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Life expectancy has increased substantially in past
decades, owing to general improvements in lifestyle
and medication; however, the ensuing prominent
demographic upward shift in age distribution has led
to an increased prevalence of diseases such as cancer
and dementia. Many treatment options, ranging from
surgery and radiotherapy to tailored pharmacological
and hormonal treatments, are now available for cancer.
However, the treatment of dementia has remained
symptomatic, and despite a large number of costly
trials, no single drug or treatment strategy has been
approved. Several reasons have been put forward to
explain this failure: selection of inappropriate popula-
tions of patients; suboptimal dosing or drug exposure
(‘too little, too late’); the challenge of defining suitable
primary end points for such trials, which reflects the
poor sensitivity of clinical instruments; and the lack of
a detailed understanding of the causes of dementia —
more specifically, an incomplete understanding of the
role that distinct forms of amyloid-β (Aβ) and tau have
in neurodegenerative disease and dementia — the major
topic of thisReview.
Dementia is marked by memory disorder, personal-
ity changes and impaired reasoning. Clinically, dementia
can have many causes, but its most prevalent form by far
is Alzheimer disease (AD), which affects an estimated
47 million people worldwide and accounts for 60–80%
of all patients with dementia. By 2050, the prevalence of
AD is expected to quadruple, and 43% of these patients
will need high levels of care1. Other prevalent forms of
dementia are dementia with Lewy bodies (DLB) and
frontotemporal dementia (FTD, the pathological hall-
mark of which is frontotemporal lobar degeneration
(FTLD)), a progressive neurodegenerative disorder
that includes semantic dementia, progressive non fluent
aphasia and behavioural variant subtypes within its spec-
trum. Dementia is also present in movement disorders
such as Parkinson disease (TABLE 1). The over arching
feature of all these conditions is the accumulation of
insoluble protein deposits in the brain. Most current
therapeutic strategies for these diseases are based on the
assumption that these proteins and their aggregation do
not constitute an epiphenomenon but in fact are causal
and drive its progression2.
Characteristic of these disorders is the propensity of
key proteins to form oligomers that act as a template or
nucleus for the conversion and co-aggregation of endo-
genous proteins, which eventually form fibrils3. The
two key molecules implicated in AD are Aβ (FIG.1) and
tau (FIG.2). Aβ is a small peptide derived by proteolytic
Clem Jones Centre for Ageing
Dementia Research
(CJCADR), Queensland Brain
Institute (QBI), The University
of Queensland, St Lucia
Campus — Brisbane, Upland
Road, Building 79, Brisbane,
Queensland 4072, Australia.
Correspondence to J.G.
j.goetz@uq.edu.au
doi:10.1038/nrneurol.2017.162
Published online 15 Dec 2017
Amyloid‑β and tau complexity
— towards improved biomarkers
and targeted therapies
Juan Carlos Polanco, Chuanzhou Li, Liviu-Gabriel Bodea, Ramon Martinez-Marmol,
Frederic A.Meunier and Jürgen Götz
Abstract | Most neurodegenerative diseases are proteinopathies, which are characterized by the
aggregation of misfolded proteins. Although many proteins have an intrinsic propensity to
aggregate, particularly when cellular clearance systems start to fail in the context of ageing, only
a few form fibrillar aggregates. In Alzheimer disease, the peptide amyloid‑β (Aβ) and the protein
tau aggregate to form plaques and tangles, respectively, which comprise the histopathological
hallmarks of this disease. This Review discusses the complexity of Aβ biogenesis, trafficking,
post‑translational modifications and aggregation states. Tau and its various isoforms, which are
subject to a vast array of post‑translational modifications, are also explored. The methodological
advances that revealed this complexity are described. Finally, the toxic effects of distinct species
of tau and Aβ are discussed, as well as the concept of protein ‘strains’, and how this knowledge
can facilitate the development of early disease biomarkers for stratifying patients and validating
new therapies. By targeting distinct species of Aβ and tau for therapeutic intervention, the way
might be paved for personalized medicine and more‑targeted treatment strategies.
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cleavage from amyloid precursor protein (APP); aggre-
gates of Aβ form histological lesions known as amyloid
plaques. Amyloid plaques are also prevalent in patients
with DLB. Tau is a microtubule-associated protein
(MAP) that forms neurofibrillary tangles. Tau pathol-
ogy is found not only in AD but also in many other dis-
eases, collectively termed tauopathies. The tauopathies
include an important subset of FTLD, termed FTLD-tau.
Although tau is mainly a neuronal protein, patients with
corticobasal degeneration and progressive supra nuclear
palsy also show prominent glial tau pathology. All these
diseases can be either sporadic or familial4.
The vast majority of AD cases are sporadic. In famil-
ial AD, disease-causing mutations have been identified
in several genes linked to Aβ formation, including APP
itself, as well as PSEN1 and PSEN2 (encoding preseni-
lin 1 and presenilin 2, respectively), whereas in familial
FTLD-tau, disease-causing mutations have been iden-
tified in the tau-encoding MAPT gene5. Together, this
genetic and histological evidence has established a role
for both tau and Aβ in AD, leading to the generation
of transgenic animal models that reproduce important
aspects of the human pathology and have been used
to study therapeutic strategies6. Because sporadic and
familial AD do not differ histologically or clinically
(except for the earlier age of onset in familial AD),
research has been guided by the assumption that a thera-
peutic strategy validated in models of familial AD would
also be of value in sporadicAD.
In this Review, we explore what is known about the
physiological roles of Aβ and tau and describe how
things go wrong in disease. We focus on the increasing
understanding that these molecules come in a vast vari-
ety of forms and assembly states, not all of which are
toxic. We explain how advancing our knowledge of dis-
tinct Aβ and tau species and their biological effects could
facilitate the development of improved biomarkers and
targeted therapies. Finally, we describe refined methods
for detecting proteinopathies and review what AD has
in common with other proteinopathies.
Physiological roles of APP, Aβ and tau
APP is a typeI transmembrane glycoprotein composed
of a large metal-binding and heparin-binding ecto-
domain, a single membrane-spanning domain and a
short cytoplasmic tail. Two paralogues exist, amyloid-
like proteins 1 and 2 (APLP1 and APLP2, respectively)7,
which, unlike APP, lack the Aβ sequence. Mice deficient
in any single APP family member are viable; however,
double-knockout mice (either APP–/–APLP2–/– or
APLP1–/–APLP2–/–) die early in postnatal life, suggesting
redundancy between APLP2 and the other two family
members8. Although APP is also expressed in many
peripheral organs, most studies have been conducted in
the brain9, where APP and its cleavage products have
important roles in neurogenesis, plasticity and synap-
tic function as well as the cellular stress response10–13.
Under conditions of metabolic stress, such as acute
hypoxia, release of the APP extracellular domain, solu-
ble APPα (sAPPα), contributes to calcium homeostasis
in a process involving voltage-gated calcium channels14,
whereas another APP cleavage product, AICD (APP
intracellular domain), has a role in lipid biosynthesis15
(FIG.1). Importantly, Aβ production is a normal physio-
logical process that is enhanced by synaptic activation
and plasticity16,17. Aβ also contributes to lipid homeo-
stasis by directly binding to and transporting choles-
terol18, but the vast majority of studies have focused on
its toxicproperties.
Tau belongs to the MAP family, which also includes
MAP2 and MAP4. Unlike MAP4, which is expressed in
many tissues, MAP2 and tau are predominantly found
in neurons. In the adult brain, MAP2 is mainly localized
to cell bodies and dendrites, whereas tau is abundant in
axons, although it is (albeit at much lower levels) also
found in the soma and dendrites. A sole MAP homo-
logue, the microtubule-associated protein PTL-1 (pro-
tein with tau-like repeats), is present in the roundworm
Caenorhabditiselegans, where it regulates ageing of the
organism and its nervous system19. In humans, tau is
encoded by a single gene on chromosome 17q21.31
that spans 16 exons. Alternative splicing gives rise to
six major brain isoforms, which differ with regard
tothe number of insertions in the projection domain
(0N, 1Nand 2N) within the amino-terminal half of the
peptide, and the presence of either three or four highly
conserved microtubule-binding repeat domains (3R
or 4R) in its carboxy-terminal half (TABLE2). Natively
unfolded in solution, tau is post-translationally modi-
fied at many sites under physiological conditions, pri-
marily via phosphorylation20, which causes tau to adopt
a paper-clip conformation and bind to microtubules21.
Increased phosphorylation reduces the affinity of tau
for micro tubules (FIG.2g), and these changes provide
tauwith the dynamic properties essential for neu-
ronal plasticity. Interestingly (and reminiscent of Aβ),
endogenous tau is released in response to neuronal
activity22–24, but the physiological relevance of this
observation remains elusive. Tau has also been local-
ized to the nucleus, where it might have a role in main-
taining DNA integrity25 (FIG.2a). Although tau has been
largely perceived as a microtubule-stabilizing protein,
Key points
• Alzheimer disease belongs to the group of proteinopathies; it is characterized by
deposition of the peptide amyloid‑β (Aβ) as amyloid plaques and of the protein tau
asneurofibrillary tangles
• Aβ neurotoxicity is attributable to specific types of Aβ, generated as a consequence
ofproteolytic cleavage and post-translational modifications, which are susceptible
toaggregation into different assembly states
• Similar to Aβ, tau exists as multiple brain isoforms that undergo aggregation and is
subject to a host of post‑translational modifications, including phosphorylation and
acetylation
• Impairment of multiple cellular functions by Aβ and tau has been demonstrated in
cellular and transgenic models, and crosstalk between these molecules has been
demonstrated, particularly at the synapse
• Assessment of Aβ and tau pathology is being facilitated by increasingly sensitive
methods, which have clinical relevance in diagnosis and in the validation of
therapeutic interventions in disease
• A prerequisite for personalized medicine is the identification of distinct Aβ and tau
species that are suitable for use as biomarkers in cerebrospinal fluid, blood, urine
andsaliva
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when tau is genetically knocked out in mouse models,
microtubules do not destabilize, possibly because of
compensatory mechanisms involving other MAP family
members26. Moreover, given the lack of overt neurologi-
cal impairment in tau-knockout mice (unless the mice
reach an advanced age), reducing tau levels has been
proposed as a suitable treatment strategy for AD20,27.
Therefore, perhaps the best descriptor of tau is that its
various isoforms act as versatile scaffoldingproteins28.
Aβ species and assembly states
Formation and intracellular location. Several APP
isoforms exist: the predominant neuronal form is
APP695, whereas astrocytes and microglia also express
APP751 and APP770 (REF 29). Most aspects of APP pro-
cessing have been studied in non-neuronal cells, which
lack the compartmentalization and long processes
of neurons30,31. However, APP processing occurs in
many neuronal compartments, including axons, nerve
terminals and dendrites, giving rise to a variety of
biologically active fragments (FIG.1; TABLE2).
In the nonamyloidogenic (that is, non-Aβ- forming)
APP-processing pathway, which is stimulated by
synaptic activity32, surface APP is mainly cleaved
by the α-secretase disintegrin and metalloprotein-
ase domain-containing protein 10 (ADAM10)33,34.
Upon release of sAPPα into the extracellular milieu,
a short piece of APP (α-secretase C-terminal frag-
ment (α-CTF), also known as C83) remains inserted
in the membrane (FIG.1). This fragment is recognized
by the γ-secretase complex, which performs an endo-
peptidase-like ε-cleavage that leads to the intracellular
release of AICD and a carboxypeptidase-like γ-cleavage
that generates the p3 fragment35. Because the initial
α-cleavage occurs within the Aβ region, Aβ formation
is precluded.
The canonical amyloidogenic pathway (which leads
to Aβ formation) posits that surface APP that has not
undergone α-cleavage is internalized into endosomes,
where it is cleaved by β-secretases 1 and 2 (BACE1 and
BACE2, respectively) at a site that becomes the amino
terminus of Aβ36. The long β-secretase C-terminal
fragment (β-CTF, also known as C99) remains teth-
ered to the membrane, whereas soluble APPβ (sAPPβ)
is released (FIG.1). The γ-secretase complex initially
cleaves β-CTF via endoproteolytic ε-cuts, generating
AICD and the two species Aβ48 and Aβ49. These two
peptides are further processed by γ-secretase, which
makes exoproteolytic γ-cuts at every three to four resi-
dues within the hydrophobic sequence, forming shorter
peptides: Aβ48 gives rise to Aβ45, Aβ42 and Aβ38,
whereas Aβ49 gives rise to Aβ46, Aβ43andAβ40
(REFS 37,38). Other even shorter (rare) cleavage
products have also beenidentified37,38.
APP processing is tightly regulated, and secretases
are trafficked together with APP through the secretory
pathway along dendrites and axons and into presynap-
tic boutons39. The interaction between BACE1 and APP
occurs in all these compartments, and neuronal activ-
ity potentiates the convergence of these enzymes and
their substrates in the same recycling endosomes40. On
the other hand, active γ-secretase resides in late recyc-
ling endosomes, lysosomes, the trans-Golgi network
and plasma membrane41 (FIG.1). Similar to BACE1, the
γ-secretase complex undergoes exocytosis to reach the
plasma membrane, followed by endocytosis and retro-
grade trafficking to reach its final active compartments,
predominantly the trans-Golgi network42. The mito-
chondria-associated endoplasmic reticulum membrane
has received increasing attention, as the γ-secretase
complex is highly active in this compartment43 (FIG.1)
and the function of this membrane is perturbed in cells
from patients with AD44. Although Aβ can be secreted
both presynaptically and postsynaptically45, the major-
ity of axonally secreted fragments are endocytosed in
the soma, processed and then transported to the pre-
synapse46. Other noncanonical (δ-secretase, meprin-β,
η-secretase and caspase) APP-processing pathways are
beginning to be explored, but their influence on disease
is not yet clear47,48.
Post-translational modifications. Aβ isolated from
AD brains shows a variety of post-translational
modifi cations at the amino terminus, including oxi-
dation, pyroglutamylation, phosphorylation, nitration,
racemiz ation, isomerization and glycosylation, which
can all modify the oligomerization and fibril-forming
properties of the peptide49. TABLE2 summarizes these
different species, and BOX1 presents selected modes
of toxicity. Oxidation of the sulfur atom of Met35 to
sulfoxide facilitates the formation of ion-channel-like
complexes of Aβ in lipid membranes50, which might
not then be available for protofibril and fibril forma-
tion51. Pyroglutamate modification of Aβ has been
reported invivo at positions 3 and 11 (3 pR-Aβ and
11 pE-Aβ, respectively)52,53 and increases the propensity
of Aβ to aggregate invitro54,55. Formation of 11 pE-Aβ
requires the enzyme glutaminyl cyclase, expression of
which is increased in AD56. Phosphorylation of Aβ at
Ser8 favours the formation of oligomeric aggregates
Table 1 | Proteinopathies associated with neurodegenerative diseases
Disease* Aggregating
protein(s)
Propagation of pathology invitro and
invivo
Alzheimer disease Amyloid‑β,
tau147
• Seeding (amyloid‑β236,237 and tau121–123,137)
• Spreading (amyloid‑β238,239 and tau136,138,147,240)
Parkinson disease
dementia with Lewy
bodies
α‑Synuclein Seeding241–243 and spreading244–246
Amyotrophic lateral
sclerosis
SOD1, TDP43,
FUS
• Seeding (SOD1 (REF.247) and TDP43
(REFS248,249))
• Spreading (SOD1 (REF.247))
Frontotemporal
dementia
Tau, TDP43,
FUS
Spreading (TDP43 (REFS250,251) and FUS252)
Huntington disease Huntingtin Seeding253–255 and spreading256,257
Prion diseases‡PrP Seeding258–260 and spreading261,262
FUS, RNA‑binding protein FUS; PrP, major prion protein; SOD1, superoxide dismutase 1;
TDP43, TAR DNA‑binding protein 43. *All have sporadic and familial forms4. ‡Prion diseases are
infectious, meaning that the aggregated proteins can transmit the propensity to aggregate to
other proteins of the same species, leading to disease in a manner that is epidemiologically
comparable to the spread of viral infection.
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with increased resistance to degradation, which have
been found in AD mouse models as well as in patients
with AD57,58. Nitrated Aβ is found in the core of amy-
loid plaques and might initiate plaque formation59.
Finally, Aβ O-glycopeptides have been identified in the
cerebrospinal fluid (CSF) of patients with AD; however,
only short Aβ peptides were glycosylated. No modi-
fied Aβ40 or modified Aβ42 was detected, suggesting
that O-glycosylation affects the ability of γ-secretase
to cleaveAPP60.
Figure 1 | Pathways of amyloid precursor protein processing and amyloid‑β generation. Full‑length amyloid precursor
protein (APP) is synthesized in the endoplasmic reticulum (ER), where it undergoes folding (step 1). APP undergoes
post‑translational modification, first in the ER and then in the Golgi (step 2). APP then undergoes anterograde transportation
through secretory vesicles into presynaptic and postsynaptic compartments (step 3). In the non‑amyloidogenic pathway, APP
reaches the plasma membrane where it is cleaved by the α‑secretase disintegrin and metalloproteinase domain‑containing
protein 10 (ADAM10), generating soluble APPα (sAPPα) and α‑secretase C‑terminal fragment (α‑CTF; also known as C83)
(step 4). Full‑length APP and α-CTF are internalized by clathrin‑dependent (CD) endocytosis, whereas the lipid‑raft‑resident
β‑secretases 1 and 2 (BACE1 and BACE2, respectively) are internalized by clathrin‑independent (CI) endocytosis (step 5).
β‑secretases, which initiates the amyloidogenic pathway: APP is cleaved into soluble APPβ (sAPPβ) and β‑secretase
C‑terminal fragment (β-CTF; also known as C99). Both nonprocessed, full‑length APP and sAPPβ can be reinserted into the
plasma membrane through recycling endosomes. The β-CTF fragment can be trafficked via the endocytic pathway to the
trans-Golgi network and the ER, as well as to late endosomes, multivesicular bodies (MVBs) and lysosomes (step 6). Trafficking
of the γ‑secretase components is complex, but the final γ‑cleavage of APP probably takes place in mitochondria‑associated
ER membranes (MAMs), MVBs and lysosomes (step 7). There, β-CTF is recognized by the γ‑secretase complex and cleaved to
generate the APP intracellular domain (AICD) and amyloid β (Aβ) peptides. In the formation of amyloid plaques, Aβ
monomers exist in equilibrium with higher‑molecular‑mass aggregates (dimers, trimers and oligomers) (step 8).
Nature Reviews | Neurology
Recycling
endosome
CD endocytosis CI endocytosis
APP
AICD
sAPPα
sAPPβ
α-CTF (C83)
β-CTF (C99)
Aβ
ADAM10
BACE1, BACE2
γ-Secretase
complex
Aβ-monomer
Aβ-dimer Aβ-trimer Aβ-oligomer
Lipid bilayer
Lipid ra
Nucleus
ER
ER
MAM
MVB
Lysosomes
Golgi
1
2
3
4
5
6
7
7
7
8
Amyloid
plaque
G
3
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Long‑term potentiation
A cellular mechanism
underlying learning and
memory that involves a
persistent increase in synaptic
strength following
high-frequency stimulation.
Sumoylation
A post-translational
modification involving
conjugation with small
ubiquitin-like modifiers
(SUMOs).
Assembly states. Adding to this complexity, several Aβ
assemblies, ranging from dimers to trimers, dodeca-
mers and multimers, have been identified invitro and
invivo61–63 and broadly categorized into two types64
(TABLE2). Type1 oligomers do not develop into larger
assemblies62; these include dodecamers (previously
described as Aβ*56 on the basis of their 56 kDa size).
Type1 oligomers appear early in AD, whereas type2
oligomers appear only after plaques have formed; at
the plaque surface, type2 oligomers self-organize into
small, stable structures with a parallel β-sheet architec-
ture. Conformation-specific anti-Aβ antibodies (A11
and OC, respectively) have facilitated the identification
of type1 and type2 oligomers65.
The specific process that leads to plaque formation
is only incompletely understood. When Aβ is secreted
into the extracellular space, it aggregates to form amyloid
plaques (FIG.1). Plaques can also be formed inside cells
upon internalization of Aβ; formation of intracellular
plaque is associated with a disturbance of multivesicular
bodies that precedes cell death66. Overall, the existence of
such a broad variety of Aβ species and aggregation states
suggests that patient-specific differences affect disease
progression and therapeutic outcomes.
How Aβ impairs neuronal function
In this section, we discuss cellular functions that are
impaired by distinct Aβ species and assemblies as well
as the cellular compartments where such disturbance
occurs (TABLE2). Early efforts aimed to determine
whether amyloid plaques (the end-stage lesions of AD)
were toxic and to discriminate between monomeric,
oligo meric and fibrillar forms of Aβ. Initially, plaque bur-
den (as distinct from neurofibrillary tangles) was thought
not to correlate with AD severity67; however, when all
plaques (rather than just limbic and neocortical ones) are
considered, amyloid deposition that has progressed to
involve the striatum is highly predictive of dementia68,69.
Amyloid plaques are not inert, as surrounding neurons
exhibit clear symptoms of toxicity, including elevated
calcium levels, dystrophic neurites and synaptic loss70.
The concept of soluble toxic oligomers (also termed
Aβ-derived diffusive ligands) has gained broad accept-
ance71. Type1oligomers can travel through the brain,
whereas type2 oligomers are confined to the vicinity
of plaques. Thus, type1 oligomers are more likely than
type2 oligomers to interfere with synaptic function and
cause cognitive deficits (TABLE2). Plaques might also act
as a reservoir of neurotoxic Aβ species that coexist in a
dynamic equilibrium with potentially inert fibrils (FIG.1).
Levels of the type1 oligomer Aβ*56 in mouse models and
in human samples correlate with cognitive impairment
and pathological tauaccumulation72.
Of the different Aβ species, Aβ42 is much more toxic
than Aβ40, possibly because of the stronger tendency of
Aβ42 to aggregate73. Whereas Aβ40 can inhibit Aβ42 oli-
gomerization74, both species are thought to drive plaque
formation and neurotoxicity (TABLE2). Nitrated Aβ can
suppress long-term potentiation to a greater degree than
unmodified Aβ75,76; however, the toxicity of any Aβ spe-
cies is ultimately related to its concentration. Aspartate
residues in Aβ can spontaneously isomerize, forming
isoaspartate, which is particularly resistant to enzymatic
degradation77. This feature might explain why levels of
isoaspartyl-modified Aβ are higher in older plaques than
in younger ones and exhibit a positive correlation with
dementia severity78. Little is known about the toxicity of
other Aβ species, with the exception of pyroglutamylated
Aβ. When glutaminyl cyclase (which is required to gen-
erate 11 pE-Aβ) was downregulated in mouse models of
AD, Aβ40 and Aβ42 levels, plaque burden and inflam-
matory reactions were all reduced, concomitant with an
improvement in learning79 (TABLE2). Thus, different Aβ
species have seemingly different effects.
As we discuss further below, the AD field has received
a lot of input from work on prions, the protein agents
that cause transmissible spongiform encephalopathies80.
One of the most intriguing findings is the existence of
different prion strains with unique biochemical profiles
and clinical features. Although the proteins implicated in
AD have so far not been convincingly demonstrated to be
infectious in the same way that prions are, the evidence of
their unique biochemical profiles has lent support to use
of the same terminology. By 2005, different Aβ40 fibril
morphologies had already been linked to distinct toxi-
cities in cell culture81. Furthermore, in a study of Aβ40
extracted from two different patients, each Aβ40 ‘strain’
was found to have a single predominant fibril structure,
which also suggested that certain structures are more
pathogenic than others82. Nuclear magnetic resonance
measurements of Aβ40 and Aβ42 fibrils prepared by
seeded growth from AD brain extracts suggested that
a rapidly progressive form of AD is related to a specific
fibrillar Aβ structure83. Similarly, an earlier study had
reported increased levels of distinctly structured Aβ42
particles composed of 30–100 monomers, and reduced
levels of particles composed of <30 monomers, in brain
samples from patients with rapidly progressive AD84.
However, what leads to these different profiles and how
they might affect the development or progression of AD
is not really understood.
Synaptic toxicity. The synapse is a major compartment
where Aβ exerts its toxicity, and because synaptic loss is
a better correlate of cognitive impairment in AD than
plaque burden, AD has been termed ‘a synapse failure’
(REF.85). Synaptic plasticity involves AMPA (α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid) and
NMDA (N-methyl--aspartate) receptors (AMPARs
and NMDARs, respectively), which induce long-term
potentiation. Both synthetic and naturally secreted Aβ
oligomers, but not fibrils, reduce long-term potenti ation
in brain slices and invivo86, although the underlying
mechanisms are not fully understood. Aβ can indirectly
activate and directly bind to NMDARs and AMPARs
and decrease levels of the adaptor protein postsynaptic
density protein 95 (PSD95, also known as DLG4), which
further negatively regulates these receptors through endo-
cytosis and a reduction in the expression of receptor sub-
units87,88. Long-term potentiation also generally involves
post-translational modifications, including sumoylation,
and this process is impaired by oligomeric Aβ42 (REF.89).
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Heterochromatin
a Tau-mediated chromatin relaxation b AMPAR-mediated memory loss
e Reduced excitability mediated by
relocation of the AIS
g Axonal degeneration
d Physiological hindrance by NFTs
c Impairment of kinesin-dependent
transport
f Spreading of tau pathology
Transcription
5ʹ
5ʹ5ʹ
Kinesin
(+)
Tau seed Tau monomer
Aggregated
tau
Exosome
Synaptic
activity
Further
seeded
aggregation Dendritic postsynapse
Recipient
neuron
Donor
neuron
Tunneling
nanotube
AA
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
AA
A
A
A
A
A
A
AMPAR KIBRA
Acetylated tau
Distal shi
Start
AIS
End
Tau binds and
potentially
stabilizes
microtubules
F-actin
P
P
P
P
P
P
P
P
P
P
PPP
P
P
P
P
P
P
P
P
P
P
PPP
P
P
P
PP
P
PP
P
P
PPP
P
P
Phosphorylated
tau
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Mitochondrial dysregulation. Mitochondria, which regu-
late both energy metabolism and apoptotic pathways, are
another important target of Aβ toxicity. High numbers
of mitochondria are present in neurons, and they are
particularly enriched in synapses. Owing to their lim-
ited glycolytic capacity, neurons are highly dependent
on mitochondrial energy production90. All four major
aspects of mitochondrial function are compromised in
AD: oxidative phosphorylation; bioenergetics; mitochon-
drial dynamics (transport, fission and fusion); and mito-
phagy (removal of damaged mitochondria by autophagy).
Dysregulation of mitochondrial function leads to dis-
rupted synaptic transmission, apoptosis and, ultimately,
neurodegeneration. Aβ and tau both have discrete roles
inthis mitochondrial dysfunction91 (FIG.3). For example, in
a transgenic mouse model of AD, Aβ specifically impairs
complex IV of the oxidative phosphorylation system,
whereas tau impairs complex I (REF.92). Mitochondrial
impairment can be caused by both oligomeric and fibrillar
Aβ, whereas monomeric Aβ has no effect93.
Mitochondria are the major producers of damaging
reactive oxygen species (ROS) as well as targets of ROS
toxicity94. However, how oxidative stress is caused by Aβ is
only incompletely understood. One proposed mechanism
involves the ability of Aβ to bind metal ions (in particular
Cu2+ and Fe3+) and reduce them into species (notably Cu+
and Fe2+) that eventually promote lipid and protein per-
oxidation95. Aβ can also form pores in lipid membranes96,
facilitating the unregulated influx of Ca2+ ions and causing
upregulation of gating of various Ca2+release channels,
ultimately leading to cell death97,98. This pore-forming
mechanism of action is similar to that of some antibacte-
rial agents. Specific blockade of these Aβ pores can reduce
both Ca2+ influx and neuronal damage99.
Effects on microglia. Finally, glia have a role in Aβ toxicity.
Aβ oligomers and amyloid plaques initiate inflammatory
responses in the brain, leading to activation of astrocytes
and recruitment of microglia, processes that have been
widely reported in AD and related tauopathies100. So far,
a consensus view has not been reached on the effect of
specific Aβ species on microglial reactivity (and thus
on microglia-elicited neurotoxicity), but oligomers and
fibrils apparently stimulate different microglial activa-
tion pathways. Specifically, oligomeric Aβ might stimu-
late microglial cytokine and chemokine production while
decreasing their phagocytic capacity101,102. However, in a
2016 study, microglia engulfed synaptic material in adult
mouse brains when exposed to soluble Aβ oligomers,
and this process was dependent on complement recep-
tor 3 (REF.103). These inflammatory responses seem to
be downstream events in the pathogenic cascade inAD.
Tau species and assembly states
Formation and intracellular location. In the human
brain, tau exists as six major isoforms, with an equi molar
ratio of the 3R and 4R isoforms (TABLE2). Distortion of
the 3R:4R tau isoform ratio in either direction is well
known to be associated with distinct clinical manifesta-
tions of tauopathies; for example, corticobasal degener-
ation is associated with >4R tau, whereas Pick disease
is associ ated with >3R tau104. Why this is the case is still
not really understood. However, changes in the 3R:4R
ratio can impair multiple cellular functions, including
axonal transport of APP105, and a loss of splicing factors
(implicated in FTLD) results in changes in the tau iso-
form ratio106. These observations highlight an interest-
ing crosstalk between Aβ and tau pathologies, which is
discussed in more detailbelow.
Tau is generally perceived as an axonal protein; tau
toxi city occurs because pathological forms of tau accu-
mulate in compartments where tau levels are normally
low, such as the soma. These abnormal deposits of tau can
sequester other proteins and prevent them from executing
their physiological function. For example, in tau trans-
genic mice, hyperphosphorylated soluble tau impaired
the axonal transport of various cargoes, including mito-
chondria, by trapping the kinesin motor adaptor protein
Jun-amino-terminal kinase-interacting protein 1 (JIP1) in
the cell body107 (FIG.2c). The question of how the ‘axonal’
protein tau accumulates in the somatodendritic compart-
ment in AD has not yet been definitively answered, but
hyperphosphorylated tau in the axon is generally assumed
to detach from the microtubules and thereby become
capable of passing through the axon initial segment
(which serves as a diffusion barrier for physiologically
phosphory lated tau), enabling its accumulation in the cell
body and dendrites. As discussed below, an alternative,
more cogent mechanism has been discovered involving
denovo protein synthesis of tau in the soma108.
Post-translational modifications. Tau undergoes sev-
eral types of post-translational modifications, including
arginine monomethylation, lysine acetylation, lysine
monomethylation and dimethylation, lysine ubiqui-
tylation, serine O-linked N-acetyl-glucosamination
(O-GlcNAc) and serine, threonine or tyrosine phospho-
rylation20, which open new avenues to link distinct tau
species to particular modes of toxicity. Of these modi-
fications, phosphorylation and acetylation are by far the
mostcommon.
The longest human tau isoform contains 45 serine,
35 threonine and 5 tyrosine residues, any of which can
be potentially phosphorylated. Under physiological
Figure 2 | Different tau species attack neuronal physiology at various levels.
a
and an abnormal reactivation of gene transcription. b
postsynaptic kidney and brain protein (KIBRA) signalling, which is involved in the
regulation of synaptic plasticity, trafficking via the α‑amino‑3‑hydroxy‑5‑methyl‑4‑
isoxazolepropionic acid (AMPA) receptor (AMPAR) and memory formation.
c
cargoes, including mitochondria, mediated by microtubule‑dependent kinesin motor
proteins. d
biologically inert, slowly increase in size, thereby interfering with vital physiological
functions and eventually killing the neuron. e
microtubules and relocates the axon initial segment (AIS) distally, resulting in reduced
excitability and decreased action potential firing. f
trans-synaptic migration pathways, some of which are dependent on synaptic activity.
Small aggregates (tau seeds) corrupt endogenous tau in recipient neurons and
propagate tau pathology. g
which is thought to destabilize them, resulting in axonal degeneration.
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conditions, a mole of tau contains on average two to
three moles of phosphate; under pathological conditions,
tau can contain as many as seven to eight moles of phos-
phate109. In this situation, termed hyperphosphorylation,
some residues are phosphorylated to a higher degree
than in the healthy brain, and others are denovo phos-
phorylated. In cell lines, recombinant tau derived from
healthy human brain promotes the assembly and bun-
dling of microtubules, whereas hyperphosphorylated tau
(isolated from AD brain cytosol) inhibits microtubule
assembly and disrupts existing microtubule networks
by sequestering normal brain tau and MAP2 (REF. 110 ).
For many years, the focus of tau research has been on
the phosphorylation of serine and threonine, which is
common in pathologically hyperphosphorylatedtau20.
Hyperphosphorylation, brought about by the
increased activity of kinases and decreased activity of
phosphatases, is thought to be a prerequisite for the
accumulation of fibrillar tau in the somatodendritic
domain. Phosphorylation of distinct serine and threo-
nine epitopes also drives tau localization to spines111,112.
Tyrosine phosphorylation is mediated by several SRC
kinases, in particular tyrosine-protein kinase FYN113,
which interacts via its SH3 domain with SH3-binding
sites (PXXP motifs) in tau and phosphorylates tau at
Tyr18 (REFS113 ,11 4 ). Tyr18 phosphorylation of tau by
FYN facilitates its direct interaction with the SH2 domain
ofFYN115.
In AD, tau also undergoes acetylation (discussed
below), ubiquitylation, methylation, glycation, nitration
and truncation116–120. Unfortunately, the investigation of
human AD tissue or that of transgenic animals typi-
cally involves only a small number of antibodies, each
of which detects a distinct post-translationally modi-
fied epitope in tau; for example, the AT8 antibody
recognizes tau phosphorylated at both Ser202 and
Thr205. By necessity, such experiments do not provide
a comprehensive map of tau modifications.
Assembly states. The critical steps leading to tau aggre-
gation in AD as a consequence of post-translational
modifications are not fully understood. As cytoplasmic
tau levels increase, tau aggregates and eventually forms
insoluble filaments that fill the entire soma, leading
to neurofibrillary tangles and neuropil threads. Fibril
formation itself occurs as a result of transition from a
random-coil architecture to the β-sheet structure typical
of all amyloid fibrils121.
The microtubule-binding repeat domain in tau —
more specifically the PHF6 hexapeptide (VQIVYK) motif
located at the beginning of the third microtubule-binding
repeat in all tau isoforms — is pivotal for tau nucleation
invitro122. Surprisingly, a 31-residue peptide containing
the VQIVYK motif was able to induce tau aggregation in
HEK-293 cells expressing a fluorescence-tagged version
of tau123. This hexapeptide was hidden (that is, conforma-
tionally inaccessible) in mono meric tau that lacked seed-
ing capacity but was exposed in tau molecules with the
ability to seed and self- assemble124. Therefore, antibodies
that target the VQIVYK motif might prevent tau aggre-
gation. Cysteine residues in tau can form intramolecu-
lar disulfide bonds, which also have a critical role in tau
aggregation125. Consequently, small molecules that bind
to cysteine and block disulfide bond formation might
prevent tau oligomerization and consequently the forma-
tion of insoluble tau aggregates. These molecules provide
a promising new therapeutic option in the management
of tauopathies125.
Tau initially forms oligomers, similarly to Aβ126,
and oligomeric tau induces synaptic dysfunction and
memory loss before fibril formation127. Such a role
is supported by the fact that the anti-tau oligomer-
specific monoclonal antibody, TOMA, both prevents
and reverses the cognitive deficits associated with
tau pathology, again without affecting neurofibrillary
tangle pathology128. Aggregation of tau into fibrils is a
defining feature of all tauopathies. Even if we assume
that intraneuronal neurofibrillary tangles are biologi-
cally inert cytoplasmic lesions, they might still inter-
fere with vital physiological functions simply because
they occupy space (FIG.2). In fact, an analysis of 20,000
dendritic spines after intracellular injections of Lucifer
yellow revealed that the early diffuse accumulation of
phosphorylated tau (before the development of mature
Table 2 | Biological effects and toxic mechanisms of distinct amyloid‑β and tau species
Characteristic Aβ only Both Aβ and tau Tau only
Variants APP cleavage generates
Aβ40, Aβ42, Aβ38, Aβ43,
Aβ45, Aβ46, Aβ48, Aβ49
NA Alternative splicing
generates 0N3R, 1N3R,
2N3R, 0N4R, 1N4R, 2N4R
Post‑translational
modifications
Pyroglutamylation,
nitration, oxidation,
racemization
Phosphorylation, glycosylation,
isomerization
Acetylation, O‑linked
N‑acetyl‑glucosamination,
ubiquitylation, sumoylation,
methylation, truncation
Assemblies and
macroscopic lesion
Amyloid plaque Oligomers*, monomers, protofibrils,
filaments
Neurofibrillary tangles
Neurotoxicity Disturbance of
multivesicular bodies
Inflammatory response, mitochondrial
dysfunction, impaired axonal
transport, synaptic excitotoxicity,
trans-synaptic propagation
Relocalization of axon
initial segment, chromatin
relaxation, steric hindrance
Aβ, amyloid‑β; APP, amyloid precursor protein; N, the number of insertions in the projection domain of tau; NA, not applicable; R,
the number of highly conserved microtubule‑binding repeat domains in tau. *Both tau and Aβ
β.
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neurofibrillary tangles) did not induce dendritic
changes. However, the accumulation of tau neurofibril-
lary tangles was associated with a progressive loss of
dendritic spines, morphological changes and dendritic
atrophy depending on the degree of tangle pathology129.
On the other hand, in an inducible tau model, reduc-
tion of tau expression still improved cognition, although
neurofibrillary tangles continued to accumulate130. This
observation suggested that soluble, nonfibrillar tau was
the species that induced neuronal dysfunction. To
resolve this discrepancy, we argue that the toxicity of
different forms of tau might depend on the particular
stage of disease; thus, fibrillar tau might become toxic
only when it starts to occupy a substantial amount of
cellular space (TABLE2).
How tau impairs neuronal function
Tau toxicity is highly dependent on post-translational
modifications, and a large number of studies have
revealed that hyperphosphorylated tau impairs neu-
ronal function. How easily tau can be phosphorylated
or dephosphorylated depends on its conformation. For
example, the cis-conformation of tau has been iden-
tified as an early pathogenic driver of AD and other
tau opathies because it has increased resistance to
protein- phosphatase-2A-mediated dephosphorylation
and degradation131,132. Ageing also has a role in acceler-
ating pathological tau phosphorylation: when transgenic
mice expressing human tau were repeatedly backcrossed
onto a senescence-accelerated SAMP8 background, mice
of the new hybrid strain showed an age-related increase
in pathological tau phosphorylation at specific residues
(namely, Ser202, Thr205 and Ser235) compared with the
parent transgenic mice133.
A completely new approach to tau toxicity reflects the
concept that the progression of tau pathology in AD, as
categorized by Braak and colleagues into six stages on the
basis of neuronal location and clinical severity134, might
in fact reflect cell-to-cell propagation of the disease,
achieved by the release of tau into the extracellular space
and reuptake by recipient neurons (seeding and spread-
ing), rather than the successive involvement of different
neuronal subpopulations with varying vulnerabilities
to the disease. Extracellular tau aggregates are now well
accepted to be capable of trans-synaptic spread, thereby
causing tau pathology in recipient neurons135,136 (FIG.2f).
Seeding-competent tau aggregates have been described
with diverse assembly states ranging from trimers137,138
through low-molecular-mass aggregates and short
fibrils139,140 to high-molecular-mass species141, although
small assemblies of at least hexamer size are the most
efficiently internalized variety and have a higher seed-
ing capacity than either larger or smaller species139–141.
One way of releasing tau is by encapsulation within
exosomes142,143; in fact, it is tempting to speculate that tau
seeds encapsulated by lipid membranes are the physio-
logical way in which tau aggregates are secreted and
passed on to neighbouring cells. In 2017, spreading of
tau down neuronal circuits was found to precede synaptic
and neuronal degeneration in an AD mouse model with
spatially confined expression oftau144.
Interestingly, tau monomers derived from aggregated
tau can themselves induce tau aggregation, owing to the
conformational exposure of a VQIVYK motif that is
normally inaccessible in physiological tau monomers124.
Hyperphosphorylation of tau might have a critical role
in the exposure of this motif145. However, seeding does
not occur in a unified way. Rather, various ‘prion-like’
strains of tau, each with unique biochemical properties,
induce diverse pathological phenotypes of aggregation
invitro and invivo and have the ability to propagate tau
pathology at different rates depending on the targeted
brain region146,147. These strain-like features of tau were
revealed by injecting brain extracts from humans who had
died with various tauopathies into the hippocampus and
cerebral cortex of transgenic mice that express human tau.
Argyrophilic tau inclusions formed in all recipient mice,
and, following the injection of the corresponding brain
extracts, the hallmark lesions of distinct tauopathies such
as progressive supranuclear palsy and corticobasal degen-
eration were recapitulated148. Thus, tau strain variation
could account for the diversity of human tauopathies.
Presynaptic and postsynaptic effects. Hyper phosphory-
lated tau also has pronounced effects in the presynaptic
and postsynaptic regions, as shown by the presence of
presynaptic deficits in the entorhinal cortex of trans-
genic mice that overexpress a mutant form of tau linked
to familial FTD149 (FIG.2b,e). Pathogenic tau can also
restrict synaptic vesicle mobilization at presynaptic ter-
minals150. Postsynaptic impairments are discussed in
more detailbelow.
Box 1 | Toxicity principles in the proteinopathies
All proteinopathies share mechanisms of toxicity, implying that targeting aggregation
itself could have therapeutic utility. Cells typically respond to abnormal increases in
protein levels by upregulating ubiquitylation and autophagy, which facilitate the
clearance of misfolded and aggregated proteins229, although excessive aggregation
overcomes these natural cellular defences. Endoplasmic reticulum stress caused by the
accumulation of misfolded proteins can activate the unfolded protein response (UPR),
but how this response interacts with protein clearance mechanisms remains unclear.
The proteasome is generally unaffected by the UPR, and the autophagic pathway can
be activated by the UPR230. A shared mechanism of disease could, therefore, involve
increased intracellular protein aggregation and UPR activation that upregulate both
proteasomal and autophagic degradative pathways231.
Moreover, the aggregated proteins themselves might be toxic. Strong evidence points
to a key pathological role of oligomers, although discussion is ongoing as to whether
and to what extent fibrils are neurotoxic232. One possible toxicity mechanism is
suggested by evidence that α‑synuclein fibrils can promote tau aggregation and inhibit
microtubule assembly233. This observation highlights another important aspect of the
proteinopathies — the coexistence of different aggregated protein species. Several
potential mechanisms might underlie this observation: the initial pathogenic signalling
cascades might upregulate the expression of multiple aggregation‑prone proteins;
oneor more forms of a pathological protein might be capable of inducing pathological
changes in a different aggregation-prone protein, which could also lead to the
formation of mixed aggregates; and aggregation itself might evoke convergence
towards mutual cell-death pathways234.
Although the removal of toxic oligomers requires therapeutic strategies tailored to
the species being targeted, these shared principles point to the possibility of
therapeutically targeting aggregation itself. For example, syntaxin‑binding protein 1
(also known as MUNC18-1), a component of the membrane fusion machinery, is an
essential chaperone that controls the self‑replicating aggregation of α‑synuclein235
andcould hence be targeted.
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Historically, many studies have investigated synap-
tic impairments, but the role of tau in neuronal excit-
ability has remained largely unexplored. However, in
2017, hyperphosphorylated tau was shown to reduce
hippocampal excitability by relocating the axon initial
segment further down the axon151 (FIG.2e). Antibody-
binding studies showed that phosphorylation of tau at
specific residues (namely, those recognized by AT180
(Thr231 and Ser235) or 12E8 (Ser262 and Ser356),
but not PHF-1 (Ser396 and Ser404)) was necessary
for this patho logical relocalization151. This observation
points towards a role for distinct species of phospho-
rylated tau in the regulation of neuronal action poten-
tial generation. Yet, tau phosphorylation is not purely
pathogenic. Site-specific tau phosphorylation at Ser396
is required for hippo campal long-term depression152,
whereas tau phosphorylation at Thr205, mediated
by mitogen-activated protein kinase 12 (also known
Nature Reviews | Neurology
Increased p-tau
and tau translation
Increased
pT205-tau
CaMKK2–AMPK
Formation of NMDAR–PSD95 complex
CaMKIIαp38γ
Aβ
Aβ
Excitotoxicity
Tau
FYN–ERK–S6
a Dendritic spine
Increased
p-tau
Increased
p-tau
Aβ
b Microtubule
Tau-dependent mechanism
(e.g. microtubule breakdown)
• Long-term potentiation impairment
• Synaptic damage
Aβ + tau
c Mitochondrion
• Oxidative phosphorylation
• Mitochondrial transportation
• Mitophagy
• Mitochondrial fission and fusion
Mitochondrial dysfunction
• ↑ ROS production
• ↓ energy production
Figure 3 | Crosstalk between amyloid‑β and tau. Amyloid‑β (Aβ) and tau interact in many neuronal compartments.
a|β facilitates assembly of the postsynaptic excitotoxic signalling complex, which consists of an
N‑methyl‑aspartate receptor (NMDAR) and its scaffolding protein, postsynaptic density protein 95 (PSD95; also known
as DLG4), via several tau‑dependent signalling cascades. The tyrosine‑protein kinase FYN–ERK–ribosomal protein S6
cascade leads to denovo tau synthesis in the somatodendritic domain, which is accompanied by calcium/calmodulin‑
dependent protein kinase type II subunit α (CaMKIIα)‑mediated and calcium/calmodulin‑dependent protein kinase
occurs in Alzheimer disease. Dashed arrows indicate hypothesized steps. At the same time, however, increased Thr205
phosphorylation of tau, mediated by p38γ, promotes dissociation of the excitotoxic complex, highlighting a protective
role of this type of tau phosphorylation. Nonetheless, a feedback loop is established that causes dendritic tau to target
FYN to dendritic spines. b|β‑induced
impairment of long‑term potentiation to cause synaptic damage (mediated by spastin and tubulin polyglutamylase TTLL6,
also known as tubulin–tyrosine ligase‑like protein 6). c|β and tau interact synergistically to impair
mitochondrial functions and disturb neuronal energy homeostasis. Blue shading indicates the tau density gradient.
Microtubules are shown only in axons. AMPK, 5’‑AMP‑activated protein kinase; ERK, extracellular‑signal‑regulated kinase;
p, phosphorylated; ROS, reactive oxygen species.
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as mitogen-activated protein kinase p38γ), allevi-
ates Aβ-induced excitotoxicity by interfering with
postsynaptic excitotoxicsignalling153.
Tau acetylation at lysine residues (such as Lys280
and Lys174) is attracting increasing attention, as this
post-translational modification can inhibit tau degrada-
tion154, impair the interaction of tau with microtubules,
promote pathological tau aggregation155, disrupt synaptic
signalling (by reducing levels of postsynaptic kidney and
brain protein (KIBRA), a memory-associated protein)
and ultimately drive cognitive deficits155–158 (FIG.2b).
Mitochondrial and nuclear effects. Distinct truncated
forms of tau, generated by caspases and asparagine
endopeptidase, contribute to accelerated neurofibrillary
tangle formation and impaired memory function119,159
and elicit mitochondrial dysfunction160,161. Indeed,
pathological forms of tau impair all major aspects of
mitochondrial function, although mitophagy has not
been studied extensively91. Additional impairments
have been reported in the nucleus. For example, in
a transgenic Drosophila model, pathogenic tau pro-
motes neurodegeneration through global chromatin
relaxation162. In primary neurons, tau directly regu-
lates the integrity of pericentromeric heterochromatin,
which seems to be disrupted in AD neurons163 (FIG.2a).
Thus, pathological tau impairs functions throughout
neurons.
Effects on microglia. With regards to glia, microglial
activation can precede neurofibrillary tangle forma-
tion, as revealed in tau transgenic mice164, whereas in
a tau transgenic strain lacking the microglial fractal-
kine receptor CX3C-chemokine receptor 1 (CX3CR1),
reactive microglia seemed to drive tau pathology and
contribute to the spreading of pathological tau165. A role
for soluble hyperphosphorylated tau in driving micro-
glial degeneration has been demonstrated in tau trans-
genic mice166. However, exactly how glia in the AD brain
respond to the different pathogenic forms of tau and Aβ
still needs to be determined.
Crosstalk between tau and Aβ pathology
The existence of crosstalk between Aβ and tau in the
dendritic postsynapse was established by the finding
that dendritic tau mediates Aβ toxicity by targeting
FYN into dendrites and spines. FYN then phosphory-
lates the NMDAR subunit NR2B (also known as gluta-
mate receptor ionotropic, NMDA 2B), which facilitates
recruitment of PSD95 to form an excitotoxic complex.
Aβ then signals through this complex to mediate excito-
toxicity. Interestingly, in the presence of elevated levels
of phosphorylated tau (as occur in FTD), FYN levels
are increased in the spines, which augments Aβ toxi-
city114 (FIG.3a). Nonetheless, tau also has a physiological
role in this neuronal compartment, as demonstrated by
the activity-dependent translocation of tau into spines,
which is disrupted by oligomericAβ167.
Accumulation of tau in the cell body and dendrites
is partly mediated by Aβ168,169. However, whether an
Aβ-mediated mechanism other than the relocalization
of tau accounts for the massive accumulation of tau in
the somatodendritic compartment is not yet known. In
2017, a cogent mechanism was demonstrated to involve
Aβ-mediated local production of tau in the somato-
dendritic domain108. In this study (which involved cell
lines, primary neuronal cultures and several invivo
tauopathy models), oligomeric Aβ caused denovo pro-
tein synthesis of tau in the somatodendritic compart-
ment, mediated by FYN, extracellular signal- regulated
kinase 1 (ERK1; also known as MAPK3), ERK2
(also known as MAPK1) and ribosomal protein S6.
Thisincrease in tau protein levels was associated with
increased phosphorylation of tau at tyrosine, threonine
and serine residues108. This novel pathological mech-
anism implies that, in AD, lowering overall tau levels
might be a better therapeutic strategy than blocking only
serine-directed or threonine-directed tau phosphory-
lation. The new data also suggest that FYN is a suitable
drug target, because it regulates not only tyrosine-
directed phosphorylation, but also serine-directed and
threonine-directed phosphorylation170.
Additional pathways have been suggested to
mediate the synaptotoxic effects of Aβ through tau,
including the calcium/calmodulin-dependent protein
kinase kinase 2 (CaMKK2)–AMP kinase pathway for
oligomers171. The typeI oligomer Aβ*56 can form a
complex with synaptic NMDARs, resulting in aberrant
increases in intracellular calcium levels and activation of
calcium/calmodulin-dependent protein kinase typeII
sub unit-α (CaMKIIα), which then pathologically phos-
phorylates tau172 (FIG.3a). Tau phosphorylation caused
by these signalling cascades was formerly assumed to
facilitate the formation of an excitotoxic complex, until
a mechanism of increased Thr205 phosphorylation
mediated by p38γ was identified in 2016 and shown to
promote dissociation of this complex, thereby inhibiting
Aβ-induced excitotoxicity153. That tau is essential for the
synaptic toxicity of Aβ was demonstrated by the find-
ing that hippocampal slices from tau- knockout mice are
resistant to the impairment of long-term potentiation
induced by oligomeric Aβ173. Aβ oligomers can also
cause synaptic impairment (by a tau-dependent mech-
anism that involves severing of microtubules) via the
proteins spastin and tubulin polyglutamylase TTLL6
(also known as tubulin–tyrosine ligase-like protein6)174
(FIG.3b). Together, these observations demonstrate a
multifaceted interplay of Aβ and tau at the synapse;
however, more work is required to complete this pic-
ture and to determine the relative contributions of these
convergentpathways.
Finally, crosstalk also exists at the level of mitochon-
drial function, because combining Aβ and tau pathol-
ogies in transgenic mouse models leads to synergistic
reductions in mitochondrial membrane potential, ATP
synthesis and respiration as well as synergistic increases
in levels of ROS92. Other aspects of mitochondrial func-
tion are also impaired by the complicated crosstalk
between Aβ and tau, including mitochondrial dynam-
ics175,176, transport177 and mitophagy161 (FIG.3c). Together,
these studies paint a complex picture of Aβ and tau
interactions.
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Assessment of Aβ and tau pathology
Validated Aβ and tau biomarkers are required to improve
the staging and differential diagnosis of AD and for use
in clinical trials (especially studies of short-term treat-
ments)178. However, the field of Aβ and tau detection
presents specific impediments. Whereas the detection of
particular Aβ species is challenging owing to their low
concentrations179, tau is generally investigated as though
it were a single protein, ignoring differences in isoforms,
subcellular localization and a wide variety of poorly
understood post-translational modification fingerprints,
which only increase in complexity under pathological
conditions21,180.
Antibody-based detection. Studies of post-mortem brain
tissue routinely use classic biochemical methods, such
as thioflavin S, Congo red or Gallyas staining, or histo-
logical detection methods that often rely on a small set
of anti bodies. Unfortunately, over time, these antibodies
can undergo changes in affinity and specificity, and these
changes (together with the lack of consensus regarding
which antibodies should be used) often hinder the com-
parison of different studies and prevent firm conclusions
from being drawn. Furthermore, some frequently used
Aβ antibodies (such as 4G8 and 6E10) also detect APP
because of the presence of a shared sequence181. Other
antibodies are specific for Aβ, such as 3D6, or plaques
(such as mE8-IgG2a, which detects pyroglutamylated Aβ
(3 pR-Aβ1–42))182. Many modification-specific anti-tau anti-
bodies became available in the early days of tau research
and enabled the identification of modified tauunder
pathological conditions20,183. Other useful anti-tau anti-
bodies are pan-specific or isoform-specific or are able to
discriminate between human and mouse tau, which is
critical when working with transgenic animal models184,185.
Imaging studies. In living patients, visualization of Aβ
and tau pathology became available with the development
of Aβ PET tracers. The first such tracer, 11C-Pittsburgh
compound B, targets Aβ plaques and has a half-life of
just 20 min186, whereas 18F-based Aβ PET tracers (such
as florbetapir, florbetaben and flutemetamol) have the
advantage of half-lives measured in hours187. As a result
of the advent of PET tracers for tau such as 18F-FDDNP,
11C-PBB3 and 18F-AV-1451 and members of the
18F-THK
arylquinoline series, which are currently in clinical
development, longitudinal studies of the evolution of
tau and Aβ pathology and how this correlates with cog-
nitive impairment during disease progression are now
possible188. However, these scans require specialized and
expensive equipment and are not widely available.
Currently available biomarkers. Other methods of
investigating Aβ or tau as pathological markers have
focused on their detection and quantification in body
fluids such as CSF and blood189–191 (TABLE3). Aβ42 levels
in CSF seem to be able to distinguish AD from FTD,
but not from other non-AD dementias (possibly because
of the presence of mixed pathologies)192, whereas the
Aβ42:tau ratio in CSF as determined by enzyme-linked
immunosorbent assay (ELISA) is a good predictor of the
development of an AD-type dementia193. However, CSF
analysis is impractical as a large-scale screening method.
Blood could potentially serve as a superior source, as it
is easily accessible and requires less-invasive sampling
techniques194,195. Indeed, a meta-analysis published in
2016 confirmed a strong association between AD and
the core CSF biomarkers of neurodegeneration (total
tau, phosphorylated tau and Aβ42) as well as with
the CSF biomarker neurofilament light chain and the
plasma biomarker total tau196. Additionally, Aβ can
now be detected in saliva in concentrations as low as
20 pg/ml with the use of a nanoparticle-based assay197,
although an earlier study employing a Luminex assay
could detect tau, but failed to detect Aβ42, in saliva198.
Salivary lactoferrin levels can discriminate patients with
mild cognitive impairment and AD from healthy con-
trols199, but salivary levels of Aβ and tau still need to be
Table 3 | Methods for the detection and characterization of toxic amyloid‑β and tau species
Technique Noninvasive Invasive Comment
Blood* Urine* Saliva* CSF* Brain
PET NA NA NA NA Yes* Can detect brain deposits of Aβ or tau invivo.
Expensive, requires specialized facilities
Histological staining
methods‡
NA NA NA NA Yes§Accessible, used in diagnosis and research
Immunohistochemistry NA NA NA NA Yes§Accessible, used in diagnosis and research
Atomic force
microscopy‡
ND ND ND ND Yes§Expensive, potential use in diagnosis and
research
Mass spectroscopy‡Yes Yes Ye s Yes Yes§Expensive, used in diagnosis and research
Size‑exclusion
chromatography‡
Yes Ye s Yes Ye s Ye s §Expensive, used in diagnosis and research
ELISA‡Yes Ye s Yes Ye s Ye s §Accessible, used in diagnosis and research
Western blot‡Yes Ye s Yes Ye s Ye s §Accessible, used in diagnosis and research
Aβ, amyloid‑β; CSF, cerebrospinal fluid; ELISA, enzyme‑linked immunosorbent assay; NA, not applicable; ND, not done.
*Ante‑mortem. ‡Biochemical approaches that facilitate the identification of prognostic biomarkers. For high‑throughput analyses,
blood requires less‑invasive collection than CSF and currently presents the greatest potential for future diagnostic use. Saliva and
urine remain underexplored. §Post‑mortem.
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established as useful biomarkers200. Even less work has
gone into detecting Aβ and tau in urine and exploring
their usefulness as biomarkers201.
Advanced assessment methods. A few emerging highly
sensitive techniques can detect traces of Aβ and tau in
various body fluids; however, these methods have not
yet been fully developed as diagnostic tools. One such
method employs voltametric detection of Aβ oligomers in
the 100 pM ranges; signals are generated from a complex
formed by anti-Aβ antibodies and DNA–peptide aptamers
combined with gold particles and thionine groups202. In
another study, a four-electrode electrochemical bio sensor
detected full-length 2N4R tau in serum with exceptionally
high sensitivity (lower limit of detection 0.03 pM), open-
ing up the possibility that extracellular tau could be used
as a biomarker inAD203.
Several cutting-edge biochemical techniques have been
employed to study protein aggregation. For example, fluo-
rescence correlation spectroscopy has been used to study
the turnover of intermediates during Aβ aggregation,
revealing aggregates that ranged from 260 kDa to >106
kDa in size204. Researchers using this same technique have
also observed an interaction of Aβ with apolipo protein
E (ApoE, an AD risk protein) at a single-molecule reso-
lution and revealed that ApoE3 (unlike ApoE4, which is
also associated with an increased risk of AD) delayed the
oligomerization of synthetic Aβ in solution, suggesting
that this process also occurs invivo205. Mass spectrom-
etry has also been employed206,207 but is not likely to be
used for routine diagnostic purposes. Surface-enhanced
Raman spectroscopy, which uses laser nanotextured
substrates as the capture surface for Aβ oligomers, has
proven useful asa fast and label-free method for testing
AD biomarkers208.
With the advent of powerful super-resolution micros-
copy techniques, it is now possible to deepen our insight
into the cellular processes and compartmentalization of
Aβ and tau processing, modification and aggregation209.
For example, stimulated emission depletion microscopy
has been used to analyse the structural organization of Aβ
and tau in the CSF of patients with AD210. Extended-focus
Fourier domain optical coherence microscopy has been
used to generate stain-free, high-resolution 3D images of
Aβ plaques, raising the possibility of performing mini-
mally invasive Aβ studies invivo211. Confocal microscopy
of APP tagged with a photo-activatable fragment of green
fluorescent protein revealed fast APP transport from the
trans-Golgi network to lysosomes, where APP is enzymat-
ically processed to generate Aβ fragments212. In conjunc-
tion with the newly available transcription activator-like
effector nuclease (TALEN) genome- editing tool, a photo-
inducible human tau transgenic mouse line was generated
to study the mobility of endogenous tau in response to
various stimuli without the confounding effects of over-
expression213. These microscopy methods are expected
to become increasingly important for understanding the
subcellular compartmentalization of Aβ and tau toxicity.
Oligomerization states remain difficult to evalu-
ate by microscopy, owing to technical limitations.
Consequently, spatial intensity distribution analysis was
developed, which can measure oligomerization states in
different subcellular compartments in live cells214; how-
ever, to our knowledge, this method has not yet been
applied to tau or Aβ. In silico modelling of the spontan-
eous aggregation of Aβ has demonstrated that monomers
tend to aggregate into stable globular-like oligomers in a
process of initial collapse followed by slow relaxation215.
We anticipate that such computer simulation models
will not only help to elucidate pathogenic mechanisms
of protein aggregation but will also facilitate therapeutic
interventions216. In 2017, cryo-electron microscopy struc-
tures of tau filaments were published at an impressive
3.5 Å resolution217, and this structural information might
be useful for drugdesign.
We expect that these new techniques will help to
uncover the pathogenic events that initiate misfolding of
Aβ and tau and lead to the formation of aggregated species
as well as add to the repertoire of biomarkers by increasing
the specificity and sensitivity of detection methods aimed
at differentially diagnosing AD at its insidiousstage.
Implications for treatment
The amyloid cascade hypothesis (which guided the first
clinical trials in AD) led to a toxic role being assigned
specifically to soluble Aβ42 species, which were consid-
ered the preferred therapeutic target. Nonetheless, clin-
ical trials of humanized monoclonal antibodies such as
solanezumab, which binds to small soluble Aβ species,
and the small-molecule verubecestat, which reduces
Aβ production by inhibiting BACE1, have all failed218.
However, given the complexity and diversity of Aβ spe-
cies, we can reasonably assume that a given monoclonal
antibody will recognize only a subset of toxic Aβ mol-
ecules and will leave other toxic species untouched, a
factor that might account for these treatment failures. By
contrast, a phaseIb clinical trial of the anti-Aβ antibody
aducanumab (derived from a cognitively healthy aged
individual) yielded promising results219, which prompted
the launch of a phaseIII clinical trial. The positive results
of the phaseIb study underscore the theme that it is
important to understand the variability of the disease-
related proteins and interacting therapeutic agents, while
also implying that a fairly straightforward approach to
lowering abnormal Aβ levels could be broadly effective
against AD, particularly if administered in the early
stages of the Aβ cascade. This possibility is reinforced
by the discovery of the A673T mutation in APP, which
both lowers the production of Aβ and reduces the risk of
developingAD220.
The failed clinical trials of Aβ-targeted agents also
led to increased enthusiasm for anti-tau approaches. Tau
aggregation inhibitors and anti-tau vaccines have been
tested in clinical trials, as have indirect strategies target-
ing enzymes such as glycogen synthase kinase 3 (GSK3),
serine/threonine-protein phosphatase 2A (PP2A) and
histone acetyltransferase p300. Many trials of anti-tau
agents (including vaccination strategies targeting distinct
phosphorylated tau species) are still ongoing, although
a shift towards pan-tau-directed agents is evident; how-
ever, the tau field has also seen its failures, as illustrated
bythe aggregation blocker methylthioninium chloride
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and GSK3 inhibitors. The finding that not all phos-
phorylation events of tau are toxic adds an additional
layer of complexity to the efforts to target tau thera-
peutically152,153. Considering that Aβ and tau both have
important physiological roles, precision medicine will
be needed to remove only the toxic species and to target
distinct forms of Aβ and tau while maintaining normal
levels of nontoxic tauand APP species200.
The current consensus is that therapies for AD should
ideally be started before the onset of symptoms; conse-
quently, several current trials are aiming to prevent or
slow the progression of AD in people at risk of devel-
oping the disease221. Improved therapeutic strategies are
also on the horizon. These include new antibody-based
techniques, such as bispecific antibodies222, gene-
therapy approaches, such as anti-Aβ-specific and anti-
tau- specific nanobodies (which can also be employed
for diagnostic purposes223,224), and novel methods that
increase brain uptake of therapeutic agents generally.
For example, thera peutic ultrasound to transiently open
the blood–brain barrier might turn out to be effective225.
Therapeutic ultrasound applied to APP mutant mice
not only effectively clears a range of Aβ species, ranging
from monomers to oligomers and high-molecular-mass
species, but also restores memory functions226,227.
Interestingly, studies in a mouse model of tauopathy
show that tau aggregates can also be partially cleared with
this approach228, and its applicability to proteinopathies
in general can beenvisaged.
Conclusions
To date, AD can be accurately diagnosed only post-
mortem, although as the disease process becomes bet-
ter understood, diagnosis and staging of AD in living
patients could become possible. Increased understanding
of AD will be facilitated by identifying relevant Aβand
tau species, characterizing their functional relevance
andemploying novel PET, CSF and blood biomarkers that
capture the different forms of Aβ and tau and the distinct
protein complexes in which they are involved. Aβ and tau
are often used as singular descriptors for proteins that in
fact encompass a large range of molecules and assembly
states. This diversity (and how it is generated) is not only
interesting from a pure research perspective, as it informs
our understanding of pathogenic processes, but also has
clinical implications for the design of therapies and the
development of highly sensitive and specific biomarkers.
The failed clinical trials of Aβ-targeted therapies have
raised concerns about the validity of the amyloid cascade
hypothesis and whether Aβ really has a direct role in AD
pathogenesis. Several lines of evidence suggest that dis-
tinct soluble species of Aβ and tau, rather than the insolu-
ble end-stage lesions, amyloid plaques and neurofibrillary
tangles, exert the majority of the observed toxic effects of
Aβ aggregates (TABLE2). To treat AD specifically and at an
early (presymptomatic) stage, biomarkers and technolo-
gies are required that enable the detection and quantifi-
cation of minute amounts of soluble oligomeric forms of
Aβ and tau, as well as the modifications they have under-
gone, in CSF — and even better, in blood samples. For
example, improved understanding of the mechanisms of
neuronal spread could lead to approaches to halt AD at
its inception.
Because of the multifactorial nature of AD, which is
caused by the combination of a host of environmental
and genetic factors, preventive or therapeutic approaches
might need to be personalized. A prerequisite for such
precision medicine is that the characteristic pattern of
risk factors and biological dysfunctions can be compre-
hensively determined for each patient, as reflected by
genomic and genetic variants, neuroimaging indicators
(structural, functional and metabolic) and fluid-based
biomarkers in CSF, blood, urine and saliva. The different
types of Aβ and the proteins it forms complexes with
could serve as excellent markers. Tau could potentially
have a crucial role; in clinically different tauopathies,
such as progressive supranuclear palsy and corticobasal
degeneration, differences in the tau isoform ratio and
post-translational modification fingerprints of the histo-
logical lesions are probably reflected by different marker
profiles in CSF and blood. Given the complexity of tau
species and their pervasive effect on neuronal physiol-
ogy, combination therapies might be required to simul-
taneously target tau and Aβ. Moreover, such therapies
might need to target more than one toxic Aβ or tau spe-
cies. Even removing two or three toxic molecular species
might not be sufficient to achieve therapeutic outcomes
because we currently do not fully understand their inter-
actions and the potential hierarchy of selected targets.
Thus, reducing tau and APP levels generally might be
an efficient strategy for eliminating several toxic tau and
Aβ species atonce.
Together, these factors indicate that approaches to
improve drug delivery to the brain, in conjunction with
combinations of targeted agents, is probably the best
strategy to achieve cost-effective therapeutic outcomes.
It is further reasonable to assume that similar complexity
exists for the signature molecules of other proteino pathies
and that this complexity could equally be exploited for
the early diagnosis and staging of these diseases.
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Acknowledgements
J.G. is supported by the Estate of Clem Jones AO, the
Australian Research Council (grant DP160103812) and the
National Health and Medical Research Council of Australia
(NHMRC; grants GNT1037746 and GNT1127999). F.A.M.
is supported by the Australian Research Council (grants
DP170100125, LE0882864 and LE130100078) and the
NHMRC (grant GNT1058769 and NHMRC Senior Research
Fellowship GNT1060075). L.‑G.B. is supported by the Peter
Hilton Fellowship. The authors thank R. Tweedale for critically
reading the manuscript.
Author contributions
All authors researched data for the article, wrote the manu‑
script, made substantial contributions to discussions of its
content and undertook review and/or editing of the manuscript
before submission.
Competing interests statement
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
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