JBC Papers in Press. Published on June 22, 2016 as Manuscript R116.

714576
The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.R116.714576

Cross interactions between the Alzheimer’s disease amyloid-β peptide and other amyloid
proteins: a further aspect of the amyloid cascade hypothesis
Jinghui Luo1*, Sebastian K. T. S. Wärmländer2, Astrid Gräslund2, Jan Pieter Abrahams3*
1,Chemical Research Laboratory, University of Oxford, OX1 3TA, Oxford, UK. 2, Department of Biochemistry and
Biophysics, Stockholm University, SE-10691 Stockholm, Sweden. 3, Biozentrum, University of Basel, CH-4056
Basel, Switzerland & Laboratory of Biomolecular Research, Paul Scherrer Institute, CH-5232 Villigen, Switzerland.
*E-mail: [email protected] & [email protected];
Keywords: Alzheimer disease; amyloid; amyloid-beta (Aβ); oligomer; oligomerization; cross-amyloid interaction;
fibrillation

Abstract other amyloid proteins such as α-synuclein (2) and

Many protein folding diseases are intimately tau (3) are observed in FAD.
associated with accumulation of amyloid The amyloid cascade hypothesis suggests that
aggregates. The amyloid materials formed by deposition of Aβ aggregates in brain plays a vital
different proteins/peptides share many struxctural role in AD development(4). The amyloid form of
similarities, despite sometimes large amino acid Aβ aggregates is generally defined by in vitro
sequence differences. Some amyloid diseases observations: originally by the so-called cross-beta
constitute risk factors for others, and the progression X-ray diffraction pattern or by observation of fibril

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of one amyloid disease may affect the progression structures in microscopy (TEM or AFM)(5).
of another. These connections are arguably related Molecular probes recognizing formation of certain
to amyloid aggregates of one protein being able to ordered molecular structures include Congo red and
directly nucleate amyloid formation of another, thioflavin T, which change their optical properties
different protein: the amyloid cross-interaction. when bound to amyloid material(5). The terms “on-
Here, we discuss such cross-interactions between pathway” and “off-pathway” intermediates are used
the Alzheimer’s disease amyloid-β (Aβ) peptide and to differentiate between self-aggregated Aβ species
other amyloid proteins in the context of what is that lead to amyloid formation and those that do not.
known from in vitro and in vivo experiments, and of Missense mutations in the AβPP, APOE, PS1, and
what might be learned from clinical studies. The PS2 genes can increase accumulation and toxicity of
aim is to clarify potential molecular associations Aβ aggregates, and the “on-pathway” intermediate
between different amyloid diseases. We argue that aggregates seem to be the most cell-damaging
the amyloid cascade hypothesis in Alzheimer’s species(6). This provides strong support for the
disease should be expanded to include cross- amyloid cascade hypothesis, which nevertheless
interactions between Aβ and other amyloid proteins. remains disputed.
Although two recent reviews(7, 8) respectively
reject and support the amyloid cascade hypothesis
Introduction they both agree on one point: while AD progression
Alzheimer’s disease (AD) is the most common form is tightly connected to Aβ aggregation, several other
of elderly dementia. Its causes have not yet been factors likely contribute to the development of AD.
clearly elucidated. The two classical AD lesions are Such factors include lysosomal dysfunction, loss of
depositions of intracellular neurofibrillary tau Ca2+ homeostasis, neuroinflammation, progressive
tangles and extracellular deposits of aggregated oxidative damage, and problems in glucose
amyloid-β (Aβ) peptides in amyloid plaques in the metabolism. The pathological AD characteristics,
gray matter of the brain, mainly the hippocampus i.e. loss of neurons and formation of Aβ plaques
and neocortex. Aβ is a 36–43 residue peptide and tau tangles, are complex processes linked by
cleaved from the amyloid-β protein precursor multiple interconnected events which cannot be
(AβPP) by γ-secretase and β-secretase enzymes. adequately explained by a single hypothesis.
Some AβPP and Aβ mutations increase Aβ The aggregates of different amyloid
production and deposition and/or extend the half-life proteins/peptides share many structural
of Aβ in the brain,, but only a fraction (5%) of similarities.Despite different clinical symptoms the
Alzheimer’s disease is familial (FAD) (1). Several amyloid-cross-b interaction motif of amyloid
studies indicate thatalterations of the pathologies of proteins appears in several distinct pathologies. The

Copyright 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
monomers of Aβ and other amyloid proteins have oligomers, and the binding depends on the integrity
highly flexible and disordered structures, which of the lipid rafts and LPR1 (the transmembrane low
provide excellent templates for promiscuous density lipoprotein receptor-related protein-1)(11).
interactions with each other in vivo. This may Single-molecule imaging of small oligomeric forms
explain, in part, why interactions between different of Aβ42 interacting with cellular PrP on neuronal
amyloid proteins seem to alter the progression of cell surfaces was recently reported, where soluble
various amyloid diseases. In addition to direct PrP suppressed Aβ42 fibrillation and protected cells
molecular interactions, two amyloid-prone partners against Aβ oligomer toxicity(12). The N-terminal
may interact with a third entity, thereby interfering PrP domain fragment, with its positively charged
with each other´s primary effects. This hypothetic residues 23–31 and 95–105, strongly binds Aβ
third entity could be a membrane receptor, another oligomeric intermediates and in cultured murine
protein, or even a metal ion. Alternatively, certain hippocampal neurons strongly mitigates Aβ toxicity
amyloid-prone proteins may compete for the same (13).
proteolytic systems, or even have them in the Conversely, Aβ42 affects PrP biological activity. as
proteolytic process, thus enhancing the prion-binding and prion-dependent inhibition of
concentration and amyloid forming propensity of long-term potentiation (LTP) are regulated by the
others(9). presence of Aβ protofibrils. These aggregates have a
Here we discuss a series of amyloid proteins as linear structure, stronger binding affinity toward

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possible modulators of Aβ peptide behavior in vitro PrP, and a stronger inhibitory effect on LTP than
and in vivo, and potential clinical consequences non-fibrillar Aβ oligomers (14).
(Fig. 1). Table 1 shows how self-aggregation of The presence of PrP enhances Aβ accumulation, and
various proteins has been linked to certain vice versa(15). Thus, in transgenic mice the two
amyloidal diseases. We suggest mutual molecular proteins mutually accelerate the progression of both
mechanisms between AD and these other diseases. pathologies (16). In AD transgenic mice, onset of
We argue that the amyloid cascade hypothesis in prion disease symptoms developed at a rate
AD remains valid, but should be expanded to proportional to the Ab brain levels(16). For humans,
involve also cross-interactions between Aβ and significant levels of Ab deposition, similar to those
other amyloid proteins. found in AD patients, were seen in brains of
Amyloid proteins displaying cross-interaction relatively young individuals that had died from
with Aβ CJD(17). In cellular form PrP may however inhibit
Prion protein (PrP) Aβ production, and one study found 53% reduction
The prion protein (PrP) is 208 residues long and of PrP in the hippocampus of aging sporadic AD
mainly expressed in nerve cells. When misfolded, patients(18), suggesting that PrP reduction may
PrP acts as an infectious agent (prion) inducing increase AD incidence in older people.
transmissible spongiform encephalopathies, such as α-synuclein
the mad cow disease. Prions also can infect the Aggregation of the 140 residues neuronal α-
human brain and induce misfolding of other proteins synuclein protein (α-syn) into Lewy bodies (LB)
into the prion form. Accumulation of prion induces Parkinson´s disease (PD). Presence of Lewy
structures leads to fatal disease, such as Creutzfeldt- bodies accelerates cognitive dysfunction also in AD
Jakob Disease (CJD) in humans. patients, and up to 50% of AD cases exhibit
PrP seems to affect the biological activity of Aβ42 significant LB pathology in addition to Aβ plaques
through direct interactions, and aggregated forms of and tau tangles(19)(19, 20).
human PrP and Aβ42 have been co-purified from Aβ40/42 and α-syn appear to strongly interact and
AD brain material (10).Cellular PrP has been mutually promote each other’s oligomerization in
identified as a high-affinity receptor for Aβ vitro. Addition of α-syn induces a global structural
oligomers. Several in vitro studies have shown change in Aβ42/40, while α-syn seems to have a
mediation of Aβ-induced synaptic dysfunction via specific binding pocket for Aβ interaction(21). Aβ
prion proteins. By binding Aβ oligomers to the cell directly interacts with α-syn to form cationic
surface, PrP reduces the production of Aβ from nanopore oligomers embedded in the cell membrane
AβPP by down-regulating the activity of β-secretase (22). Aβ and α-syn cross-seeding fibrillation effects
BACE1(11). PrP recognizes only soluble Aβ suggest that the aggregation pathways of both

2
molecules can be significantly stimulated by the contribute to the synaptic dysfunction involved in
presence of fibrils of either molecule. Although non- AD.
fibrillar oligomers may also stimulate aggregation, Lysozyme
they were less effective(23). Thus, synergistic cross- Human lysozyme is a 148 residues glycoside
amyloid interactions of hydrolase, functioning as an antibacterial agent
monomeric/oligomeric/fibrillar Aβ and α-syn may mainly in blood(34). Lysozyme is also present in
promote protein aggregation and contribute to both CSF, where substantially increased levels have been
PD and AD progression. reported during various disease conditions -
In transgenic mice, Aβ enhances α-syn especially inflammation, including the inflammatory
accumulation and neuronal damage(24). In DLB reactions triggered in the AD brain. AD patients
(dementia with Lewy bodies)-AD mice, a dramatic display increased CSF lysozyme levels, and
increase of amyloidal Aβ42 was observed(19). AD Aβ/lysozyme complexes have been found in AD
patients with this Lewy body variant have lower plaques(35). Because of its capacity to self-
survival rate and more pronounced cognitive assemble, lysozyme is often used as a model to
dysfunction than pure AD patients(25). For PD study protein stability, folding, and aggregation.
patients, accumulation of Aβ aggregates produces We have found that human lysozyme prevents Aβ
aggressive PD with dementia(26). α-syn may also aggregation at a 1:1 ratio in vitro. CD and NMR
promote Aβ-related tau inclusion in neurons and in spectroscopy showed that lysozyme does not affect

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vivo(27). Aβ and α-syn therefore appear to the random coil structure of monomeric Aβ, while
synergistically accelerate cognitive decline in AD theoretical simulations indicated that human
and PD. lysozyme stabilizes the Aβ N-terminus and interacts
Tau with the C-terminus via a hydrophobic surface(36).
The tau proteins, a family of 352-441 residues As an amyloidal protein, lysozyme can modulate the
microtubule stabilizers, are abundant in the central Aβ conformation and fibrillation, which may in part
nervous system. Presence of neurofibrillary tau explain the physiological association between AD
tangles is a characteristic AD histopathology. Tau and inflammation.
and Aβ interactions appear to mutually influence the Insulin
aggregation and toxicity of both molecules, as well Insulin is a 51 residues peptide hormone primarily
as the progression of synaptic dysfunction in AD. involved in glucose regulation. It also modulates
Three mechanisms were proposed(28): Aβ drives numerous brain functions. A positive effect of
tau pathology or tau modulates Aβ toxicity, or insulin has been found on cognitive performance in
synergistic toxicity exists between Aβ and tau. AD, even though treatment with insulin may
The Aβ C-terminus can bind multiple tau domains increase the risk of AD among diabetes mellitus
and subsequently form soluble Aβ/tau complexes in (DM) patients.
vitro (29). Such intracellular Aβ/tau complexes In vivo, insulin regulates the activity of
could conceivably accelerate tau hyperphosphorylated tau in the formation of AD
hyperphosphorylation and Aβ nucleation. neurofibrillary tangles(37). Insulin affects also Aβ
Extracellular fibrillar and oligomeric Aβ peptides production and degradation(37), and increases Aβ
seem to promote tau hyperphosphorylation, thereby extracellular levels via regulation of γ-secretase
inducing loss of tau’s microtubule binding activity, activity (38) and via release of intra-neuronal β-
leading to neural dysfunction and degeneration(30). amyloid(39). Insulin inhibits Aβ degradation by
Similarly, Aβ aggregation induces tau blocking the activity of the insulin degrading
hyperphosphorylation in AβPP transgenic enzyme, which degrades also Aβ in neuronal and
mice(31).Injection of extracellular Aβ fibrils into microglial cell cultures (40). Insulin has been
tau transgenic mice accelerates the tau tangle reported to facilitate hepatic cleavage of plasma Aβ
pathology(32). However, no aggressive Aβ plaque by intracellular translocation of the lipoprotein
pathology has been observed neither in tau receptor to the plasma membrane (41).
transgenic mice nor in cross offspring of tau Conversely, Aβ regulates the function of insulin. Aβ
transgenic mice and AβPP transgenic mice(33). In inhibits the effect of insulin on the secretion of
conclusion, Aβ/tau amyloid cross interactions likely AβPP, competes with insulin for binding to the
insulin receptor, and induces insulin resistance by

3
regulating the signal transduction of the insulin production and deposition of TTR amyloid is age-
receptor (42). The underlying interaction and mutation-dependent. TRR is deposited in
mechanisms between insulin and Aβ remain peripheral nerves and in the heart, but is also present
unknown, although we recently showed that in the eyes, choroid plexus, and kidney (55).
monomeric insulin interacts with soluble Aβ in Expression of TTR in brain regions such as the
vitro, inducing formation of less toxic Aβ oligomers hippocampus and cortex has been observed in both
(43). wild-type animals and in AD rodent models. During
IAPP aging a TTR-null mouse suffers reference memory
The islet amyloid polypeptide (IAPP), a 37 amino deficits, but no other impairments(56). TRR
acid peptide hormone, is cleaved from the pro-islet promotes Aβ clearance, decreases its deposition, and
amyloid polypeptide and secreted with insulin by suppresses cognitive deficits in AD mouse
pancreatic β-cells into the circulation (44). IAPP has models(57). TTR has therefore been suggested to
38% sequence similarity with Aβ (Fig. 2). Both generally slow AD progression. TTRR appears to be
peptides can regulate the homeostasis of free Ca2+ to a major Aβ-sequestering protein in human CSF,
control cell death (45). IAPP amyloidosis is a inhibiting and even reverting formation of amyloid
characteristic feature of type 2 diabetes (T2D) (46). fibrils, as well as reducing their toxicity in vitro(58,
IAPP in T2D and Aβ in AD adopt antiparallel β- 59). TTR forms a complex with Aβ
sheet secondary structures, and associate with the monomers/dimers, with stronger binding affinity

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same cellular components, such as apolipoprotein E observed for the more structurally flexible S85A
(APOE) and heparin sulfate proteoglycan (47). T2D TTR mutant(60), reinforcing the idea that less
patients are 1.5 times more likely to develop AD structured forms of amyloid proteins may be more
than control individuals (48). In diabetic SAMP8 likely to engage in cross-amyloid interactions.
mice, cerebral Aβ is increased, tau phosphorylation Apolipoprotein AI
is interrupted, and memory deficiencies are Apolipoprotein AI (Apo AI) is the 396 residues
observed, indicating AD-like changes (48). main member of human high-density lipoproteins,
In vitro results show that IAPP fibrils are poor seeds which play an important role in lipid metabolism. It
for Aβ aggregation (49). IAPP however binds to is present in human CSF and can also be detected in
prefibrillar Aβ40 and blocks the cytotoxicity of Aβ senile AD plaques (61). Apo AI can self-assemble
aggregates. Conversely, Aβ binds prefibrillar IAPP, into amyloid fibrils and generate atherosclerotic
and Aβ and IAPP aggregates reciprocally regulate plaques (61). Apo AI directly interacts with
each other’s cytotoxicity (50). IAPP inhibits the AβPP(62), and has a nanomolar affinity for Aβ.
cytotoxicity of Aβ aggregates at nanomolar Upon binding to Apo AI, Aβ fibril formation is
concentration and inhibits Aβ fibrillation at inhibited and the toxicity of Aβ aggregates is
stoichiometric ratios(51). Several small Aβ attenuated(62). Polymorphisms of Apo AI’s
fragments bind to full-length IAPP, some with promoter region are associated with increased AD
nanomolar affinity(52). These results agree with the risk (63). In an AD mouse model, overexpression of
hypothesis that amyloidal peptides can dissolve Apo AI impaired learning and caused memory
amyloid material containing similar sequence deficits(64).
motifs(53). Cystatin C
Thus, although IAPP suppresses Aβ fibrillation and Cystatin C (CysC) is a 13.3 kDa basic protein
toxicity in vitro, there seem to be aggressive effects abundantly located and expressed in brain tissue
of IAPP in vivo, particularly as the molecule induces (65). CysC plays a role in different diseases, from
cleavage of Aβ from AβPP. cancer to neurodegenerative disorders(66).
Transthyretin Mutations of CysC can lead to fatal hereditary
Transthyretin (TTR) is a 55 kDa protein, secreted by cystatin C amyloid angiopathy. CysC counteracts
the liver into the blood stream and functioning as a formation of Aβ oligomers and protofibrils(67) and
serum and CSF carrier of Thyroxine(T4) and the thereby reduces Aβ neurotoxicity(68). A specific
retinol-binding protein. Aggregation of wild type high-affinity Aβ/CysC binding has been observed in
TTR causes a sporadic, non-genetic disease, while vitro(69), while in vivo Aβ/CysC complexes have
aggregation of a mutated TTR leads to familial been detected in the human central nervous
amyloid cardiomyopathy (54). Like for Aβ, system(70). CysC may function as an endogenous

4
inhibitor of cysteine proteases such as Cathepsin B non-toxic aggregating proteins such as beta-
(71),which can degrade Aβ and thereby lower Aβ lactoglobulin in milk could interact with and
levels in vivo(72). CysC is thus likely indirectly promote toxic amyloid formation.
involved in Aβ regulation. Epidemiologically, a The co-factors and loci of cross-amyloid
polymorphism in the CysC gene (CST3) has been interaction
linked to enhanced risk for AD(66), and CysC Various metal ions are known to bind Aβ and
modulates cerebral β-amyloidosis in AβPP interfere with its aggregation process (15, 81).
transgenic mice(71). Recent work has shown that multiple amyloid
Serum Amyloid P component and fibrinogen protein molecules may share coordination of a
Blood proteins like Serum Amyloid P component single metal ion, promoting protein aggregation and
(SAP) and fibrinogen are found in human amyloid possibly also cross interactions(82). Cross-amyloid
deposits. SAP is a 25 kDa pentameric plasma interactions may also be modulated by other clusters
glycoprotein that generally binds to amyloid fibrils, involving e.g. small charged molecules.
including those formed from aggregated Aβ. Recent Polyamines(83, 84) modulate the conformation,
studies show that SAP accelerates the formation and fibrillation, and toxicity of Aβ, α-syn, and IAPP in
enhances the proteolytic stability of Aβ42 vitro.
fibrils(73). In vivo, human amyloid deposits often We recently found that certain non-chaperone
contain SAP together with a primary amyloid proteins such as lysozyme and catalase prevent Aβ

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component such as Aβ (74). SAP may be removed fibrillation and toxicity (36, 85). These enzymes
from blood and/or CSF by pharmaceutical could act according to the model of molecular
intervention. It has been suggested that such crowding in vivo to regulate cross-amyloid effects
removal might be beneficial to AD patients (75). (86). Proteostasis capacities (referring to protein
The 340 kDa clotting precursor fibrinogen is present quality control in vivo) are decreased in
only in blood plasma but not in serum. Fibrinogen- neurodegenerative amyloidoses(87). Increased Aβ
Aβ interactions have been shown to induce production could overload the proteostasis system,
oligomerization of fibrinogen and fibrillation of the leading to aggregation of various other amyloid
Aβ peptide(76). Abnormal depositions of fibrinogen proteins. These entirely indirect effects of cross-
have been found in AD patients. Similar to SAP, amyloid interactions may explain, at least in part,
fibrinogen modulates Aβ deposition and fibrillation, the association of different amyloidoses. We
and also further affects neurodegeneration (76). propose that the direct and indirect effects discussed
Other amyloid proteins here are likely to be complementary to each other in
For several other amyloid proteins associated with cross-amyloid interactions.
Aβ, the types of interaction and their effects are less Cell membranes are obvious location candidates for
known. The levels of galectin-3, associated with cross-amyloid interactions, given their hydrophobic
idiopathic pulmonary fibrosis, are increased in the interiors and the large proportion of hydrophobic
serum of AD patients. In vitro galectin-3 has been residues in amyloid protein sequences. Most
found to reduce the neurotoxicity of Aβ42 (76). The amyloid proteins travel between different cellular
levels of lactadherin, playing a vital role in compartments and tissues, and the membrane
phagocytosis, are decreased in AD patients (77). boundaries would be natural places for these
Lactadherin amyloid, a deposit known as medin that proteins to accumulate and/or interact. Lipid
is localized in aortic media, occurs in virtually all membranes are known to influence the structure,
individuals older than 60 years. The huntingtin- aggregation, cell permeability, and toxicity of
associated protein 1 modulates the AβPP subcellular amyloid proteins. Aβ, IAPP, and α-syn all adopt
trafficking pathway, thus negatively regulating Aβ more well-defined structures in lipid membranes.
production in neurons (78). Loss of superoxide Cell membrane damage has been proposed as a
dismutase (SOD) increases production of Aβ in disease mechanism in amyloidosis, and damage
neurons and SHSY5Y cells, an effect caused by could result from uptake of lipids into amyloid
enhanced AβPP processing by the β-site AβPP aggregates formed on or in lipid membranes (88).
cleaving enzyme (79), while earlier studies have Amyloid proteins may also form harmful nanopores
shown that overexpression of SOD reduces Aβ in lipid membranes (89). Although α-syn and tau
neurotoxicity (80). Another question is whether predominantly appear as intracellular proteins, and

5
Aβ and IAPP mainly function as extracellular aggregation may then be governed by their initial
peptides, all of them can appear intracellularly as interactions and by hydrophobic associations.
well as extracellularly. Both intra- and extracellular As shown in Fig. 1 and Table 1, the effects of cross-
amyloid proteins are associated with the progression amyloid interactions between different amyloid
of amyloid diseases (90–92). proteins may vary substantially. TTR(59),
Implications of Aβ cross-amyloid interactions CysC(67), and ApoAI(62) all suppress Aβ
Although the sequences of amyloid proteins vary in fibrillation and delay AD progression in mice(57,
length, all amyloid proteins discussed above can 64). In contrast, α-syn(23), tau(28), and fibrinogen-
form highly similar beta-cross amyloid fibrils. In α(95) promote Aβ toxicity and/or fibrillation and
non-aggregated states, most amyloid proteins exist increase the risk of AD in mice(32) and/or
as random coil structures prone to conformational patients(25, 76). IAPP prevents Aβ fibrillation in
changes. Surprisingly, the N- and C-terminal vitro(50); yet IAPP-associated T2D may promote
sequences of amyloid proteins show a high AD progression in vivo. The different ways amyloid
probabilistic consistency (Fig. 2). This is in proteins modulate Aβ fibrillation may depend on
agreement with e.g. the observed interaction their varying structures and stabilities. Most proteins
between Aβ oligomers and the PrP N-terminus (13). preventing Aβ amyloid fibrillation have a well-
We here propose that the N- and C-termini of many folded or partially folded monomeric structure (eg.
amyloid proteins can initialize cross-amyloid lysozyme), while amyloid proteins with random or

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interactions. disordered structures are prone to promote Aβ
Cross-amyloid interactions could be driven by fibrillation. Many amyloidal proteins have been
hydrophobic associations, as the presence of reported to protect cells against the toxicity of Aβ
hydrophobic amino acids is known to yield higher aggregates. The different roles of the amyloid
amyloidal propensity(93). Most amyloid proteins proteins affecting fibrillation and toxicity of the Aβ
display an abundance of hydrophobic residues, peptide could be regulated also by other in vivo
which could facilitate hydrophobic associations factors, such as protein homeostasis.
between e.g. misfolded amyloid proteins and other Interactions between Aβ and the RAGE receptor
amyloid proteins with different sequences. Such have been proposed to induce cellular perturbations
associations might interfere with e.g. the Aβ self- via oxidative stress and synaptic dysfunction. Some
fibrillation pathway. Our observation of Aβ peptides Aβ-binding amyloid proteins have been reported to
adsorbing on the surfaces of hydrophobic carbon compete for the RAGE receptor and inhibit its
nanotubes appears to support this hypothesis (94). interaction with Aβ (96). Interruption of Aβ-RAGE
For Aβ, the hydrophobic regions around residues receptor interaction by other amyloid proteins could
16-21 and 29-35 form the two legs of the Aβ affect the cell toxicity of Aβ and its aggregates.
hairpin, which is considered to be the basic unit for Other questions concern how, where, and if cross-
Aβ self-aggregation and co-aggregation with other amyloid interactions should be inhibited. While
molecules(5). molecules such as beta-sheet breakers(97) and
Most amyloid proteins adopt a variable and cyclic peptides (98, 99) have been devised to
heterogeneous conformation in solution, often prevent amyloid aggregation, traditional antibodies
displaying an extremely flexible loop structure have so far provided the best preliminary treatment
which allows amyloid proteins to act as results at least for AD(100). It is unclear to what
promiscuous binding partners for other molecules. extent current amyloid inhibitors will block
For instance, the Aβ N-terminus (residues 1-15) formation of amyloid co-aggregates. As for location,
interacts with many different small charged it might turn out important to prevent cross-amyloid
molecules (15, 84). Interaction between two interactions in or on lipid membranes A drastic yet
heterogeneous amyloid proteins may prevent simple way to prevent cross-amyloid interactions is
fibrillation of one of them, but may also be the of course to remove one of the components – cf. the
precursor of a cross-amyloid interaction. Initial pharmacological removal of SAP discussed above.
cross-amyloid protein interactions are most likely Cross-interactions between various amyloid proteins
limited by the flexibility/heterogeneity of the concern not only potentially therapeutic
proteins involved. The subsequent rate of co- interventions against amyloidosis, but also point at
molecular associations between different diseases.

6
As shown in table 1, Aβ can interact with at least 10 Acknowledgments
other amyloidal disease proteins. In our opinion this We thank the anonymous reviewers for helpful
supports and expands the amyloid cascade comments on the manuscript. Due to the limits of
hypothesis as an underlying cause for AD: cross- the minireview format, we had to omit a number of
amyloid interactions between Aβ and other relevant references.
amyloidal proteins may play a critical role in AD Conflict of interest
progression, and cross-amyloid interactions might The authors declare that they have no conflicts of
modulate amyloidosis also in other diseases. interest with the contents of this article.

References:
1. Gessel, M. M., Bernstein, S., Kemper, M., Teplow, D. B., and Bowers, M. T. (2012) Familial
Alzheimer ’ s Disease Mutations Differentially Alter Amyloid β -Protein Oligomerization. ACS
Chem Neurosci. 3, 909–918
2. Lippa, C. F., Fujiwara, H., Mann, D. M. A., Giasson, B., Baba, M., Schmidt, M. L., Nee, L. E.,
Connell, B. O., Pollen, D. A., George-hyslop, P. S., Ghetti, B., Nochlin, D., Bird, T. D., Cairns, N.
J., Lee, V. M., Iwatsubo, T., and Trojanowski, J. Q. (1998) Short Communication Lewy Bodies
Contain Altered Alpha -Synuclein in Brains of Many Familial Alzheimer ’ s Disease Patients with
Mutations in Presenilin and Amyloid Precursor Protein Genes. Am. J. Pathol. 153, 1365–1370

Downloaded from http://www.jbc.org/ by guest on June 23, 2016

3. Porquet, D., Camins, A., Ferrer, I., Canudas, A. M., and Valle, J. Del (2015) Amyloid and tau
pathology of familial Alzheimer ’ s disease APP / PS1 mouse model in a senescence phenotype
background. Age (Omaha). 37, 12
4. Huang, H.-C., and Jiang, Z.-F. (2009) Accumulated amyloid-beta peptide and hyperphosphorylated
tau protein: relationship and links in Alzheimer’s disease. J. Alzheimers. Dis. 16, 15–27
5. Abelein, A., Abrahams, J. P., Danielsson, J., Gräslund, A., Jarvet, J., Luo, J., Tiiman, A., and
Wärmländer, S. K. T. S. (2014) The hairpin conformation of the amyloid β peptide is an important
structural motif along the aggregation pathway. JBIC J. Biol. Inorg. Chem. 19, 623–634
6. Luo, J., Wärmländer, S. K. T. S., Gräslund, A., and Abrahams, J. P. (2014) Alzheimer peptides
aggregate into transient nanoglobules that nucleate fibrils. Biochemistry. 53, 6302–8
7. Herrup, K. (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci. 18, 794–
799
8. Musiek, E. S., and Holtzman, D. M. (2015) Three dimensions of the amyloid hypothesis: time,
space and “wingmen.” Nat Neurosci. 18, 800–806
9. Saido, T., and Leissring, M. A. (2012) Proteolytic degradation of amyloid beta-protein. Cold
Spring Harb Perspect Med. 2, a006379
10. Zou, W.-Q., Xiao, X., Yuan, J., Puoti, G., Fujioka, H., Wang, X., Richardson, S., Zhou, X., Zou,
R., Li, S., Zhu, X., McGeer, P. L., McGeehan, J., Kneale, G., Rincon-Limas, D. E., Fernandez-
Funez, P., Lee, H., Smith, M. a, Petersen, R. B., and Guo, J.-P. (2011) Amyloid-beta42 interacts
mainly with insoluble prion protein in the Alzheimer brain. J. Biol. Chem. 286, 15095–105
11. Rushworth, J. V, Griffiths, H. H., Watt, N. T., and Hooper, N. M. (2013) Prion protein-mediated
toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1. J. Biol. Chem.
288, 8935–51
12. Nieznanski, K., Choi, J.-K., Chen, S., Surewicz, K., and Surewicz, W. K. (2012) Soluble prion
protein inhibits amyloid-β (Aβ) fibrillization and toxicity. J. Biol. Chem. 287, 33104–8
13. Fluharty, B. R., Biasini, E., Stravalaci, M., Sclip, A., Diomede, L., Balducci, C., La Vitola, P.,
Messa, M., Colombo, L., Forloni, G., Borsello, T., Gobbi, M., and Harris, D. (2013) An N-terminal
fragment of the prion protein binds to amyloid-β oligomers and inhibits their neurotoxicity in vivo.
J. Biol. Chem. 288, 7857–66
14. Nicoll, A. J., Panico, S., Freir, D. B., Wright, D., Terry, C., Risse, E., Herron, C. E., O’Malley, T.,
Wadsworth, J. D. F., Farrow, M. a, Walsh, D. M., Saibil, H. R., and Collinge, J. (2013) Amyloid-β
nanotubes are associated with prion protein-dependent synaptotoxicity. Nat. Commun. 4, 2416–23
15. Wärmländer, S., Tiiman, A., Abelein, A., Luo, J., Jarvet, J., Söderberg, K. L., Danielsson, J., and

7
 Gräslund, A. (2013) Biophysical studies of the amyloid β-peptide: Interactions with metal ions and
small molecules. ChemBioChem. 14, 1692–1704
16. Morales, R., Estrada, L. D., Diaz-Espinoza, R., Morales-Scheihing, D., Jara, M. C., Castilla, J., and
Soto, C. (2010) Molecular cross talk between misfolded proteins in animal models of Alzheimer’s
and prion diseases. J. Neurosci. 30, 4528–35
17. Jaunmuktane, Z., Mead, S., Ellis, M., Wadsworth, J. D. F., Nicoll, A. J., Kenny, J., Launchbury, F.,
Linehan, J., Richard-Loendt, A., Walker, A. S., Rudge, P., Collinge, J., and Brandner, S. (2015)
Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy.
Nature. 525, 247–50
18. Whitehouse, I. J., Jackson, C., Turner, A. J., and Hooper, N. M. (2010) Prion protein is reduced in
aging and in sporadic but not in familial Alzheimer’s disease. J. Alzheimers. Dis. 22, 1023–31
19. Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q., and LaFerla, F. M. (2010)
Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology
and cognitive decline. J. Neurosci. 30, 7281–9
20. Hamilton, R. L. (2000) Lewy Bodies in Alzheimer’s Disease: A Neuropathological Review of 145
Cases Using alpha-Synuclein Immunohistochemistry. Brain Pathol. 384, 378–84
21. Mandal, P. K., Pettegrew, J. W., Masliah, E., Hamilton, R. L., and Mandal, R. (2006) Interaction
between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of

Downloaded from http://www.jbc.org/ by guest on June 23, 2016

Alzheimer’s and Parkinson's in dementia with Lewy body disease. Neurochem. Res. 31, 1153–62
22. Tsigelny, I. F., Crews, L., Desplats, P., Shaked, G. M., Sharikov, Y., Mizuno, H., Spencer, B.,
Rockenstein, E., Trejo, M., Platoshyn, O., Yuan, J. X.-J., and Masliah, E. (2008) Mechanisms of
hybrid oligomer formation in the pathogenesis of combined Alzheimer’s and Parkinson's diseases.
PLoS One. 3, e3135
23. Ono, K., Takahashi, R., Ikeda, T., and Yamada, M. (2012) Cross-seeding effects of amyloid β-
protein and α-synuclein. J. Neurochem. 122, 883–90
24. Masliah, E., Rockenstein, E., Veinbergs, I., Sagara, Y., Mallory, M., Hashimoto, M., and Mucke,
L. (2001) β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a
transgenic mouse model linking Alzheimer’s disease and Parkinson's disease. Proc. Natl. Acad.
Sci. U.S.A. 98, 12245–50
25. Hansen, L., Salmon, D., Galasko, D., Masliah, E., Katzman, R., DeTeresa, R., Thal, L., Pay, M.
M., Hofstetter, R., Klauber, M., Rice, V., Butters, N., and Alford, M. (1990) The Lewy body
variant of Alzheimer’s disease: A clinical and pathologic entity. Neurology. 40, 1–1
26. Kotzbauer, P. T., Cairns, N. J., Campbell, M. C., Willis, A. W., Racette, B. A., Tabbal, S. D., and
Perlmutter, J. S. (2012) Pathologic accumulation of α-synuclein and Aβ in Parkinson disease
patients with dementia. Arch. Neurol. 69, 1326–31
27. Guo, J. L., Covell, D. J., Daniels, J. P., Iba, M., Stieber, A., Zhang, B., Riddle, D. M., Kwong, L.
K., Xu, Y., Trojanowski, J. Q., and Lee, V. M. Y. (2013) Distinct α-synuclein strains differentially
promote tau inclusions in neurons. Cell. 154, 103–117
28. Ittner, L. M., and Götz, J. (2011) Amyloid-β and tau--a toxic pas de deux in Alzheimer’s disease.
Nat. Rev. Neurosci. 12, 65–72
29. Guo, J., Arai, T., Miklossy, J., and Mcgeer, P. L. (2006) Abeta and tau form soluble complexes
that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s
disease. Proc Natl Acad Sci U S A. 103, 1953–8
30. Zempel, H., Thies, E., Mandelkow, E., and Mandelkow, E.-M. (2010) Abeta oligomers cause
localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and
destruction of microtubules and spines. J. Neurosci. 30, 11938–50
31. Terwel, D., Muyllaert, D., Dewachter, I., Borghgraef, P., Croes, S., Devijver, H., and Van Leuven,
F. (2008) Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am. J.
Pathol. 172, 786–98
32. Lewis, J., Dickson, D. W., Lin, W. L., Chisholm, L., Corral, A., Jones, G., Yen, S. H., Sahara, N.,
Skipper, L., Yager, D., Eckman, C., Hardy, J., Hutton, M., and McGowan, E. (2001) Enhanced

8
 neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 293,
1487–91
33. Götz, J., Streffer, J. R., David, D., Schild, A., Hoerndli, F., Pennanen, L., Kurosinski, P., and Chen,
F. (2004) Transgenic animal models of Alzheimer’s disease and related disorders: histopathology,
behavior and therapy. Mol. Psychiatry. 9, 664–83
34. Santhoshkumar, P., and Sharma, K. K. (2004) Inhibition of amyloid fibrillogenesis and toxicity by
a peptide chaperone. Mol. Cell. Biochem. 267, 147–55
35. Helmfors, L., Boman, A., Civitelli, L., Nath, S., Sandin, L., Janefjord, C., McCann, H., Zetterberg,
H., Blennow, K., Halliday, G., Brorsson, A. C., and Kågedal, K. (2015) Protective properties of
lysozyme on beta-amyloid pathology: Implications for Alzheimer disease. Neurobiol. Dis. 83,
122–133
36. Luo, J., Wärmländer, S. K. T. S., Gräslund, A., and Abrahams, J. P. (2013) Human lysozyme
inhibits the in vitro aggregation of Aβ peptides, which in vivo are associated with Alzheimer’s
disease. Chem. Commun. (Camb). 49, 6507–9
37. Gasparini, L., Netzer, W. J., Greengard, P., and Xu, H. (2002) Does insulin dysfunction play a role
in Alzheimer’s disease? Trends Pharmacol Sci. 23, 288–93
38. Phiel, C. J., Wilson, C. A., Lee, V. M., and Klein, P. S. (2003) GSK-3 a regulates production of
Alzheimer’s disease amyloid-beta peptides. Nature. 17, 435–9

Downloaded from http://www.jbc.org/ by guest on June 23, 2016

39. Gasparini, L., Gouras, G. K., Wang, R., Gross, R. S., Beal, M. F., Greengard, P., and Xu, H. (2001)
Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-
amyloid and requires mitogen-activated protein kinase signaling. J. Neurosci. 21, 2561–70
40. Qiu, W. Q., and Folstein, M. F. (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide
in Alzheimer’s disease: review and hypothesis. Neurobiol. Aging. 27, 190–8
41. Tamaki, C., Ohtsuki, S., and Terasaki, T. (2007) Insulin facilitates the hepatic clearance of plasma
amyloid beta-peptide (1-40) by intracellular translocation of low-density lipoprotein receptor-
related protein 1 (LRP-1) to the plasma membrane in hepatocytes. Mol Pharmacol. 72, 850–5
42. Zhao, W.-Q., De Felice, F. G., Fernandez, S., Chen, H., Lambert, M. P., Quon, M. J., Krafft, G. A.,
and Klein, W. L. (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors.
FASEB J. 22, 246–60
43. Luo, J., Wärmländer, S. K. T. S., Gräslund, A., and Abrahams, J. P. (2016) Reciprocal molecular
interactions between the Aβ peptide linked to Alzheimer’s Disease and insulin linked to Diabetes
Mellitus type II. ACS Chem. Neurosci. 10.1021/acschemneuro.5b00325
44. Jaikaran, E. T., and Clark, A. (2001) Islet amyloid and type 2 diabetes: from molecular misfolding
to islet pathophysiology. Biochim. Biophys. Acta. 1537, 179–203
45. Kawahara, M. (2000) Alzheimer’s beta -Amyloid, Human Islet Amylin, and Prion Protein
Fragment Evoke Intracellular Free Calcium Elevations by a Common Mechanism in a
Hypothalamic GnRH Neuronal Cell Line. J. Biol. Chem. 275, 14077–83
46. Cao, P., Marek, P., Noor, H., Patsalo, V., Tu, L.-H., Wang, H., Abedini, A., and Raleigh, D. P.
(2013) Islet amyloid: from fundamental biophysics to mechanisms of cytotoxicity. FEBS Lett. 587,
1106–18
47. Nicolls, M. (2004) The Clinical and Biological Relationship between Type II Diabetes Mellitus
and Alzheimers Disease. Curr. Alzheimer Res. 1, 47–54
48. Mehla, J., Chauhan, B. C., and Chauhan, N. B. (2014) Experimental Induction of Type 2 Diabetes
in Aging-Accelerated Mice Triggered Alzheimer-Like Pathology and Memory Deficits. J.
Alzheimers. Dis. 39, 145–62
49. O’Nuallain, B., Williams, A. D., Westermark, P., and Wetzel, R. (2004) Seeding specificity in
amyloid growth induced by heterologous fibrils. J. Biol. Chem. 279, 17490–9
50. Yan, L.-M., Velkova, A., Tatarek-Nossol, M., Andreetto, E., and Kapurniotu, A. (2007) IAPP
mimic blocks Ab cytotoxic self-assembly: Cross-suppression of amyloid toxicity of Ab and IAPP
suggests a molecular link between Alzheimer’s Disease and Type II Diabetes. Angew. Chem. Int.
Ed. Engl. 46, 1246–52

9
51. Yan, L.-M., Velkova, A., Tatarek-Nossol, M., Rammes, G., Sibaev, A., Andreetto, E., Kracklauer,
M., Bakou, M., Malideli, E., Göke, B., Schirra, J., Storr, M., and Kapurniotu, A. (2013) Selectively
N-methylated soluble IAPP mimics as potent IAPP receptor agonists and nanomolar inhibitors of
cytotoxic self-assembly of both IAPP and Aβ40. Angew. Chem. Int. Ed. Engl. 52, 10378–83
52. Andreetto, E., Yan, L.-M., Tatarek-Nossol, M., Velkova, A., Frank, R., and Kapurniotu, A. (2010)
Identification of hot regions of the Abeta-IAPP interaction interface as high-affinity binding sites
in both cross- and self-association. Angew. Chem. Int. Ed. Engl. 49, 3081–5
53. Cheng, P.-N., Liu, C., Zhao, M., Eisenberg, D., and Nowick, J. S. (2012) Amyloid β-sheet mimics
that antagonize protein aggregation and reduce amyloid toxicity. Nat. Chem. 4, 927–33
54. Ruberg, F. L., and Berk, J. L. (2012) Transthyretin (TTR) cardiac amyloidosis. Circulation. 126,
1286–300
55. Li, X., and Buxbaum, J. N. (2011) Transthyretin and the brain re-visited: is neuronal synthesis of
transthyretin protective in Alzheimer’s disease? Mol. Neurodegener. 6, 79
56. Sousa, J. C., Marques, F., Dias-Ferreira, E., Cerqueira, J. J., Sousa, N., and Palha, J. A. (2007)
Transthyretin influences spatial reference memory. Neurobiol. Learn. Mem. 88, 381–5
57. Ribeiro, C. A., Oliveira, S. M., Guido, L. F., Magalhães, A., Valencia, G., Arsequell, G., Saraiva,
M. J., and Cardoso, I. (2014) Transthyretin Stabilization by Iododiflunisal Promotes Amyloid-β
Peptide Clearance, Decreases its Deposition, and Ameliorates Cognitive Deficits in an Alzheimer’s

Downloaded from http://www.jbc.org/ by guest on June 23, 2016

Disease Mouse Model. J. Alzheimers. Dis. 39, 357–70
58. Kuo, Y., Emmerling, M. R., Lampert, H. C., Hempelman, S. R., Kokjohn, T. A., Woods, A. S.,
Cotter, R. J., and Roher, A. E. (1999) High Levels of Circulating Abeta42 Are Sequestered by
Plasma Proteins in Alzheimer ’ s Disease. Biochem Biophys Res Commun. 791, 787–91
59. Costa, R., Gonçalves, A., Saraiva, M. J., and Cardoso, I. (2008) Transthyretin binding to A-Beta
peptide--impact on A-Beta fibrillogenesis and toxicity. FEBS Lett. 582, 936–42
60. Du, J., Cho, P. Y., Yang, D. T., and Murphy, R. M. (2012) Identification of beta-amyloid-binding
sites on transthyretin. Protein Eng. Des. Sel. 25, 337–45
61. Obici, L., Franceschini, G., Calabresi, L., Giorgetti, S., Stoppini, M., Merlini, G., and Bellotti, V.
(2006) Structure, function and amyloidogenic propensity of apolipoprotein A-I. Amyloid. 13, 191–
205
62. Koldamova, R. P., Lefterov, I. M., Lefterova, M. I., and Lazo, J. S. (2001) Apolipoprotein A-I
directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity.
Biochemistry. 40, 3553–60
63. Vollbach, H., Heun, R., Morris, C. M., Edwardson, J. A., McKeith, I. G., Jessen, F., Schulz, A.,
Maier, W., and Kölsch, H. (2005) APOA1 polymorphism influences risk for early-onset
nonfamiliar AD. Ann. Neurol. 58, 436–41
64. Lewis, T. L., Cao, D., Lu, H., Mans, R. A., Su, Y. R., Jungbauer, L., Linton, M. F., Fazio, S.,
LaDu, M. J., and Li, L. (2010) Overexpression of human apolipoprotein A-I preserves cognitive
function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of
Alzheimer disease. J. Biol. Chem. 285, 36958–68
65. Håkansson, K., Huh, C., Grubb, A., Karlsson, S., and Abrahamson, M. (1996) Mouse and rat
cystatin C: Escherichia coli production, characterization and tissue distribution. Comp. Biochem.
Physiol. B. Biochem. Mol. Biol. 114, 303–11
66. Kaur, G., and Levy, E. (2012) Cystatin C in Alzheimer’s disease. Front. Mol. Neurosci. 5, 79
67. Selenica, M. L., Wang, X., Ostergaard-Pedersen, L., Westlind-Danielsson, A., and Grubb, A.
(2007) Cystatin C reduces the in vitro formation of soluble Abeta1-42 oligomers and protofibrils.
Scand. J. Clin. Lab. Invest. 67, 179–90
68. Tizon, B., Ribe, E. M., Mi, W., Troy, C. M., and Levy, E. (2010) Cystatin C protects neuronal cells
from amyloid-beta-induced toxicity. J. Alzheimers. Dis. 19, 885–94
69. Sastre, M., Calero, M., Pawlik, M., Mathews, P. M., Kumar, A., Danilov, V., Schmidt, S. D.,
Nixon, R. A., Frangione, B., and Levy, E. (2004) Binding of cystatin C to Alzheimer’s amyloid
beta inhibits in vitro amyloid fibril formation. Neurobiol. Aging. 25, 1033–43

10
70. Mi, W., Jung, S. S., Yu, H., Schmidt, S. D., Nixon, R. A., Mathews, P. M., Tagliavini, F., and
Levy, E. (2009) Complexes of amyloid-beta and cystatin C in the human central nervous system. J.
Alzheimers. Dis. 18, 273–80
71. Sun, B., Zhou, Y., Halabisky, B., Lo, I., Cho, S.-H., Mueller-Steiner, S., Devidze, N., Wang, X.,
Grubb, A., and Gan, L. (2008) Cystatin C-cathepsin B axis regulates amyloid beta levels and
associated neuronal deficits in an animal model of Alzheimer’s disease. Neuron. 60, 247–57
72. Wang, C., Sun, B., Zhou, Y., Grubb, A., and Gan, L. (2012) Cathepsin B degrades amyloid-β in
mice expressing wild-type human amyloid precursor protein. J. Biol. Chem. 287, 39834–39841
73. Mold, M., Shrive, A. K., and Exley, C. (2012) Serum amyloid P component accelerates the
formation and enhances the stability of amyloid fibrils in a physiologically significant under-
saturated solution of amyloid-beta 42. J. Alzheimer’s Dis. 29, 875–881
74. Pepys, M. B., Booth, D. R., Hutchinson, W. L., Gallimore, J. R., Collins, I. M., and Hohenester, E.
(1997) Amyloid P component. A critical review. Amyloid. 4, 274–295
75. Pepys, M. B., Herbert, J., Hutchinson, W. L., Tennent, G. A., Lachmann, H. J., Gallimore, J. R.,
Lovat, L. B., Bartfai, T., Alanine, A., Hertel, C., Hoffmann, T., Jakob-Roetne, R., Norcross, R. D.,
Kemp, J. A., Yamamura, K., Suzuki, M., Taylor, G. W., Murray, S., Thompson, D., Purvis, A.,
Kolstoe, S., Wood, S. P., and Hawkins, P. N. (2002) Targeted pharmacological depletion of serum
amyloid P component for treatment of human amyloidosis. Nature. 417, 254–259

Downloaded from http://www.jbc.org/ by guest on June 23, 2016

76. Cortes-Canteli, M., Zamolodchikov, D., Ahn, H. J., Strickland, S., and Norris, E. H. (2012)
Fibrinogen and altered hemostasis in Alzheimer’s disease. J. Alzheimers. Dis. 32, 599–608
77. Boddaert, J., Kinugawa, K., Lambert, J.-C., Boukhtouche, F., Zoll, J., Merval, R., Blanc-Brude, O.,
Mann, D., Berr, C., Vilar, J., Garabedian, B., Journiac, N., Charue, D., Silvestre, J.-S., Duyckaerts,
C., Amouyel, P., Mariani, J., Tedgui, A., and Mallat, Z. (2007) Evidence of a role for lactadherin in
Alzheimer’s disease. Am. J. Pathol. 170, 921–9
78. Yang, G.-Z., Yang, M., Lim, Y., Lu, J.-J., Wang, T.-H., Qi, J.-G., Zhong, J.-H., and Zhou, X.-F.
(2012) Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and
modulates amyloid beta levels in neurons. J. Neurochem. 122, 1010–22
79. Gray, E. H., De Vos, K. J., Dingwall, C., Perkinton, M. S., and Miller, C. C. J. (2010) Deficiency
of the copper chaperone for superoxide dismutase increases amyloid-β production. J. Alzheimers.
Dis. 21, 1101–5
80. Celsi, F. (2004) Overexpression of superoxide dismutase 1 protects against β-amyloid peptide
toxicity: effect of estrogen and copper chelators. Neurochem. Int. 44, 25–33
81. Wallin, C., Kulkarni, Y. S., Abelein, A., Jarvet, J., Liao, Q., Strodel, B., Olsson, L., Luo, J.,
Abrahams, J., Sholts, S., Roos, P., Kamerlin, S., Gräslund, A., and Wärmländer, S. (2016)
Characterization of Mn(II) ion binding to the amyloid-β peptide in Alzheimer’s disease. J. Trace
Elem. Med. Biol. 10.1016/j.jtemb.2016.03.009
82. Hane, F., Tran, G., Attwood, S. J., and Leonenko, Z. (2013) Cu 2 + Affects Amyloid-β(1–42)
Aggregation by Increasing Peptide-Peptide Binding Forces. PLoS One.
10.1371/journal.pone.0059005
83. Luo, J., Mohammed, I., Wärmländer, S. K. T. S., Hiruma, Y., and Abrahams, J. P. (2014)
Endogenous polyamines reduce the toxicity of soluble Aβ peptide aggregates associated with
Alzheimer’s Disease. Biomacromolecules. 15, 1985–1991
84. Luo, J., Yu, C.-H., Yu, H., Borstnar, R., Kamerlin, S. C. L., Gräslund, A., Abrahams, J. P., and
Wärmländer, S. K. T. S. (2013) Cellular polyamines promote amyloid-Beta (aβ) Peptide
fibrillation and modulate the aggregation pathways. ACS Chem. Neurosci. 4, 454–62
85. Luo, J., Wärmländer, S. K. T. S., Gräslund, A., and Abrahams, J. P. (2014) Non-chaperone
Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid β Peptide. J. Biol. Chem.
289, 27766–75
86. Munishkina, L. a, Cooper, E. M., Uversky, V. N., and Fink, A. L. (2004) The effect of
macromolecular crowding on protein aggregation and amyloid fibril formation. J. Mol. Recognit.
17, 456–64

11
87. Kim, Y. E., Hipp, M. S., Bracher, A., Hayer-Hartl, M., and Hartl, F. U. (2013) Molecular
chaperone functions in protein folding and proteostasis. Annu. Rev. Biochem. 82, 323–55
88. Sparr, E., Engel, M. F. M., Sakharov, D. V, Sprong, M., Jacobs, J., Killian, J. A., Kruijff, B. De,
and Jo, W. M. H. (2004) Islet amyloid polypeptide-induced membrane leakage involves uptake of
lipids by forming amyloid fibers. FEBS Lett. 577, 117–120
89. Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T., and Peter, T. L. (2002) Amyloid pores from
pathogenic mutations. Nature. 418, 4–5
90. Lee, H., Bae, E., and Lee, S. (2014) Extracellular α‑synuclein—a novel and crucial factor in Lewy
body diseases. Nat. Rev. Neurosci. 10, 92–98
91. Ettle, B., Reiprich, S., Deusser, J., Schlachetzki, J. C. M., Xiang, W., Prots, I., Masliah, E., Winner,
B., Wegner, M., and Winkler, J. (2014) Molecular and Cellular Neuroscience Intracellular alpha-
synuclein affects early maturation of primary oligodendrocyte progenitor cells. Mol. Cell.
Neurosci. 62, 68–78
92. Wang, Y., and Mandelkow, E. (2015) Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–
21
93. Adler-Abramovich, L., Vaks, L., Carny, O., Trudler, D., Magno, A., Caflisch, A., Frenkel, D., and
Gazit, E. (2012) Phenylalanine assembly into toxic fibrils suggests amyloid etiology in
phenylketonuria. Nat. Chem. Biol. 8, 701–6

Downloaded from http://www.jbc.org/ by guest on June 23, 2016

94. Luo J, Wärmländer SK, Yu CH, Muhammad K, Gräslund A, Abrahams, J. P. (2014) The Abeta
peptide forms non-amyloid fi brils in the presence of carbon nanotubes. Nanoscale. 6, 6720–6726
95. Ahn, H. J., Zamolodchikov, D., Cortes-Canteli, M., Norris, E. H., Glickman, J. F., and Strickland,
S. (2010) Alzheimer’s disease peptide beta-amyloid interacts with fibrinogen and induces its
oligomerization. Proc. Natl. Acad. Sci. U. S. A. 107, 21812–7
96. Li, X.-H., Lv, B.-L., Xie, J.-Z., Liu, J., Zhou, X.-W., and Wang, J.-Z. (2012) AGEs induce
Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation.
Neurobiol. Aging. 33, 1400–10
97. Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castaño EM, F. B. (1998) Beta-sheet breaker
peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer’s
therapy. Nat. Med. 4, 822–826
98. Luo, J., Otero, J. M., Yu, C.-H., Wärmländer, S. K. T. S., Gräslund, A., Overhand, M., and
Abrahams, J. P. (2013) Inhibiting and reversing amyloid-β peptide (1-40) fibril formation with
gramicidin S and engineered analogues. Chemistry. 19, 17338–48
99. Luo, J., and Abrahams, J. P. (2014) Cyclic Peptides as Inhibitors of Amyloid Fibrillation.
Chemistry. 20, 2410–2419
100. Reardon, S. (2015) Alzheimer’s drugs show progress. Nature. 523, 509–510

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Table and Figure legends

Figure 1. A cross-amyloid network for the Aβ peptide. Red lines: amyloid proteins that enhance the risk
of AD in mice models or in vivo. Green lines: amyloid proteins that decrease the progression of AD in
mice models. Blue circles: amyloid proteins that promote Aβ fibrillation in vitro. Green circles: amyloid
proteins that suppress Aβ fibrillation in vitro. Grey circles and lines: unknown. The details of the
interactions on which the connections are based are discussed in the article for each protein.

Figure 2. A probabilistic consistency-based multiple alignment of amyloid protein sequences calculated

by the T-coffee server (www.tcoffee.org/Projects/tcoffee/). Consistencies range from poor (blue) to good
(red). It is clear that both the N- and C- termini of amyloid proteins display high probabilistic sequence
consistency.

Table 1. Associations between amyloid proteins and certain diseases, according to current understanding.
An association is indicated if aggregation of the protein leads to amyloidosis associated with the disease,
based on results either in vivo, in vitro, or in mice as discussed in the article for each protein.

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14
Figure 1.
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15
Figure 2.
 Table 1

Immunoglobulin light chain

Superoxide dismutase
β-2-microglobulin

Serum amyloid A

Transthyretin
Fibrinogen α

Lactadherin
α-synuclein
Tau protein

Huntingtin

Lysozyme
Cystatin

APOA1

Insulin
Abeta

IAPP
Alzheimer × × × × × × × × × ×
Huntington × ×
Aortic medial amyloid ×
Hepatic or renal amyloidosis ×

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Familial amyotrophic lateral sclerosis ×
Type 2 diabetes × × ×
System amyloidosis × × × ×
Rheumatoid arthritis ×
Parkinson × × ×
Injection-localized amyloidosis ×
Dialysis related amyloidosis ×
Familial amyloid polyneuropathy ×

16
 Cross interactions between the Alzheimer′s disease amyloid-β peptide and other
amyloid proteins: a further aspect of the amyloid cascade hypothesis
Jinghui Luo, Sebastian K.T.S. Wärmländer, Astrid Gräslund and Jan Pieter Abrahams
J. Biol. Chem. published online June 20, 2016 originally published online June 20, 2016

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