Amylin at the interface between metabolic and neurodegenerative disorders

Abstract

The pancreatic peptide amylin is best known for its role as a satiation hormone in the control of food intake and as the major component of islet amyloid deposits in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Epidemiological studies have established a clear association between metabolic and neurodegenerative disorders in general, and between T2DM and Alzheimer's disease (AD) in particular. Here, we discuss that amylin may be an important player acting at the interface between these metabolic and neurodegenerative disorders. Abnormal amylin production is a hallmark peripheral pathology both in the early (pre-diabetic) and late phases of T2DM, where hyperamylinemic (early phase) and hypoamylinemic (late phase) conditions coincide with hyper- and hypo-insulinemia, respectively. Moreover, there are notable biochemical similarities between amylin and β-amyloids (Aβ), which are both prone to amyloid plaque formation and to cytotoxic effects. Amylin's propensity to form amyloid plaques is not restricted to pancreatic islet cells, but readily extends to the CNS, where it has been found to co-localize with Aβ plaques in at least a subset of AD patients. Hence, amylin may constitute a “second amyloid” in neurodegenerative disorders such as AD. We further argue that hyperamylinemic conditions may be more relevant for the early processes of amyloid formation in the CNS, whereas hypoamylinemic conditions may be more strongly associated with late stages of central amyloid pathologies. Advancing our understanding of these temporal relationships may help to establish amylin-based interventions in the treatment of AD and other neurodegenerative disorders with metabolic comorbidities.

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published: 16 June 2015
doi: 10.3389/fnins.2015.00216
Frontiers in Neuroscience | www.frontiersin.org 1June 2015 | Volume 9 | Article 216
Edited by:
Tommaso Cassano,
University of Foggia, Italy
Luca Steardo,
Sapienza University of Rome, Italy
Reviewed by:
Massimo Grilli,
University of Genova, Italy
Fabio Di Domenico,
Sapienza University of Rome, Italy
*Correspondence:
Thomas A. Lutz,
Institute of Veterinary Physiology,
University of Zurich,
Winterthurerstrasse 260, 8057 Zurich,
Switzerland
tomlutz@vetphys.uzh.ch
Specialty section:
This article was submitted to
Neuropharmacology,
a section of the journal
Frontiers in Neuroscience
Received: 30 April 2015
Accepted: 29 May 2015
Published: 16 June 2015
Citation:
Lutz TA and Meyer U (2015) Amylin at
the interface between metabolic and
neurodegenerative disorders.
Front. Neurosci. 9:216.
doi: 10.3389/fnins.2015.00216
Amylin at the interface between
metabolic and neurodegenerative
disorders
Thomas A. Lutz 1, 2*and Urs Meyer 3
1Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland, 2Zurich Center of Integrative Human Physiology,
University of Zurich, Zurich, Switzerland, 3Institute of Veterinary Pharmacology and Toxicology, University of Zurich, Zurich,
Switzerland
The pancreatic peptide amylin is best known for its role as a satiation hormone in
the control of food intake and as the major component of islet amyloid deposits in
the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Epidemiological
studies have established a clear association between metabolic and neurodegenerative
disorders in general, and between T2DM and Alzheimer’s disease (AD) in particular. Here,
we discuss that amylin may be an important player acting at the interface between these
metabolic and neurodegenerative disorders. Abnormal amylin production is a hallmark
peripheral pathology both in the early (pre-diabetic) and late phases of T2DM, where
hyperamylinemic (early phase) and hypoamylinemic (late phase) conditions coincide
with hyper- and hypo-insulinemia, respectively. Moreover, there are notable biochemical
similarities between amylin and β-amyloids (Aβ), which are both prone to amyloid plaque
formation and to cytotoxic effects. Amylin’s propensity to form amyloid plaques is not
restricted to pancreatic islet cells, but readily extends to the CNS, where it has been found
to co-localize with Aβplaques in at least a subset of AD patients. Hence, amylin may
constitute a “second amyloid” in neurodegenerative disorders such as AD. We further
argue that hyperamylinemic conditions may be more relevant for the early processes of
amyloid formation in the CNS, whereas hypoamylinemic conditions may be more strongly
associated with late stages of central amyloid pathologies. Advancing our understanding
of these temporal relationships may help to establish amylin-based interventions in the
treatment of AD and other neurodegenerative disorders with metabolic comorbidities.
Keywords: amylin, Alzheimer’s disease (AD), β-amyloid, dementia, hyperglycemia, insulin, obesity, type-2 diabetes
Introduction
A growing number of individuals suffer from aging-associated neurological and cognitive
dysfunctions that are characterized by progressive neurodegeneration and dementia. The global
prevalence of dementia is currently estimated to be as high as 30–40 million, and is predicted to
quadruple by the year 2050 (Reitz et al., 2011; Hurd et al., 2013; Reitz and Mayeux, 2014). The
most common form of aging-associated dementia is late-onset or sporadic Alzheimer’s disease
(AD) (Hampel et al., 2011; Reitz et al., 2011), a neurodegenerative disorder affecting multiple
cognitive and behavioral functions. AD patients typically show progressive cognitive decline
along with the concomitant appearance of several neuropathological hallmarks, including amyloid

Lutz and Meyer Amylin in neurodegenerative disorders
plaque deposition, neurofibrillary tangle formation, vascular
malfunction, and synaptic loss (Ferrer, 2012). Several other
pathological processes have been identified in the early stages
of the disease, which in turn may play a major etiopathological
role in sporadic AD. These include increased oxidative stress,
neuroinflammation, and impairments in brain glucose uptake
and metabolism (Eikelenboom et al., 2010; Bassil et al., 2014;
Chen and Zhong, 2014; Morales et al., 2014). Hence, sporadic AD
likely represents a multifactorial disease caused by a multitude
of synergistically interacting pathological changes, resulting in
severe cognitive impairments and extensive brain tissue atrophy
(McDonald, 2002).
In parallel to the global increase in neurodegenerative
disorders, there is a rising prevalence of metabolic diseases, most
notably obesity and type-2 diabetes mellitus (T2DM) (Ginter and
Simko, 2012a,b). Obesity is typically referred to as a medical
condition, in which excess body fat has accumulated to the extent
that the body mass index (BMI) exceeds 30 kg/m2(Chiang et al.,
2011). It is thought to be one of the primary causes of T2DM
(Chiang et al., 2011; Ginter and Simko, 2012a,b). Depending
on its clinical course and disease stage, T2DM involves altered
glycemic regulation and hyperglycemia, resistance to insulin
actions, inadequate insulin secretion from pancreatic β-cells, as
well as progressive loss of pancreatic β-cells which is paralleled by
deposition of islet amyloid polypeptide, or amylin, as pancreatic
amyloid (Kahn et al., 2014).
Besides their negative effects on body homeostasis, peripheral
metabolic diseases also appear to play an important role in
aging-associated cognitive impairments and neurodegenerative
disorders such as AD (de la Monte and Tong, 2014; Ríos
et al., 2014). Epidemiological studies have repeatedly shown a
significant association between (midlife) obesity and late-onset
dementias (Yaffe, 2007; Arnoldussen et al., 2014; Kiliaan et al.,
2014; Emmerzaal et al., 2015). Likewise, patients with T2DM
are 2- to 5-times more likely to develop AD compared to
non-diabetic individuals (Ott et al., 1996; Li and Hölscher,
2007; Butterfield et al., 2014; Desai et al., 2014). Additional
support for these epidemiological associations can be derived
from investigations in animal models showing that diet-
induced obesity and T2DM impair behavioral and cognitive
functions relevant to human dementia (Greenwood and
Winocur, 2005; Winocur and Greenwood, 2005; Morris
and Tangney, 2014) and exacerbate neuropathological and
cognitive deficits in genetic mouse models of AD (Leboucher
et al., 2013; Vandal et al., 2014). Based on these findings, it
has been proposed that AD and related neurodegenerative
disorders may represent a form of “type-3 diabetes.” According
to this hypothesis, impaired brain insulin and insulin-like
growth factor (IGF) signaling, or “brain insulin resistance,”
may trigger and promote neurodegenerative processes via
multiple interrelated pathological mechanisms, including
attenuation of brain glucose uptake and subsequent emergence
of central hypometabolism, mitochondrial dysfunction and
oxidative stress, cerebro-vascular disruption, as well as
imbalances in neuroinflammatory reactions (reviewed in
de la Monte and Wands, 2008; de la Monte, 2012; Bassil
et al., 2014; Sebastião et al., 2014). At the same time, some
of the AD-associated neuropathologies themselves, especially
extracellular amyloid plaques, may promote brain insulin
resistance (de la Monte, 2012). Hence, there could be a
positive feedback loop between brain insulin resistance and
amyloid plaque formation, which together may facilitate
progressive neurodegeneration and cognitive decline (de la
Monte, 2012). This hypothesis is also supported by recent
preclinical investigations and clinical trials demonstrating
beneficial effects of compounds with anti-diabetic properties
on attenuating or normalizing cognitive impairments and
AD-related neuropathologies (for review, see Bassil et al., 2014;
Sebastião et al., 2014).
In the present article, we discuss the potential role of the
pancreatic peptide amylin, also called islet amyloid polypeptide
(IAPP), as a link between metabolic and neurodegenerative
disorders in general, and between T2DM and AD in particular.
Amylin is best known for its role as a satiation hormone in
the control of food intake (Lutz, 2005, 2009, 2010) and as
the major component of amyloid deposits in pancreatic islets
of patients with T2DM and of cats (Lutz and Rand, 1993;
Westermark et al., 2000; Osto et al., 2013). Because of its
propensity to form amyloid deposits in susceptible species like
primates and cats, amylin shares several pathological features
with β-amyloids (Aβ), a family of amyloidogenic peptides most
frequently implicated in the neuropathology of AD (Karran
et al., 2011; Seeman and Seeman, 2011). Here, we discuss these
similarities following a concise introduction in amylin’s main
physiological roles. Particular emphasis is then placed on the
potential mechanisms of amylin and Aβamyloidogenesis, and on
the recent findings directly implicating amylin amyloids in the
neuropathology of AD.
Physiological Roles and Actions of Amylin
Amylin Acts as a Satiation Signal
Amylin is a pancreatic β-cell hormone co-released with insulin
in response to food intake (Kahn et al., 1990). It reduces
eating, gastric acid secretion, limits the rate of gastric emptying,
and diminishes pancreatic glucagon secretion (Lutz, 2010). One
of the best-studied functions of amylin relates its role as a
satiation signal: via regulating meal size (Lutz et al., 1995b;
Reidelberger et al., 2002; Mollet et al., 2004), it contributes to
meal termination akin to other typical satiating hormones such
as cholecystokinin (CCK) (Young and Denaro, 1998; Lutz, 2010).
The anorectic actions of amylin represent physiological effects as
eating leads to a rapid increase in circulating amylin levels, and
the administration of exogenous amylin reduces eating within
minutes after application. Further, amylin’s capacity to reduce
meal size is dose dependent and is effectively and specifically
blocked by amylin antagonists like AC187 (Mollet et al., 2004;
Reidelberger et al., 2004). Importantly, amylin and its synthetic
analogs reduce meal size without producing signs of conditioned
taste aversion or visceral illness (Lutz et al., 1995b; Rushing
et al., 2002; Mack et al., 2007). Overall, these data indicate that
amylin acts as a specific and physiological satiating hormone that
mediates its short-term effects on food intake mainly via reducing
meal sizes.
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Amylin Acts as Adiposity Signal
The concept of “homeostatic eating controls” classically
distinguishes between adiposity (“tonic”) signals and meal-
associated (“episodic”) signals. Adiposity signals are secreted
by adipose tissue (leptin) or the pancreas (insulin, amylin) in
proportion to body adiposity and are thought to reduce eating
by enhancing the effects of satiation signals. For example, amylin
enhances the satiating effects of cholecystokinin (CCK) (Bhavsar
et al., 1998; Mollet et al., 2003). A number of other findings
support a role for amylin as an adiposity signal. For example,
basal plasma levels of amylin are higher in obese relative to
lean rats (Pieber et al., 1994), and high-fat fed obese rats have
higher baseline amylin levels compared to lean controls (Boyle
and Lutz, 2011; Boyle et al., 2011). Moreover, chronic peripheral
(Arnelo et al., 1996; Lutz et al., 2001) or central (Rushing et al.,
2002) administration of amylin decreases body weight and fat
gain, whereas treatment with amylin antagonists increases body
adiposity (Rushing et al., 2001). Together, these data suggest that
central amylin, like leptin or insulin, may encode a certain level
of body weight, and therefore, may contribute to the relative
constancy of body weight throughout adult life.
Amylin and Energy Expenditure
The physiological roles and actions of amylin have been further
explored using pair-feeding research designs in rats, in which
the amount of food available for vehicle-treated animals was
determined by the amount of food ingested by amylin-treated
animals. These studies showed that the reduction in body fat
is greater in rats chronically treated with exogenous amylin as
compared to pair-fed controls (Isaksson et al., 2005; Roth et al.,
2006; Mack et al., 2007). These findings indicate that amylin not
only reduces food intake but also increases energy expenditure
(Isaksson et al., 2005; Wielinga et al., 2007, 2010). Again, these
dual effects of amylin are similar to those induced by leptin,
which is known to influence energy balance through concomitant
effects on eating and an energy expenditure (Friedman, 1997;
Schwartz et al., 2000, 2003). Increases in energy expenditure can
also been seen in rats after acute central infusion of amylin into
discrete brain areas, including the third cerebral ventricle or area
postrema (AP) (Osaka et al., 2008; Wielinga et al., 2010).
Two recent studies provided novel mechanistic insights into
amylin’s effect on energy metabolism (Zhang et al., 2011;
Fernandes-Santos et al., 2013). Similar to humans, total energy
expenditure in rodents partially depends on the thermogenic
activity of the brown adipose tissue (BAT), which in turn is
controlled by the sympathetic nervous system (Nedergaard and
Cannon, 2014). BAT thermogenic activity is increased by amylin
through actions involving the sympathetic nervous system, and
these effects are enhanced in transgenic mice that overexpress
the receptor activity-modifying protein 1 (RAMP1) of the
amylin receptor complex. More specifically, transgenic mice
with neuronal overexpression of RAMP1 show a potentiated
metabolic response to exogenous amylin treatment and display
a number of basal metabolic changes, including reduced body
weight and fat mass, increased energy expenditure and body
temperature, and hypophagia. It has been further shown that
the effects of RAMP1 overexpression on energy expenditure
are mediated by an increased sympathetic tone in efferents
innervating BAT (Zhang et al., 2011; Fernandes-Santos et al.,
2013).
Central Mechanisms Underlying the
Actions of Amylin
Amylin receptor autoradiography studies demonstrate that
several brain areas have high affinity binding sites for amylin
(Sexton et al., 1994). Amylin binding is particularly strong
in the circumventricular organs such as the subfornical organ
(SFO) and AP. A large number of studies indicate that the AP
plays an important role in mediating the physiological effects
of peripheral amylin. Amylin appears to activate AP neurons
by direct humoral actions, whilst vagal or non-vagal afferents
do not seem to be required in these processes (Edwards et al.,
1998; Lutz et al., 1995a, 1998a,b; Wickbom et al., 2008; Mack
et al., 2010; Braegger et al., 2014). Local amylin administration
into the AP recapitulates the effects of peripheral amylin, and
AP-directed infusion of the amylin antagonist AC187 exerts the
opposite effects. Furthermore, local administration of AC187 into
the AP has been shown to abolish the eating inhibitory effect of
peripheral amylin (Mollet et al., 2004), suggesting that central
actions in the AP are necessary for mediating the anorectic effects
of peripheral amylin.
Amylin-induced activation of AP neurons readily induces a
number of neuronal downstream effects, including stimulation
of dopamine-beta-hydroxylase (DBH) and subsequent increase
in noradrenaline synthesis and release in noradrenergic
output areas (Potes et al., 2010). In addition to its effects
on noradrenergic neurons, amylin may further target other
neurotransmitter systems in the AP, including presynaptic
glutamatergic terminals innervating AP neurons (Fukuda et al.,
2013). The functional contribution of these glutamatergic
terminals, however, remains unknown with regards to amylin’s
effects on food intake, metabolism, and other physiological
processes.
Stimulation of AP neurons by peripheral amylin likely leads
to the activation of a neuroaxis that projects rostrally to the
forebrain and includes the nucleus tractus solitarii (NTS),
lateral parabrachial nuclus (LPB), and central amygdala (CeA)
(Rowland et al., 1997; Riediger et al., 2004). In addition to its
stimulating effects on these brain regions, which most likely
follows primary AP activation (Riediger et al., 2004), amylin
further seems to activate key areas of the mesolimbic dopamine
system, including the ventral tegmental areas (VTA) and nucleus
accumbens (NAc). These two regions display high affinity amylin
binding sites and seem to contain virtually all components
of the amylin receptor complex (Mietlicki-Baase et al., 2013;
Mietlicki-Baase and Hayes, 2014). The mesolimbic dopamine
system has long been recognized to play a crucial role in reward
processing including eating associated rewards (Berridge and
Robinson, 1998; Volkow et al., 2013). With respect to the latter,
it has been suggested that pathological conditions of overeating
may represent a compensation for decreased activity of the
mesolimbic and nigrostriatal dopamine circuits (Wang et al.,
2001). This hypothesis is consistent with the notion that the
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rewarding properties of food can stimulate feeding behavior even
when energy requirements have been met, thereby contributing
to excessive weight gain and obesity (Kenny, 2011).
In this context, it is interesting that direct local administration
of the amylin receptor and calcitonin receptor agonist salmon
calcitonin into the VTA of rats has been found to reduce the
intake of standard rodent chow diet and of palatable sucrose.
These anorectic effects appeared to result from reductions in
meal size, suggesting that activation of VTA neurons by salmon
calcitonin may modulate the reward value of food, thereby
reducing the size of a meal. On the contrary, administration
of the amylin antagonist AC187 into the VTA increased
eating, and intra-accumbens injection of AC187 attenuated the
anorectic effects of peripheral treatment with salmon calcitonin
(Mietlicki-Baase et al., 2013); local knockdown of the calcitonin
receptor (CTR)—the core component of functional amylin
receptors (Bailey et al., 2012)—in the VTA also resulted in
hyperphagia (Mietlicki-Baase et al., 2015). Further, salmon
calcitonin administered to the VTA resulted in reduced phasic
dopamine release into the NAc core, and blockade of dopamine
D1 and D2 receptors in the NAc core blunted salmon calcitonin’s
eating inhibitory effect (Mietlicki-Baase et al., 2015). Finally, the
NAc shell may also be directly responsive to amylin receptor
stimulation because low doses of amylin given into the NAc shell
reduced eating in rats; amylin also inhibited the eating response
induced by opioid receptor activation indicating that amylin
signaling may negatively modulate opioid reward driven eating
(Baisley and Baldo, 2014).
Together, these findings indicate that peripheral amylin may,
in addition to its actions on the AP and interconnected areas,
exert a direct influence on VTA or NAc neurons and induce
physiologically relevant effects on satiation and food reward. It
will be important to test in future studies whether the observed
effects via the VTA or NAc do depend on a primary action of
amylin in these areas or perhaps still in the AP. It has been shown
that the rat amylin-1 receptor (Bailey et al., 2012) is activated
equally by amylin but also the neurotransmitter calcitonin gene-
related peptide (CGRP), and, importantly, that the effects of
both peptides at the amylin-1 receptor are blocked by AC187.
Hence, it is possible that primary activation of AP neurons
may trigger CGRP release in various brain areas, including
the VTA or the NAc, to explain the observations discussed
above.
Amylin Amyloid Formation
The aforementioned physiological effects of amylin all require
solubility of the monomeric hormone so that it can effectively
reach the target organs and cells upon release by pancreatic
β-cells. Under certain pathological conditions such as T2DM,
however, amylin can self-aggregate and eventually form insoluble
amylin amyloid plaques. As described in detail in the subsequent
sections, this effect is only relevant in few species, including
humans, other primates and cats when amylin amyloid
loses its common physiological actions, but instead, induces
toxic effects on both peripheral and central organs and
cells.
Mechanisms of Amyloidogenesis
The secreted and biologically active form of amylin contains
37 amino acids. It is initially expressed as a pre-pro-protein
containing 89 amino acids, which includes the actual signal
peptide domain (22 acids) and two short flanking peptides
(Höppener et al., 1994; Marzban et al., 2004, 2005; Wang et al.,
2011). Similar to pro-insulin, pre-pro-amylin is processed to pro-
amylin in the endoplasmic reticulum (ER), during which the
signal peptide and flanking peptides are cleaved from the rest.
The resulting pro-amylin is then further processed by proteolysis
and posttranslational modifications in the Golgi apparatus, where
a disulfide bond between cysteine residues 2 and 7 is formed. The
biologically active amylin is then stored in the halo region of the
secretory granules of the β-cell and is co-secreted with insulin
(Westermark et al., 1996).
The amino acid sequence of amylin is strongly conserved
among mammalian species. Formation of amylin amyloids,
however, can only emerge in the pancreatic islets of humans,
primates, and cats, but not in rodents. The reason for this species
differences is that only the former contain an amyloidogenic
region within their amino acid sequence that is essential for
amyloid formation and toxicity (Betsholtz et al., 1989; Höppener
et al., 1994; Moriarty and Raleigh, 1999; Matveyenko and Butler,
2006). In the case of amylin, amyloidogenesis seems to be
associated with the heterogeneity of the amino acid residues
20–29 of the amylin sequence. In species where pancreatic
amyloid deposition does not occur (e.g., mouse or rat), one or
more proline residues can be found in this region. Hence, it is
believed that the presence of proline prevents the formation of
ordered secondary structures such as the β-sheet conformation,
which is an essential prerequisite for amyloidogenesis (Betsholtz
et al., 1989; Höppener et al., 1994; Moriarty and Raleigh, 1999;
Matveyenko and Butler, 2006).
Under physiological conditions, monomeric amylin is soluble
and natively unfolded. It is believed that amylin is protected
from aggregation under these conditions by interactions with
other components of the secretory vesicles, including insulin,
pro-insulin, or their processing intermediates (Westermark et al.,
1996). It seems that a relative increase in the concentration
of amylin within the halo region of pancreatic islet cells can
initiate their aggregation and formation of fibrils under certain
conditions (Paulsson et al., 2006). When fibril formation begins,
the molecules in β-sheet conformation are bound to each other,
predominantly by hydrogen bounds. The β-sheet conformation
typically forms thin and stable layers, in which the β-strands are
oriented perpendicular to the fibril axis.
Interestingly, amylin’s amyloidogenic properties are not
restricted to mature amylin but further extend to pro-amylin
and its intermediates (Westermark et al., 2000; Paulsson and
Westermark, 2005; Paulsson et al., 2006). In fact, the latter may
be the starting point of oligomerization and amylin aggregation
within the pancreatic islets (Westermark et al., 2000; Jaikaran
and Clark, 2001; Jaikaran et al., 2001; Paulsson et al., 2006).
It should be noted, however, that no precise localization of
the aggregates within the cells has been demonstrated yet.
In studies using baboons, amyloid deposits were observed in
the cytoplasm of β-cells as well as bound to the outer β-cell
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Lutz and Meyer Amylin in neurodegenerative disorders
membrane (Guardado-Mendoza et al., 2009). In other studies,
where islets from diabetic patients were transplanted into nude
mice or cultured in vitro, amylin-derived amyloid was found
to form an intracellular network, suggesting its presence in the
ER, Golgi apparatus and secretory vesicles (Westermark et al.,
1995a,b; Yagui et al., 1995; Paulsson et al., 2006). Recent evidence
further suggests that the early processes of amyloidogenesis
from amylin depend on pH, which can markedly affect the
electrostatic interactions required for β-sheet formation and
amylin fibrillization (Li et al., 2013; Jha et al., 2014).
Abnormalities in the processing of amylin and its deposition
as amyloid in the islets may contribute to the progressive loss of
pancreatic β-cells, which is a pathological hallmark of T2DM.
Indeed, islet amyloid formation is a striking abnormality of
human T2DM and can be found in more than 90% of T2DM
patients (Clark and Nilsson, 2004). Similarly, islet amyloid is
a very prominent feature in diabetic cats (Lutz and Rand,
1993; Osto et al., 2013). Even though the association between
amylin amyloid deposition and pancreatic β-cell loss in T2DM
seems robust, the underlying etiopathological processes remain
to be determined. According to one hypothesis, prolonged
hyperglycemia may lead to a higher concentration of pro-amylin
within the β-cells (Hou et al., 1999), which in turn may create a
core for amylin aggregation and ultimately cause β-cell loss and
deposition of extracellular amyloid (Paulsson and Westermark,
2005). An alternative (but mutually not exclusive) mechanism for
amylin aggregation may include increased retention of amylin in
β-cell granules as a result of increased sympathetic stimulation
(Watve et al., 2014). In addition, high levels of circulating
free fatty acids, as observed in pre-diabetic patients or patients
with overt T2DM, has been implicated as possible mechanism
facilitating amyloid formation (Li and Hölscher, 2007).
Pathological Effects of Amylin Deposits on
Pancreatic β-Cells
Islet amyloid formation plays a key role in β-cell apoptosis
and dysfunction as seen in T2DM (Westermark et al., 2000,
2011; Paulsson and Westermark, 2005; Höppener and Lips, 2006;
Jurgens et al., 2011). As discussed in the subsequent sections, it is
believed that the toxic effects induced by amylin amyloid deposits
depend on a combination of mechanisms that act both intra- and
extra-cellulary.
One of the prominent features associated with amylin-related
β-cell toxicity is ER stress (Preston et al., 2009). Peripheral insulin
resistance triggers β-cells to produce more insulin in parallel
with an increased synthesis of amylin. As these proteins are
destined for exocytosis, they are transported through the ER
and trans-Golgi complex and stored in secretory granules before
secretion. ER stress is characterized by the unfolded protein
response (UPR), which is induced to cope with an increase
in protein synthesis or obstruction in the ER-Golgi transport
(Preston et al., 2009). UPR involves the upregulation of ER-
located chaperones to assist in the folding of proteins that are
prone to aggregation. Under homeostatic conditions, misfolded
proteins are normally transported to the ubiquitin-proteasome
system for degradation, thus preventing protein aggregation
and amyloidogenesis. Failure of such homestatic responses
typically leads to induction of cell apoptosis (Oyadomari et al.,
2002; Marciniak and Ron, 2006; Davenport et al., 2008). Such
processes may be operational especially during the early phase of
T2DM, during which amylin and insulin syntheses are markedly
increased as a consequence of insulin resistance, leading to non-
homeostatic UPR and eventually β-cell apoptosis.
Abnormally enhanced accumulation of fibrillar material in the
halo region of secretory vesicles may also lead to a disruption
of the vesicles and result in the release of fibrillar material into
the cytosol. Because the proteasome pathway can only degrade
misfolded single proteins but not their aggregates, a cellular
process commonly referred to as “autophagy” dissolves the latter.
It is a well-preserved catabolic process that is activated to degrade
and recycle misfolded proteins and excess or defective organelles
(Stienstra et al., 2014). Under non-pathological conditions,
autophagosomes typically fuse with lysosomes. This causes the
formation of autophagolysosomes, where misfolded proteins or
excess/defective organelles can be degraded efficiently. Under
pathological conditions such as the early phase of T2DM,
however, the formation of autophagolysosomes is attenuated,
which in turn causes the accumulation of material in autophagic
vacuoles without being further processed (Stienstra et al., 2014).
Accumulation of autophagic vacuoles may disturb intracellular
cell transport and induce a cascade of intracellular toxic effects
(Marciniak et al., 2006; Marciniak and Ron, 2006; Davenport
et al., 2008; Stienstra et al., 2014). It has been suggested that
pathological processes involving accumulation of autophagic
vacuoles may also play a role in pancreatic β-cell toxicity (Bursch
et al., 2000; Stienstra et al., 2014).
The overexpression of pro-amylin or amylin during the early
phases of T2DM may further lead to the formation of toxic
oligomers, which enter the cytosol and disrupt the membrane of
organelles such as mitochondria. The disruption of mitochondria
function may then result in increased cellular oxidative stress and
the formation of reactive oxygen species (ROS). Increased ROS
levels may ultimately lead to significant damage to cell structures
and cause cell loss (Parks et al., 2001; Scherz-Shouval and Elazar,
2007; Gurlo et al., 2010). Finally, it appears that increased
amylin production can activate the inflammasome, which is a
multiprotein component of the innate immune system producing
the inflammatory cytokine interleukine-1β(IL-1β). Increased
inflammatory processes in general, and overproduction of IL-1β
in particular, may represent another important mechanism by
which amylin aggregation can cause β-cell death (Masters et al.,
2010; Donath and Shoelson, 2011; Westwell-Roper et al., 2011;
Donath et al., 2013).
Amylin Amyloids: A Comparison with the
Formation and Pathological Consequences
of AβAmyloids
The propensity of amylin to form pancreatic amyloids and their
cytotoxic consequences are remarkably similar to β-amyloids
(Aβ), which are prone to self-aggregate in the CNS following
enzymatic processing of the amyloid precursor protein (APP).
The type-I transmembrane glycoprotein APP is one of the
most abundant proteins in the human CNS and is ubiquitously
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Lutz and Meyer Amylin in neurodegenerative disorders
expressed in the plasma membrane and in several organelles,
such as the ER, Golgi apparatus, and mitochondria (van der Kant
and Goldstein, 2015).
In general, APP can be processed by two distinct and mutually
exclusive pathways, namely the secretory pathway and the
amyloidogenic pathway (Karran et al., 2011). Whilst the former
leads to soluble fragments, the latter creates proteolytic products
that are prone to self-aggregation. In the secretory pathway, APP
is first cleaved by α-secretase, which results in the release of a
soluble N-terminal fragment (sAPPα) and a C-terminal fragment
(C83). The C-terminal fragment is then further processed by
another cleaving enzyme (γ-secretase) to generate a smaller
and soluble C-terminal fragment of approximately 3 kDa (C3).
Notably, the cleavage of APP by α-secretase occurs within the
sequence of amino acids that would form the Aβpeptide, and
therefore, this proteolytic pathway is crucial and readily prevents
the formation of self-aggregating amyloid peptides (Karran et al.,
2011). In the amyloidogenic pathway, however, APP is cleaved by
β-secretase, which releases a small N-terminal fragment (sAPPβ)
and a long C-terminal fragment (C99). The latter contains the full
amyloidogenic sequence of amino acids and is further processed
by γ-secretase to yield amyloid-β(Aβ) peptides. These are then
released as monomers and eventually aggregate progressively
into oligomers and finally into amyloid plaques.
Aβoligomers are considered the most neurotoxic forms
of all amyloid species. As extensively reviewed elsewhere
(Hardy and Selkoe, 2002; Karran et al., 2011; van der Kant
and Goldstein, 2015), they interact with neuronal and glial
cells to cause mitochondrial dysfunction and oxidative stress,
impairments of intracellular signaling pathways and synaptic
plasticity, and eventually neuronal apoptosis. It is believed
that these mechanisms can give rise to a positive feedback
loop that facilitates the production of Aβpeptides through
stimulation of the amyloidogenic pathway (Hardy and Selkoe,
2002; Karran et al., 2011; van der Kant and Goldstein, 2015).
Hence, the amyloidogenic pathway seems to be more active
under pathological conditions, whereas APP is preferentially
processed via the secretory pathway under physiological
conditions.
The maintenance of physiological conditions is further
dependent on the equilibrium between the production of
(soluble) Aβpeptides and their clearance from the brain (Ueno
et al., 2014; Baranello et al., 2015). Even though the precise
mechanisms by which Aβpeptides are cleared from the CNS
remain to be identified, two proteins seem to be pivotal for
this process, namely apolipoprotein E (APOE) and the insulin-
degrading enzyme (IDE) (Baranello et al., 2015). It has been
proposed that these proteins may bind to the Aβpeptide, thereby
preventing aggregation and promoting clearance from the brain.
Some of the known genetic risk factors of AD, including
polymorphisms in the ε4 allele of APOE, may predisposes
individuals to impaired clearance of Aβpeptides from the
CNS, and thus facilitate the formation of Aβplaques (Baranello
et al., 2015). Aβclearance can also be disrupted by several
metabolic disturbances in general, and by those associated
with T2DM in particular. Indeed, T2DM has been linked to
IDE deficiency, which in turn can facilitate the aggregation of
amyloidogenic proteins (Steneberg et al., 2013), including Aβ
(Farris et al., 2003) and amylin-derived amyloid (Bennett et al.,
2003).
These associations have several important implications. First,
the effects of IDE hypofunction on Aβplaque formation may
represent a crucial pathological link between metabolic disorders
such as T2DM and increased risk of AD. Second, IDE deficiency
may not only be a driving force for amylin oligomerization and
cytotoxicity in pancreatic islet cells, but it may further facilitate
the formation of amylin amyloid in the CNS. In support of the
latter hypothesis and in contrast to the original belief that amylin-
derived amyloid occurs exclusively in pancreatic islets, amylin
oligomers and plaques were recently identified in the temporal
lobe gray matter from patients with T2DM (Jackson et al., 2013).
Moreover, similar amylin deposits were also detected in brain
parenchyma of patients with late onset AD, and these amylin
amyloids co-localized with Aβoligomers and plaques (Jackson
et al., 2013). These observations suggested for the first time that
metabolic disorders such as T2DM and perhaps also aging might
similarly promote the accumulation of amylin amyloid in the
CNS. Based on these findings, it has been hypothesized that
amylin could constitute a “second amyloid” in AD (Jackson et al.,
2013).
More recent studies indicated that amylin and Aβco-localize
in plaques of AD brains, and that amyloid deposits consisting
of both amylin and Aβare also present in blood vessel walls
(Oskarsson et al., 2015). While it is not yet clear whether the
amylin that forms deposits in the brain is produced locally or
is rather secreted by the pancreas, it is of note that intravenous
injection of preformed amylin fibrils did enhance local amyloid
deposition in the pancreas, hence a systemic origin is plausible
(Oskarsson et al., 2015; see also next section).
How Is Altered Amylin Secretion Linked to
Central Amyloid Formation?
Despite the existing evidence for amylin oligomerization in
the brains of T2DM and AD patients (Jackson et al., 2013),
it remains controversial whether this neuropathological effect
can be related to, or even induced by, alterations in peripheral
amylin homeostasis. Some researchers suggest that the primary
mechanism leading to amylin deposition in the brains of patients
with T2DM and AD may be hyperamylinemia, i.e., a pathological
condition of chronic hypersecretion of amylin by pancreatic
β-cells (Srodulski et al., 2014). Hyperamylinemia is frequently
observed in individuals with obesity or pre-diabetic insulin
resistance (Johnson et al., 1989; Enoki et al., 1992) and often
coincides with hyperinsulinemia (Westermark et al., 2011).
Furthermore, genetically enforced overexpression of amylin in
rodents transgenic for the human form of amylin leads to
amylin oligomerization and amyloid formation in pancreatic
β-cells, β-cell apoptosis, and eventual development of T2DM
(Matveyenko and Butler, 2006; Huang et al., 2007). Another
cornerstone of the “hyperamylinemia hypothesis” of central
amylin deposition is that peripherally produced amylin readily
crosses the blood-brain barrier (Banks and Kastin, 1998). Hence,
increased peripheral secretion and central uptake of amylin
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Lutz and Meyer Amylin in neurodegenerative disorders
may facilitate amylin oligomerization and eventually amyloid
formation in the brain, thereby disrupting the integrity of CNS
structures and functions. Support for this hypothesis has recently
been obtained in a “humanized” rat model of hyperamylinemia
(Srodulski et al., 2014): Rats with pancreatic overexpression of
human amylin showed marked amylin amyloid formation, an
effect that was paralleled by neuroinflammatory processes such
as clustering of activated microglia in areas of amylin infiltration.
These neuropathological changes were further associated with
the development of behavioral and cognitive deficits, including
impaired recognition memory and motor learning (Srodulski
et al., 2014). These findings suggest that hypersecretion of
amyloidogenic forms of amylin might indeed represent a
pathological link between amylin amyloid formation and the
development of neurological deficits.
The “hyperamylinemia hypothesis,” however, may only hold
true for central amylin deposition, but not for the accumulation
and oligomerization of other amyloidogenic peptides such as
Aβ. Indeed, in the Tg2576 genetic mouse model of AD, which
harbors a mutant form of APP that is prone to marked Aβplaque
formation, amylin plasma levels were not significantly elevated
at an age when mice exhibited clear signs of T2DM (Fawver
et al., 2014). These findings argued against the hypothesis that
altered systemic amylin levels might promote cross-seeding of
Aβin the CNS, despite the fact that amylin crosses the blood-
brain barrier and efficiently facilitates Aβoligomerization in vitro
(Fawver et al., 2014). A limitation of these findings, and the
interpretations thereof, is that transgenic Tg2576 mice only
harbor mutations that facilitate Aβplaque formation, but not
amylin plaque formation. Indeed, unlike in humans, primates
and cats, rodent amylin per se is not amyloidogenic (Betsholtz
et al., 1989; Höppener et al., 1994; Moriarty and Raleigh, 1999;
Matveyenko and Butler, 2006). Therefore, the missing association
between systemic amylin and Aβplaque formation in Tg2576
mice may be explained by the native incapacity of mouse amylin
to form amylin plaques, which in turn may limit the capacity of
amylin to cross-seed Aβin the CNS. In this respect, mice clearly
differ from humans.
Adding to these controversies, recent research even suggests
that reduced, rather than increased, systemic levels of amylin
may facilitate the development of AD-like pathology. For
example, Zhu et al. (2015) revealed that the augmentation of
endogenous amylin by chronic systemic administration of non-
amyloidogenic amylin, or its clinical analog pramlintide, has
beneficial effects against neuropathological and cognitive deficits
in a mouse model of AD. Specifically, peripheral treatment
with amylin or pramlintide reduced the number of Aβplaques
and improved the deficits in short- and long-term memory
in PP/PS1 double transgenic mice that harbor five familial
genetic mutations implicated in AD (Zhu et al., 2015). Zhu
et al. (2015) further demonstrated that peripheral amylin or
pramlintide treatment similarly increased the concentrations of
Aβ1−42 in cerebral spinal fluid (CSF) and serum, suggesting
that the augmentation of non-amyloidogenic amylin might
facilitate the clearance of Aβpeptides from the CNS. Similar
beneficial effects have been found by another research group,
who found that chronic administration of the amylin analog
pramlintide, which lacks amyloidogenic properties, improved
AD-related neuropathological and cognitive deficits in SAMP8
mice, a genetic mouse model of sporadic AD (Adler et al.,
2014). Importantly, there is also initial evidence suggesting that
elders with mild cognitive impairment or established AD have
lower concentrations of plasma amylin compared to age-matched
healthy control subjects (Adler et al., 2014; Qiu and Zhu, 2014).
Taken together, the findings by Adler et al. (2014) and Zhu
et al. (2015) emphasize the possibility that blunted (rather
than increased) levels of peripheral amylin may underlie the
development of neurological and cognitive impairments typically
seen in mild cognitive impairment or established AD. This
pathological link may be explained by a competition between
amylin and Aβto bind to its receptor in the CNS. Amylin
and Aβpeptide both bind to the CTR, which in the CNS is
ubiquitously expressed and complexed with the receptor activity
modifying protein 3 (RAMP3) (Götz et al., 2013). According
to a recent hypothesis (Qiu and Zhu, 2014), increased binding
of Aβto the CTR-RAMP3 complex which corresponds to the
amylin-3 receptor occurs under conditions of hypoamylinemia
when amylin fails to compete with Aβfor binding to this
receptor complex. This in turn may facilitate Aβoligomerization
and plaque formation in the CNS (Qiu and Zhu, 2014).
When hypoamylinemic conditions are restored by exogenous
administration of non-amyloidogenic amylin or its clinical
analogs, non-aggregated amylin may prevent the binding of Aβto
the CTR-RAMP3, thereby reducing the potency of Aβpeptides to
oligomerize (Qiu and Zhu, 2014). In addition, the augmentation
of non-amyloidogenic amylin may facilitate the clearance of
Aβfrom the brain, probably through its effects on cerebral
vasculature (Westfall and Curfman-Falvey, 1995; Edvinsson et al.,
2001; Qiu and Zhu, 2014).
Whatever precise mechanisms involved, it appears that hypo-
and hyper-amylinemic conditions can both be associated with
and promote the pathological effects of amyloid formation in
the CNS. Further investigations are clearly warranted to explore
how alterations in peripheral amylin secretion are linked to
central amyloid formation. In the course of these attempts,
it is of primordial importance to take into account the exact
experimental conditions and in particular the clear species
differences regarding the innate propensity of amylin to from
plaques. Hence, it is absolutely critical to distinguish between
amyloidogenic and non-amyloidogenic forms of amylin; the
former is the case for human, other primates’ and feline amylin,
the latter for rodents (Betsholtz et al., 1989; Höppener et al., 1994;
Moriarty and Raleigh, 1999; Matveyenko and Butler, 2006).
Another important factor that needs careful consideration is
the clinical course of metabolic disturbances across aging, which
in turn may critically determine the nature of peripheral amylin
pathologies. As stated above, individuals with obesity or pre-
diabetic insulin resistance often show signs of hyperamylinemia
that precede the onset of full-blown T2DM (Johnson et al.,
1989; Enoki et al., 1992; Westermark et al., 2011). Chronic
over-production of amylin during these early stages of T2DM
are readily toxic to pancreatic β-cells and eventually lead to β-
cell loss (Höppener and Lips, 2006; Jurgens et al., 2011; Desai
et al., 2014). As a consequence of the latter, the production
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Lutz and Meyer Amylin in neurodegenerative disorders
and secretion of amylin may be severely impaired, thus leading
to states of hypoamylinemia during late stages of T2DM (Qiu
et al., 2014). Hence, both hyper- and hypo-amylinemia likely
play a role in metabolic diseases such as T2DM depending on
the clinical course and duration of the disease (Zhang et al.,
2014).
The consideration of these temporal changes in amylin
production may be important for attempts to explain why both
hypo- and hyper-amylinemic conditions have been associated
with increased amyloid formation in the CNS. On speculative
ground, hyperamylinemic conditions may be more relevant
for early processes of amyloid formation in the CNS, whereas
hypoamylinemic conditions may be more strongly associated
with late stages of central amyloid pathologies (Figure 1).
The former conditions could indeed offer an explanation why
amylin deposits can be present in brain parenchyma of AD
patients who do not suffer from full-blown T2DM (Jackson
et al., 2013), whereas the latter condition could explain why
augmentation of non-amyloidogenic amylin can exert beneficial
effects on amyloid clearance from the CNS once marked amyloids
had already been established (Adler et al., 2014; Zhu et al.,
2015).
Concluding Remarks
Epidemiological studies have established a clear association
between metabolic and neurodegenerative disorders in general
(Kleinridders et al., 2015), and between T2DM and AD in
particular (Ott et al., 1996; Li and Hölscher, 2007; Butterfield
et al., 2014; Desai et al., 2014). Amylin seems to be an
important player at the interface between these metabolic
and neurodegenerative disorders for several reasons. First,
abnormal amylin production is a hallmark peripheral pathology
both in the early (pre-diabetic) and late phases of T2DM,
where hyperamylinemic (early phase) and hypoamylinemic (late
phase) conditions coincide with hyper- and hypo-insulinemia,
respectively (Figure 1). Second, there are notable biochemical
similarities between amylin and Aβ, which (in some but not all
species) are prone to self-aggregation and amyloid formation.
The propensity of amylin to form amyloid plaques is not
restricted to the peripheral organs such as pancreatic islet cells,
but readily extends to the CNS, where is has been found to co-
localize with Aβplaques in at least a subset of AD patients.
Hence, amylin may constitute a “second amyloid” relevant
for the etiopathogenesis of AD and related neurodegenerative
FIGURE 1 | Model for the temporal association between abnormal
amylin production and peripheral and central pathologies relevant to
neurodegenerative disorders. The graphical illustration shows the putative
relationship between age (x-axis) and peripheral amylin levels (y-axis) under
normal conditions (blue) and conditions of type 2 diabetes mellitus (T2DM;
red). The early phase of T2DM is typically associated with increased
peripheral amylin (and insulin, not shown) secretion. Chronic over-production
of amylin during the early stages of T2DM may facilitate amylin amyloid
formation in pancreatic islet cells and eventually promote islet cell loss. As a
consequence of the latter, the production and secretion of amylin (and
insulin, not shown) may be severely impaired, thus leading to states of
hypoamylinemia during late stages of T2DM. The initial hyperamylinemic
condition occurring during the early phase of T2DM may further lead to
amylin amyloid formation in the brain, which in turn may facilitate central Aβ
amyloid formation and associated neurodegenerative processes during the
late phase of T2DM.
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Lutz and Meyer Amylin in neurodegenerative disorders
disorders (Jackson et al., 2013). In T2DM, the precise relationship
between altered peripheral amylin production and central amylin
amyloid formation appears complex and may be critically
dependent on the temporal course of progressive pancreatic β-
cell dysfunctions: Hyperamylinemic conditions may be more
relevant for the early processes of amyloid formation in the
CNS, whereas hypoamylinemic conditions may be more strongly
associated with late stages of central amyloid pathologies.
Normalization of hyperamylinemia during the early phase
of T2DM may attenuate of even prevent subsequent amylin
amyloid formation in the CNS, thereby exerting beneficial effects
on progressive neurodegenerative disorders such as AD. On
the other hand, augmentation of non-amyloidogenic amylin
during late phases of T2DM, which are characterized by
hypoamylinemic conditions, may offer a therapeutic strategy
to facilitate amyloid clearance from the CNS and to block
ongoing neurodegenerative processes once marked amyloids are
established. More in-depth knowledge about these temporal
relationships seems highly desirable as it may optimize the
efficacy of amylin-based interventions in the treatment of
AD and related neurodegenerative disorders with metabolic
comorbidities.
Acknowledgments
TL receives financial support granted by the Swiss National
Science Foundation (31003A_156935), the European Union’s
Seventh Framework Programme (FP7/2007–2011) under
grant agreement No. 305707, the National Health and
Medical Research Council (NIDDK). UM receives financial
support granted by the Swiss National Science Foundation
(310030_146217), the European Union’s Seventh Framework
Programme (FP7/2007–2011) under grant agreement No.
259679, the National Health and Medical Research Council
(NHMRC), Australia (APP1057883), and ETH Zurich,
Switzerland (ETH Research Grant 25_13-2).
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Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
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