble oligomers are the pri-
mary toxic species, they could mediate their toxic effects
inside the neuron. Although the majority of Aβ is elimi-
nated from the cell through the secretory pathway (FIG. 3),
supporting the idea that Aβ exerts its effects extracellu-
larly,thereismountingevidencethatintracellularpoolsof
Aβ could also have an important role in the disease proc-
ess. The disease-associated isoform of Aβ, Aβ42, seems to
be more prone to intracellular accumulation than Aβ40.
Also, intracellular Aβ occurs most frequently in the hip-
pocampus and entorhinal cortex (eRC), which are the
brain regions to be affected first in Alzheimer’s disease104
.
expression of the ε4 allele of apolipoprotein e (APoe4),
a major genetic risk factor for Alzheimer’s disease, also
increases intracellular Aβ105
. More recent studies have
found that increased synaptic activity reduces intracellu-
lar Aβ106
, and overexpression of neprilysin, which signifi-
cantly ameliorates plaque pathology in APP-transgenic
mice,alsodecreasesintracellularAβ107
.Therapiesaimedat
reducing intracellular Aβ levels therefore warrant further
investigation. The ability of current methods to influence
intracellular Aβ levels might be indicative of their efficacy.
Indeed, Aβ immunotherapy can reduce intracellular Aβ
in addition to its other effects, even when the antibody
is not internalized108
. Interestingly, Aβ immunotherapy
has recently been used to reduce intracellular Aβ and
attenuate motor impairment in a mouse model of inclu-
sion body myositis — a disease in which intracellular Aβ
accumulation is a prominent feature109
.
The idea that soluble oligomeric intermediates and
intraneuronal pools of Aβ have key roles in pathogenesis
issteadilygainingsupport,indicatingthattraditionalideas
about amyloid are rapidly evolving. Nevertheless, the idea
that amyloid deposits are entirely non-pathological seems
unlikely. In the case of Alzheimer’s disease, it is well
established that neurons surrounding neuritic plaques
have an abnormal appearance. It is likely that many
forms of Aβ can contribute to neuronal dysfunction, as
proposed by one recent study investigating neuronal Arc
expression in the vicinity of extracellular and intracell-
ular pools of Aβ110
. The extent to which each Aβ pool
contributes to the disease process at different stages will
undoubtedly be the subject of future studies.
Infectious amyloid: the prion diseases
Prion diseases, also known as transmissible spongiform
encephalopathies, include Creutzfeldt–Jakob disease,
kuru, fatal familial insomnia and Gerstmann–Sträussler–
Scheinker syndrome in humans; scrapie in sheep; bovine
spongiformencephalopathyincattle;andchronicwasting
disease in cervids111
. The prion protein (PrP) is normally
present in its native conformation (PrPC
). However, in
all prion diseases, the protein is present in an abnormal
conformation (PrPSc
) that accumulates and forms depos-
its around neurons (FIG. 4a,b). A unique feature of prion
diseases is that they are transmissible among humans
and across species. Although a seeding mechanism with
subsequent propagation of amyloid fibrils is thought to
occur generally in amyloidoses, prion diseases seem to be
theonlyamyloidosesthataregenuinelyinfectiousdiseases
(with the possible exception of AA amyloidosis)112,164
.
Remarkably, the infectious agent in all prion diseases
appears to be composed exclusively of PrPSc
aggregates,
although the conversion process from PrPC
to PrPSc
may require other cellular cofactors. upon association
with the PrPSc
conformer, PrPC
undergoes a dramatic
shift in secondary structure from a protein composed of
~45% α-helices and relatively few β-sheets to a protein
composed of ~30% α-helices and ~45% β-sheets. PrPSc
aggregates are unusually resistant to degradation, and
proteinase K digestion (which entirely degrades PrPC
,
but only partially degrades PrPSc
) is the most common
biochemical method of distinguishing PrPC
from PrPSc
in tissues and cells (FIG. 4c,d). The unusual properties of
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a b
c d
C57BL/6 Prnp–/–
PK + +
MW
(kDa)
25
20
15
PrPSc PrPC
Histoblot
(PrP
Sc
)
prion amyloid propagation have presented considerable
challenges for the development of effective therapeutics
to treat prion diseases, as well as opportunities to explore
unique therapeutic modalities.
The immune system revisited: prion immunotherapy.
The immune system has a complex role in the course of
many amyloidoses, and prion diseases are no exception.
The peripheral immune system is crucial for extraneu-
ral prion replication and the spread of prions to the
CNS. Mice that lack various components of the immune
system — for example, B cells and follicular dendritic
cells (FDCs) — are much less susceptible to prion dis-
ease upon peripheral infection113–116
. Conversely, pro-
inflammatory conditions increase susceptibility to prion
infection117,118
, promote peripheral prion deposition119,120
and accelerate prion pathogenesis113–115,121
.
However, the role of the immune system in prion
replication in the CNS is less clear. Although extensive
astrogliosis is a hallmark of prion diseases, transgenic
mice in which various components of inflammatory
pathways had been deleted were not more susceptible to
prion infection when inoculated intracerebrally, indicat-
ing that many key immune pathways do not contribute
to prion replication in the CNS. However, depletion of
microglia led to a nearly 15-fold increase in prion infec-
tivity in a slice culture model of prion disease122
. This
suggests that immune-mediated phagocytic activity in
the CNS might be involved in degrading prion aggre-
gates and prolonging neuronal survival. In either case, as
with Alzheimer’s disease, targeting the immune system
(both peripherally and in the CNS) has become a prime
therapeutic strategy against prion disease pathogenesis.
Targeting peripheral immune cells. unlike other neuro-
degenerative diseases, prion diseases can spread from
the periphery to the CNS (and possibly vice versa). The
immune system has a pivotal role in this process. FDCs
in secondary lymphoid organs accumulate PrPSc
in both
acquired and inherited forms of the disease. In the case
of most acquired prion diseases, it is from these sites
that PrPSc
is subsequently transmitted to the CNS123
.
Consequently, targeting FDCs has proved to be an effec-
tive method of preventing the spread of PrPSc
from the
periphery to the CNS in animal models. For example,
lymphotoxin-β receptor (LTβR) signalling is required for
FDC maintenance and might even be directly involved
in enabling prion replication at the cellular level116,124–126
.
Blocking peripheral LTβR signalling in mice by adminis-
teringsolubleLTβR–immunoglobulinfusionproteintran-
siently depletes FDCs and prevents PrPSc
accumulation in
peripheral lymphoid organs (for example, the spleen) and
subsequent transmission of PrPSc
to the CNS124,165
. The
drawback to this approach is that it requires the time of
peripheral prion infection to be known, which is not pos-
sible in many cases of acquired prion disease. However,
this approach may prove useful to medical personnel for
cases of accidental prion infection in the clinic.
From Aβ to PrP: PrP immunization. The initial success
of Aβ immunotherapy for the treatment of Aβ pathology
in APP-transgenic mice inevitably led to the investigation
of whether the immune system could also be mobilized
to clear PrPSc
aggregates. Both active and passive PrP
immunotherapy have been tested for efficacy in the treat-
ment of prion disease. These approaches have revealed
additional challenges facing the immunotherapeutic
approach to amyloid diseases. In the case of active PrP
immunization, the immune systems of wild-type mice
were largely tolerant to PrP as it is ubiquitously expressed.
The result was the generation of low PrP-specific anti-
body titres and minimal or non-significant increases in
survival time when used to treat intraperitoneal prion
inoculation127–131
. Transgenic expression in mice of a PrP
epitope raised in Prnp–/–
mice prevented disease following
intraperitoneal prion inoculation and showed that PrP
immunotherapy is theoretically an effective strategy for
combating prion infection132
. Despite these encouraging
results, subsequent attempts of passive PrP immuniza-
tion have required unrealistically high levels of PrP anti-
bodies to elicit any meaningful effect on the survival of
Figure 4 | characteristics of prion disease. a | A human cortical section from a
patient affected by prion disease, stained with prion protein (PrP)-specific antibodies.
All prion diseases are marked by this widespread accumulation of insoluble deposits
in the brain consisting of the human prion protein (PrPC
) folded in an abnormal
conformation (PrPSc
). b | A haematoxylin- and eosin-stained human cortical section from
a patient affected by prion disease. As seen here, another pathological hallmark of prion
diseases is the formation of large vacuoles, or ‘spongiosis’, in the affected brain tissue.
It is because of this lesion that prion diseases are also known as transmissible
spongiform encephalopathies. c | Proteolytic degradation followed by PrPSc
-specific
immunostaining (PrPSc
histoblot) of coronal mouse brain sections from C57BL/6
(prion-susceptible) and Prnp–/–
(prion-resistant) mice infected with a mouse-adapted
prion strain, Rocky Mountain Laboratory passage 5 (RML5). d | A PrP-specific
immunoblot of brain homogenates digested by proteinase K (PK) and separated by
SDS–PAGE, taken from RML5-infected C57BL/6 (PrPSc
) or uninfected (PrPC
) mice.
PrPSc
and PrPC
have identical amino-acid sequences and are thought to differ only in
secondary structure. Although the crystal structure of PrPSc
has not been solved, its
conformation can be distinguished from that of PrPC
using biochemical techniques.
For example, PrPSc
is partially resistant to protease digestion, whereas PrPC
is fully
sensitive to proteolytic degradation. MW, molecular weight. Panel c is reproduced,
with permission, from REF. 163 © (2007) Elsevier Science.
REVIEWS
10

mice following intraperitoneal inoculation with prions.
Furthermore, passive immunization has so far been
ineffective in slowing the rate of disease progression in
mice following intracerebral prion inoculation or in mice
showing clinical signs of disease133
.
Another potential problem with the PrP immuno-
therapy approach was highlighted by the observation
that certain PrP-specific antibodies are capable of trig-
gering a pro-apoptotic signalling cascade in neurons
that is reminiscent of PrPSc
infection or deletion of the
central domain of PrPC
(REF. 134). Fortunately, not all
PrP-specific antibodies seem to have this capability.
Nevertheless, this study urges caution to those inves-
tigating PrP immunotherapeutics. In its current state,
PrP immunotherapy is still far from entering the clinic.
However, new innovations, such as antibodies that are
able to penetrate the BBB more readily or PrP–antibody
fusion proteins designed to specifically target the
immune system to PrPSc
deposits, may dramatically
increase the efficacy of PrP immunotherapy.
Preventing amyloid formation: aggregation inhibitors. In
recentyears,therehasbeentremendousprogressindevel-
opingtherapeuticstrategiesaimedatreducingtheproduc-
tion or enhancing the degradation of amyloid-forming
proteins. However, in the case of prion diseases, in which
the amyloid-forming protein is not produced from enzy-
maticactivityandthepathologicalaggregatesareunusually
resistant to degradation, it is likely that alternative strate-
gies will have to be pursued. one viable approach might
be to physically interfere with the aggregation process.
As the process of aggregation itself is not entirely under-
stood, this is a difficult approach at present. Nonetheless,
numerous compounds, peptides and nucleic acids have
been investigated for their ability to prevent PrPSc
aggre-
gation and slow the progression of prion disease. These
types of compounds and their efficacy in different model
systems have been extensively reviewed elsewhere135
. The
exact mechanism of action of this type of therapy is not
known; however, it is thought that the three-dimensional
structure of this class of molecules might enable them to
intercalate within growing amyloid structures, preventing
further recruitment of monomers and promoting the dis-
solutionofaggregates.Alternatively,thesecompoundsmay
mimic the amyloid-binding properties of and/or compete
with endogenous amyloid-stabilizing proteins. Certain
endogenous proteins (and metal ions) associate with and
promotethestabilityofamyloid in vivo,includingheparin
sulphateproteoglycans,APoe,APoJ(alsoknownasclus-
terin), α1-antichymotrypsin, complement factors, serum
amyloid P (SAP), copper and zinc.
A potential concern with this class of compounds
is that mimicking the properties of amyloid-stabilizing
proteins could also promote aggregation of amyloid-
forming proteins. This may partially explain the conflict-
ing results on the efficacy of these compounds on PrPSc
aggregationacrossstudiesandindifferentmodelsystems.
An interesting alternative approach may be to deplete
endogenous levels of amyloid-stabilizing proteins. For
example, successful depletion of SAP from serum and
cerebrospinal fluid of patients with Alzheimer’s disease
has been achieved using subcutaneous injections of the
compound CPHPC (R-1-[6-[R-2-carboxy-pyrrolidin-
1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid),
which binds SAP and targets this peptide for hepatic
degradation136
.
Another class of drugs that may prevent the aggrega-
tion of PrPSc
are the antimalarial compounds quinacrine
and chloroquine137–139
. These drugs localize to lysosomes,
the cellular compartment in which PrPSc
accumulates,
and presumably interfere with the interaction of PrPC
with PrPSc
and the formation of PrPSc
aggregates.
However, antimalarial compounds also interfere with
lysosomal function. As lysosomes might be involved in
degrading endogenous PrPC
, these drugs have the poten-
tial to prolong PrPC
half-life, thereby promoting PrPC
–
PrPSc
interaction and the conversion of PrPC
to PrPSc
.
This might explain why some studies have reported an
accelerated disease course and enhanced PrPSc
depo-
sition following administration of antimalarial com-
pounds140,141
. Despite these conflicting data about the
efficacy of antimalarial drugs in preventing PrP aggre-
gation, quinacrine was recently tested in a clinical trial
of patients with Creutzfeldt–Jakob disease. The drug was
reasonably well tolerated, but it did not have a significant
effect on the course of prion disease142
.
A viable alternative strategy could be to develop agents
thatcompetewithendogenousamyloid-stabilizingproteins
using a compound or peptide that cannot be incorporated
into aggregates and has no known amyloid-stabilizing
properties. The effectiveness of this approach has been
demonstrated by transgenic overexpression of a soluble
form of PrP (PrP-Fc), which significantly delayed incu-
bation time following prion inoculation132
. A similar
mechanismmightunderlietheactionofseveralotheranti-
aggregationcompounds.Forexample,proteinXmimetics
of PrP are compounds designed to interact with and block
PrP amino acids that are thought to comprise the binding
site of an unknown endogenous protein required for the
conversion of PrPC
to PrPSc
(REFS 143,144). Compounds
known as β-sheet breakers contain sequences from tar-
get amyloid-forming proteins plus additional proline
residues designed to interfere with amyloid formation145
.
Similar compounds have been developed to interfere with
the interaction of Aβ and APoe or Aβ and SAP146–148
.
Additionally, the ability of Congo red to interfere with
amyloid formation in some studies raises the intriguing
possibilitythatcommonlyusedamyloiddiagnosticorbio-
chemical tools may also have therapeutic applications. An
example of one such tool is luminescent conjugated poly-
mers (LCPs), which bind amyloids in a manner similar
to Congo red or thioflavin but are sterically more flexible
thanthesecompounds,perhapsmakingthemlesslikelyto
stabilize amyloid conformations149,166
. Interestingly, com-
pounds that block amyloid aggregation may ultimately
reach the clinic for the treatment of systemic amyloidoses
(which do not have the additional requirement for com-
pounds to cross the BBB) long before neurodegenerative
disorders. For example, two such compounds for the
treatmentofATTRamyloidosis(tafamidisfromFoldRx150
andscyllo-inositolfromelan)arecurrentlyinPhaseIIand
III clinical trials.
REVIEWS
10

a Physiological levels of oligomers b Pathological levels of oligomers
Cytoplasm
Lysosome
Lysosomal
enzymes
Toxic oligomer
PrPc
Conformationally
altered PrP
Lipid
raft
Long-term potentiation
A persistent increase in
synaptic response following
repeated stimulation of a
neuron, which is thought to
be associated with synaptic
plasticity and the acquisition
of memories.
The prion protein as an aggregate receptor: the normal
function of PrPC
revealed? Another fascinating impli-
cation of the toxic-oligomer theory is that specific cell
surface receptors could trigger neuronal dysfunction
and/or neuronal apoptotic pathways following binding
of oligomeric species. This concept is not new to the
prion field: it has long been known that PrPSc
-mediated
neuronal toxicity is completely abrogated in the absence
of Prnp expression, even in experimental paradigms in
which PrPSc
can still accumulate151–153
.
Intriguingly,arecentstudyhasclaimedthatendogenous
PrPC
may be one of the cell surface receptors mediating
synaptic dysfunction associated with oligomeric Aβ154
.
In this study, PrPC
was identified in an expression clon-
ing screen for proteins that could enhance oligomeric
Aβ binding to the surface of CoS-7 cells. Furthermore,
it was shown that the absence of PrP expression partially
rescued Aβ oligomer-mediated deficits in long-term
potentiation. Conformation-specific antibodies that rec-
ognize oligomeric forms of Aβ also seem to be capable
of recognizing the oligomeric forms of other amyloid-
forming proteins, indicating that oligomers of diverse
proteins have common structural motifs, similar to
mature amyloid fibrils. This observation suggests the
interesting possibility that PrPC
might be capable of
binding other oligomeric species and function physio-
logically as a general ‘aggregation receptor’ for a wide
range of amyloid-forming proteins.
Several seemingly unrelated observations support this
hypothesis. For example, PrPC
is a glycosylphosphatidyl-
inositol-anchored protein and therefore a permanent
resident of lipid rafts155,156
. If PrPC
is an aggregation detec-
tor, this could explain why oligomerization increases the
affinity of proteins for lipid rafts157
. Furthermore, it has
been shown that endosomes containing lipid rafts are
preferentially targeted to the lysosomal pathway rather
than recycling to the cell surface158
, which implies that
PrPC
binding of protein aggregates could target these
aggregates for degradation. So, at what point does pro-
tein aggregation become toxic? one possibility is that, at
sufficient concentrations, extracellular protein aggregates
may cause clustering of PrPC
, leading to a conformational
change in PrP secondary structurethat activatesapoptotic
pathways. This hypothesis is supported by several lines
of evidence indicating that aggregation and/or conforma-
tional change of PrPC
triggers a pro-apoptotic signalling
cascade134,159–161,167
. Alternatively, internalization and lyso-
somal accumulation of insoluble aggregates might also be
toxic (FIG. 5). Regardless of the precise mechanism, it is
an intriguing idea that PrPC
may serve as a general cell
surface aggregation detector, and it could have important
therapeutic consequences. First, this theory implies that
oligomeric species from diverse aggregation disorders
mayalltriggercellulartoxicitythroughcommonpathways.
Second,itraisesthepossibilitythatPrPC
-targetedtherapies
might be broadly applicable to many amyloidoses.
The future of amyloid therapeutics
Although many challenges remain for amyloid therapeu-
tics, the field is steadily moving forward thanks to vigor-
ous and innovative research efforts. encouraging results
from animal models and several promising immuno-
therapies, secretase inhibitors and anti-aggregation
compounds that are currently in clinical trials provide
hope that the first disease-modifying treatments for
amyloidoses may soon become available.
Figure 5 | Possible roles of PrPc
in oligomer-mediated toxicity. a | Normally folded prion protein (PrPC
) is a glyco-
phosphatidylinositol -anchored cell surface protein and a permanent resident of lipid rafts. The physiological function
of PrPC
is unknown; however, an intriguing possibility is that cell surface PrPC
may bind potentially toxic extracellular
oligomeric species and target them to the lysosome for degradation. b | At high, pathological concentrations, toxic
oligomers may induce clustering of and/or a conformational change in cell surface PrPC
. This may lead to the direct
induction of cell death pathways. Alternatively (or in combination), PrPC
-mediated lysosomal accumulation of
oligomers may induce cellular toxicity.
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Acknowledgements
Stained sections from human Alzheimer’s diseased brains,
prion-diseased brains, kidney amyloidosis, and the PrPSc
histo-
blot were provided courtesy of J. Haybaeck, H. Fischer, V. Kana
and M. Heikenwälder of the Institute for Neuropathology at
the University Hospital of Zürich, Switzerland. The Aguzzi labo-
ratory is supported by grants of the Ernst-Jung-Foundation,
the Stammbach foundation, the EU (LUPAS, PRIORITY), the
Swiss National Science Foundation, a Sinergia grant, and the
National Competence Center on Neural Plasticity and Repair.
A.A. is a recipient of an Advanced Grant of the European
Research Council.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
OMIM: http://www.ncbi.nlm.nih.gov/omim
Alzheimer’s disease | Creutzfeldt–Jakob disease |
fatal familial insomnia | Gerstmann–Sträussler–Scheinker
syndrome | Huntington’s disease | Parkinson’s disease
UniProtKB: http://www.uniprot.org
APP | BACE1 | PrP | PS1 | SAP | tau
FURTHER INFORMATION
Adriano Aguzzi’s homepage: http://www.en.usz.ch/
MedicalServices/DeptPathology/Pages/Neuropathology.aspx
All links Are AcTive in The online PDf
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