Neuropharmacology xxx (2017) 1e11

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Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm

Invited review

Crosstalk between endoplasmic reticulum stress and brain

inflammation in Alzheimer's disease
Luis E. Santos a, Sergio T. Ferreira a, b, *
a
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
b
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: While most often noted for its cognitive symptoms, Alzheimer's disease (AD) is, at its core, a disease of
Received 29 September 2017 protein misfolding/aggregation, with an intriguing inflammatory component. Defective clearance and/or
Accepted 8 November 2017 abnormal production of the amyloid-b peptide (Ab), and its ensuing accumulation and aggregation,
Available online xxx
underlie two hallmark features of AD: brain accumulation of insoluble protein deposits known as am-
yloid or senile plaques, and buildup of soluble Ab oligomers (AbOs), diffusible toxins linked to synapse
Keywords:
dysfunction and memory impairment. In neurons, as in typical eukaryotic cells, the endoplasmic retic-
Alzheimer's disease
ulum (ER) serves as a main compartment for the folding, maturation, trafficking and quality control of
Endoplasmic reticulum stress
Unfolded protein response
newly synthesized proteins. The ER lumen, a calcium-rich, oxidizing environment, provides favorable
Inflammation conditions for these physiological functions to occur. These conditions, however, also favor protein ag-
gregation. Several stressors, including metabolic/nutrient stress and certain pathologies, may upset the
ER homeostasis, e.g., by affecting calcium levels or by causing the accumulation of unfolded or misfolded
proteins. Whatever the underlying cause, the result is what is commonly known as “ER stress”. This, in
turn, triggers a conserved cellular response mechanism known as the “unfolded protein response” (UPR).
The UPR comprises three pathways involving transcriptional or translational regulators aimed at
normalizing ER function, and each of them results in pro-inflammatory signaling. A positive feedback
loop exists between ER stress and inflammation, with clear implications for neurodegeneration and AD.
Here, we explore recent findings on the role of ER stress and the UPR in inflammatory processes leading
to synapse failure and memory impairment in AD.
© 2017 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. The UPR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. The UPR in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. The inflammatory component of AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. ER stress intersects with neuroinflammation and AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Nitric oxide regulation of the UPR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Potential therapeutic approaches targeting ER stress/inflammation in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction
* Corresponding author. Institute of Biophysics Carlos Chagas Filho, Federal
University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil. Protein synthesis, folding, maturation and trafficking are highly
E-mail address: ferreira@bioqmed.ufrj.br (S.T. Ferreira).

https://doi.org/10.1016/j.neuropharm.2017.11.016
0028-3908/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Santos, L.E., Ferreira, S.T., Crosstalk between endoplasmic reticulum stress and brain inflammation in
Alzheimer's disease, Neuropharmacology (2017), https://doi.org/10.1016/j.neuropharm.2017.11.016
2 L.E. Santos, S.T. Ferreira / Neuropharmacology xxx (2017) 1e11
regulated processes, which readily respond to metabolic state,
physiological signals and pathological stressors. In eukaryotic cells,
the endoplasmic reticulum (ER) is responsible for a significant
portion of these functions, processing all membrane-bound and
secretory proteins following their synthesis at adjacent ribosomes.
Any perturbation of ER homeostasis may result in the accumulation
of unfolded or misfolded proteins in its lumen - a condition known
as ER stress (Hetz and Glimcher, 2009; Hotamisligil, 2010;
Chaudhari et al., 2014; Hetz and Mollereau, 2014).
The ever-growing list of pathologies linked to ER stress includes
several amyloidoses, a family of diseases defined wholly or in part
by protein misfolding and aggregation, which includes type 2 dia-
betes (T2D), prion diseases, Parkinson's disease, and Alzheimer's
disease (Lindholm et al., 2006; Mukherjee et al., 2015; Torres et al.,
2015; Chiti and Dobson, 2017; Dogan, 2017). Interestingly, however,
ER stress has also been implicated in the development of many
conditions with weaker or as yet unknown ties to protein mis-
folding and deposition. A notable example is major depressive
disorder (Bown et al., 2000; Nevell et al., 2014; Timberlake and
Dwivedi, 2016), a condition associated with brain inflammation.
Indeed, it is becoming increasingly clear that the connection be-
tween ER stress and related pathologies may go well beyond pro-
teostasis, resting to some extent on its overlap with inflammation
(Gold et al., 2013).
Although a complex inflammatory component in Alzheimer's
disease (AD) has been recognized for decades, whether it is a
consequence of neurodegeneration, a contributing factor, or part of
the underlying mechanism of pathogenesis remains to be deter-
mined (Griffin et al., 1989, 1995; Holmes et al., 2009; Glass et al.,
2010; De Felice and Ferreira, 2014; Ferreira et al., 2014). Mounting
evidence also points to a role for ER stress in AD, which, as argued
in the following sections, may be non-dissociable from the in-
flammatory response in causing neuronal/synapse dysfunction and
memory failure in AD.
2. The UPR
The unfolded protein response (UPR) is a conserved adaptive
mechanism triggered by ER stress and aimed at restoring proper ER
function. Through the activation of one or more of its three
branches (see below), the early UPR attenuates protein synthesis,
while facilitating protein folding, degradation and autophagy.
However, upon sustained activation by prolonged stress, the UPR
becomes maladaptive and may promote apoptosis (Hetz, 2012).
Several foldases and chaperones populate the ER (Jansen et al.,
2012), driving the protein maturation steps that take place in its
lumen: folding, quality control, ER-associated protein degradation
(ERAD) and export. The most abundant ER chaperone is BiP
(immunoglobulin heavy chain binding protein), sometimes
referred to as GRP78 (78-kDa glucose-regulated protein), one the
first proteins identified as ER stress responsive (Kozutsumi et al.,
1988; Lenny and Green, 1991; Li et al., 1994). BiP binds exposed
hydrophobic domains in partially folded proteins, preventing their
misfolding and aggregation. An ATPase domain in the N-terminal of
BiP regulates its affinity for protein targets, allowing proteins to be
bound and released in a cyclic manner as they fold (Naidoo, 2009).
In animals, three transmembrane ER protein sensors serve as
the main regulators of the UPR: IRE-1 (inositol requiring protein 1;
Cox et al., 1993; Morl et al., 1993), PERK (PKR-like ER kinase;
Harding et al., 1999), and ATF6 (activating transcription factor 6;
Haze et al., 1999). Under normal conditions, all three of these
sensors are bound to BiP in their luminal domains. This prevents
competing interactions, and keeps them inactive. However, upon
ER stress, BiP sequestration by accumulating misfolded/partially
folded proteins releases the sensors to trigger UPR signaling. The
Please cite this article in press as: Santos, L.E., Ferreira, S.T., Crosstalk between endoplasmic reticulum stress and brain inflammation in
Alzheimer's disease, Neuropharmacology (2017), https://doi.org/10.1016/j.neuropharm.2017.11.016
exact process by which BiP removal leads to such activation is not
fully understood but, at least for PERK and IRE-1, appears to rely on
their oligomerization and cross-phosphorylation (Bertolotti et al.,
2000; Janssens et al., 2014). Notably, in addition to this canonical
mechanism based entirely on BiP, more recent reports have begun
to describe novel sources of UPR sensor activation. These include
the direct binding of unfolded proteins (Gardner and Walter, 2011)
and lipids (Volmer et al., 2013) to the UPR sensors, and the
participation of an additional ER protein, CNPY2, which may be
required for full PERK activation after BiP release (Hong et al., 2017).
IRE-1 signaling is mediated by its endoribonuclease activity.
Phosphorylated IRE-1 catalyzes splicing of the mRNA encoding
XBP1 (X box-binding protein 1). The alternatively spliced version of
this transcription factor, often termed XBP1s, finds its way into the
nucleus to upregulate the expression of several ER chaperones and
enzymes involved in ERAD, contributing to restore normal ER
function (Lee et al., 2003).
Once active, the second UPR sensor, PERK, inhibits overall pro-
tein synthesis by phosphorylating the alpha subunit of eukaryotic
initiation factor 2 (eIF2a), which delays formation of the ternary
complex comprising eIF2/tRNAMet/GTP and the assembly of func-
tional ribosomes (Jackson et al., 2010). Attenuated translation is
essential to lower the unfolded protein burden in the ER during
stress conditions, and promotes cell survival, at least in the short-
term (Ron and Walter, 2007). PERK is one of the four known
eIF2a kinases, and the only one resident in the ER. The other three,
HRI (heme-regulated inhibitor), GCN2 (general control non-
derepressible 2) and PKR (double-stranded RNA-dependent pro-
tein kinase), have links to ER stress but are also subject to inde-
pendent activation pathways (Donnelly et al., 2013). For this reason,
they are considered part of what is known as the integrated stress
response (ISR; Harding et al., 2003; Pakos-Zebrucka et al., 2016).
The last branch of the UPR to be identified operates via trans-
location of ATF6 to the Golgi under ER stress. Releasing BiP unmasks
Golgi localization signals present in the ATF6 protein, which guide
its trafficking to the Golgi. Once in the Golgi apparatus, ATF6 is
processed by two local proteases, site-1 (S1P) and site-2 (S2P),
releasing its active form, known as ATF6 fragment (ATF6f) or 50kD-
ATF6, in reference to its cleaved, shorter size (Shen et al., 2002). Like
XBP1s, ATF6f is an active transcription factor that directs the
expression of genes involved in protein folding and ERAD (Janssens
et al., 2014).
3. The UPR in AD
AD, the most common form of old-age dementia, a group of
conditions affecting nearly 47 million people worldwide (Prince
et al., 2015), is a prototypical amyloidosis: misfolded and aggre-
gated proteins compose its defining neuropathological lesions,
namely amyloid-b (Ab) plaques (Glenner and Wong, 1984) and
neurofibrillary tangles made up of hyperphosphorylated tau
(Grundke-Iqbal et al., 1986a, 1986b; Kosik et al., 1986). Clinically, AD
presents with gradual cognitive decline, accompanied by debili-
tating behavioral symptoms, including apathy, depression and de-
lusions, among others (Lyketsos et al., 2011; Santos et al., 2016). At
the neuronal level, it involves excitotoxicity, neuronal oxidative
stress, deregulation of intracellular signaling pathways, and syn-
apse damage/loss (Haass and Selkoe, 2007; Ferreira and Klein,
2011; Ferreira et al., 2015; Selkoe and Hardy, 2016).
In 1991, before any of the UPR sensors had been formally
described, Hamos and co-workers reported the first measurements
of BiP expression in post-mortem AD brains (Hamos et al., 1991).
They found BiP was upregulated in AD brains, especially in the
hippocampus and entorhinal cortex, but only in neurons retaining
normal morphology. Another UPR-related chaperone, HSP72,
 L.E. Santos, S.T. Ferreira / Neuropharmacology xxx (2017) 1e11
which is expressed in the cytoplasm rather than in the ER (Gupta
et al., 2010), was also notably increased in AD, and was often
associated with Ab plaques and tau tangles (Hamos et al., 1991).
That same year, an independent group reported increased levels of
HSP72 and HSP73 (another cytoplasmic chaperone) in the temporal
cortex of AD patients (Perez et al., 1991).
Those early results were recently revisited and expanded by
other authors. The increase in BiP expression was confirmed, and
phosphorylated forms of PERK, IRE1a and eIF2a were found to be
markedly increased in AD brains compared to age-matched con-
trols (Hoozemans et al., 2005, 2009; Yoon et al., 2012; Stutzbach
et al., 2013; Duran-Aniotz et al., 2017). Interestingly, Stutzbach
et al. (2013) further reported that UPR activation correlates with
age, even in the absence of pathology. Consistent with the initial
report by Hamos et al. (1991), increased levels of UPR markers have
been found mostly in morphologically intact neurons (Hoozemans
et al., 2009, 2005). The UPR thus appears to be an early event
preceding overt protein deposition in AD and may be neuro-
protective, at least in the short-term (Hoozemans et al., 2012).
On the other hand, pro-apoptotic components of the UPR have
also been found to be elevated in AD brains, possibly as a conse-
quence of prolonged ER stress. A transcription factor known as
CHOP/GADD153 (CCAAT-enhancer-binding protein homologous
protein/Growth arrest and DNA damage-inducible gene 153),
which is possibly the main link between ER stress and apoptosis, is
increased in the brains of AD patients (Yoon et al., 2012), along with
downstream effectors such as caspase-12 (Lee et al., 2010) and
GADD34 (Honjo et al., 2015). CHOP/GADD153 is induced to some
extent by all three UPR branches, but is mostly associated with
PERK. While eIF2a phosphorylation by activated PERK or other ki-
nases impairs general translation, it promotes synthesis of specific
proteins, including ATF4, a transcription factor that drives CHOP
expression (Chaudhari et al., 2014). Stress-induced apoptosis may
have physiological roles, such as eliminating cells that become
unresponsive to the UPR, but in AD it is a likely cause of neuro-
degeneration (Baleriola et al., 2014).
In mouse models of AD, where specific aspects of the disease can
be studied in isolation and correlations put to test, robust data
support similar conclusions. AD-like pathology induced by
administration of the Ab peptide or its genetic overproduction was
shown to increase levels of BiP (Barbero-Camps et al., 2014),
phosphorylated eIF2a and CHOP (Baleriola et al., 2014; Yoon et al.,
2012), GADD34 and cleaved caspase-12 (Barbero-Camps et al.,
2014; Xu et al., 2015). Notably, neurodegeneration associated
with intrahippocampal injections of Ab was shown to require
activation of the ATF4-CHOP pathway (Baleriola et al., 2014).
Three eIF2a kinases have been implicated in synapse loss and
cognitive deficits in AD mouse models. Ma et al. (2013) crossed PERK
and GCN2 knockouts with APPswePS1DE9 transgenic mice, a ge-
netic model of the disease, in order to test whether those kinases
could be potential targets for therapy in AD. Interestingly, they found
that eliminating either enzyme reduced brain levels of Ab and pre-
vented memory deficits associated with the APPswePS1DE9
phenotype (Ma et al., 2013). Around the same time, work by our
group showed that PKR-mediated phosphorylation of eIF2a un-
derlies synapse damage and memory impairment in the same
APPswePS1DE9 transgenic mice as well as in mice that received an
intracerebroventricular infusion of Ab oligomers (Lourenco et al.,
2013).
These results are consistent with the established role of eIF2a in
the physiology of memory, and the potential of ER stress and the UPR
to interfere with it. Indeed, protein synthesis is required for late-LTP
and long term memory, and a disruption in translation due to eIF2a
phosphorylation is expected to impair synaptic plasticity and overall
memory performance (Costa-Mattioli et al., 2009, 2007, 2005).
Please cite this article in press as: Santos, L.E., Ferreira, S.T., Crosstalk between endoplasmic reticulum stress and brain inflammation in
Alzheimer's disease, Neuropharmacology (2017), https://doi.org/10.1016/j.neuropharm.2017.11.016
3
IRE1 was the latest ER sensor to be linked to AD. In a case control
study involving 276 AD subjects (diagnosed using NINCDS-ADRDA
criteria) and 254 healthy age-matched controls, an association was
found between an XBP1 polymorphism and AD risk (Liu et al.,
2013). Establishing the clinical relevance of this early report, an
important role of XBP1 in memory formation was recently
demonstrated (reviewed by Cisse ! et al. (2016)). Martinez et al.
(2016) used conditional knockout mice to show that lack of XBP1
in the central nervous system (CNS) impairs long-term potentiation
(LTP) and memory, while overexpression of XBP1s is beneficial, and
that these effects were connected to BDNF expression. Shortly after,
Cisse! et al. (2016a) showed that directed expression of XBP1s in the
hippocampus restores cognitive deficits in a triple transgenic
mouse model of AD. This effect depended on activation of the
Kalirin-7 pathway, which is downstream to NMDA receptor acti-
vation, linked to synaptic plasticity, and known to be impaired in
AD patients and animal models.
Interestingly, in a recent development, the consequences of
direct IRE-1 deficiency on the AD-like phenotype of 5xFAD mice
were assessed. While results similar to those seen with conditional
XBP1 knockouts might have been expected, AD mice harboring an
IRE-1 variant that lacked its ribonuclease domain were surprisingly
found to have lower amyloid burden, improved cognition and to
form and sustain LTP at wild-type levels (Duran-Aniotz et al., 2017).
This result underscores the complex role of the UPR sensors in AD,
and suggests that XBP1 may have unknown functions that are in-
dependent of IRE-1. Indeed, the authors of the latter study noted
that, unlike XBP1 knockouts, mice deficient in IRE-1 had no alter-
ations in hippocampal BDNF levels (Duran-Aniotz et al., 2017).
4. The inflammatory component of AD
The notion that neuroinflammation is a component of AD pa-
thology is arguably as old as the disease's first description. In Alz-
heimer's seminal report, in 1907 (translated and commented in
Stelzmann et al., 1995), he mentions glial alterations in the
affected brain, including “numerous fibers”, which most likely re-
flected reactive gliosis - activated astrocytes and microglia. The
precise role of neuroinflammation in AD, however, is yet to be
completely understood. A range of hypotheses currently suggest
inflammation may be a beneficial response, a driver of symptoms,
or even a primary causal factor of the disease (Heneka et al., 2015;
Santos et al., 2016).
The latter possibility, sometimes referred to as the ‘inflamma-
tory hypothesis of AD’, has gained significant traction in later years.
Evidence in its support includes notable correlations between
increased incidence of AD and conditions involving local or
generalized inflammation (De Felice, 2013). These include major
depression (Green et al., 2003; Lyketsos and Olin, 2002), traumatic
brain injury (Breunig et al., 2013), periodontitis (Ide et al., 2016),
infections (Honjo et al., 2009), and metabolic disorders such as type
2 diabetes and obesity (De Felice and Ferreira, 2014; Ferreira et al.,
2014). As the list of these AD-related conditions becomes more
diverse, neuroinflammation and the release of inflammatory me-
diators - either systemically or in the brain - increasingly seems to
be their common denominator.
Even during low-grade insults, prostaglandins or cytokines such
as TNF-a and IL-1b may cross the blood-brain-barrier and prime
brain cells to respond to inflammatory stimuli in a dysfunctional
manner (Shie et al., 2005; Teeling et al., 2007; Maes et al., 2012;
Norden et al., 2015). While such primed cells do not actively
release cytokines, they do, however, upregulate genes related to
antigen recognition, cytokine production and phagocytosis, which
exaggerate their responses when a secondary pro-inflammatory
stimulus arrives, often resulting in cytotoxicity (Perry and
4 L.E. Santos, S.T. Ferreira / Neuropharmacology xxx (2017) 1e11
Holmes, 2014). Microglia, the resident macrophages of the brain,
are typically described as the only CNS cell population susceptible
to priming, perhaps, at least in part, because this concept was first
noted in peripheral macrophages (Cherry et al., 2014). However,
recent findings suggest a similar phenomenon may also occur in
astrocytes (Hennessy et al., 2015).
Abnormally elevated responses to inflammatory stimuli have
been described in a transgenic mouse model of AD (Sly et al., 2001),
as well as in microglia isolated from AD patients (Lue et al., 2001).
Additionally, microglial priming was shown to be, to some extent,
an aspect of normal aging (Luo et al., 2010), suggesting that
increased susceptibility to neuroinflammation may explain, at least
in part, why age is the main risk factor for AD.
There is also evidence for a causal connection between micro-
glial activation and both cognitive and non-cognitive behavioral
symptoms (e.g., mood alterations) in AD (Henry et al., 2008; Maes
et al., 2012; Sarlus and Heneka, 2017). While mood alterations are
not unique to Alzheimer's, the link to activated microglia is well-
established both in and out of the AD context, having been
demonstrated in models of inflammation-induced ‘sickness
behavior’ (Henry et al., 2008; Maes et al., 2012), mouse models of
AD (Hong et al., 2016; Ledo et al., 2016, 2013; Spangenberg et al.,
2016), and in dementia patients (Femminella et al., 2016).
By genetically labeling and long-term tracking of a subset of
cortical microglia, a recent report elegantly showed that APPswe/
PS1L166P mice undergo a threefold expansion of the microglial
population throughout the course of amyloid pathology (Füger
et al., 2017). This observation confirmed earlier results reached
with more limited techniques (Radde et al., 2006). Further, under
physiological conditions, half of the microglia in the mouse brain
likely survive for the entire lifespan of the animal (Füger et al.,
2017). Such a long turnover is compatible with the long-lasting
priming effects suggested to link inflammatory conditions to late-
onset AD (Green et al., 2003; Santos et al., 2016).
As a corollary to the inflammatory hypothesis, therapies tar-
geting inflammation hold potential in AD prevention or treatment.
For example, observational studies have suggested beneficial ef-
fects of non-steroidal anti-inflammatory drugs (NSAIDs) on AD
incidence, although randomized controlled trials have not
confirmed this effect (Wang et al., 2015). This apparent discrepancy
may be due to the fact that NSAIDs, as most current approaches,
lack the specificity to preserve any desirable type of inflammatory
response. Some extent of microglial activation appears, in fact, to be
beneficial and required for encapsulating amyloid plaques
(Condello et al., 2015) and for proper amyloid clearance (Minter
et al., 2016), rendering treatment duration critical, and therapeu-
tic windows narrow. Nonetheless, based on currently available
data, additional studies are warranted to determine whether the
inflammatory component of AD is a valuable therapeutic target.
5. ER stress intersects with neuroinflammation and AD
When active, each of the UPR branches has been shown to in-
crease production and release of pro-inflammatory mediators. The
three pathways converge on activating nuclear factor-kB (NF-kB;
Salminen et al., 2009; Zhang and Kaufman, 2008), a transcription
factor that drives expression of cytokines such as TNFa, IL-1, IL-6
and IL-8 (Bo€ hrer et al., 1997; Brand et al., 1996). These, in turn, may
further activate the NF-kB pathway, in a chronic feed-forward loop
that has been implicated in AD (Chung et al., 2009).
At the cytoplasmic side, activated IRE-1 was shown to bind the
transducer protein TRAF-2 (TNF receptor-associated factor 2; Urano
et al., 2000) and recruit the IKK (IkB kinase) complex. This signaling
hub integrates several pathways and activates NF-kB by phos-
phorylating IkB, which normally keeps NF-kB inactive and
Please cite this article in press as: Santos, L.E., Ferreira, S.T., Crosstalk between endoplasmic reticulum stress and brain inflammation in
Alzheimer's disease, Neuropharmacology (2017), https://doi.org/10.1016/j.neuropharm.2017.11.016
restricted to the cytoplasm. Phosphorylated IkB is prone to ubiq-
uitination and degradation, leaving NF-kB free to translocate to the
nucleus and drive gene expression (Hinz and Scheidereit, 2014; Hu
et al., 2006; Kaneko et al., 2003; Leonardi, 2002). The TRAF2-IRE-1
complex may also bind ASK-1 (apoptosis signal-regulating kinase
1) to activate the JNK (c-Jun N-terminal kinase) pathway, promot-
ing inflammatory signaling through the transcription factor known
as AP-1 (activator protein-1; Nishitoh et al., 2002) (Fig. 1). Addi-
tionally, in the recent report that examined deletion of the IRE-1
ribonuclease domain in 5xFAD mice, the authors found that AD
mice harboring the IRE-1 mutation had significantly reduced
astrogliosis in the hippocampus (Duran-Aniotz et al., 2017).
Although this result was not explored in depth, it suggested that
XBP1s may also have a direct or indirect role in driving inflam-
mation in AD.
As mentioned above, PERK (and, subsequently, eIF2a) phos-
phorylation leads to overall inhibition of protein synthesis, with
certain mRNAs being preferentially translated (Baleriola et al.,
2014; Hetz, 2012). IkB is amongst the proteins with inhibited
translation, and its reduced expression under ER stress underlies an
additional mechanism for NF-kB activation (Deng et al., 2004). In
the mouse brain, activated PERK in astrocytes was also shown to
produce inflammation by increasing IL-6 expression through the
JAK1-STAT3 pathway (Meares et al., 2014). Further, PERK may
directly phosphorylate GSK-3b (Glycogen Synthase Kinase 3b;
Baltzis et al., 2007; Resende et al., 2008), an enzyme not only well-
described as a regulator of inflammatory pathways, including NF-
kB (Maixner and Weng, 2013), but also thoroughly linked to AD
pathology, where it influences Ab synthesis and functions as one of
the major tau kinases (Llorens-Martín et al., 2014).
Finally, the ATF6 branch of the UPR was also shown to promote
inflammation in certain contexts, through the CREBH transcription
factor (Zhang et al., 2006) or protein kinase B(Akt)/NF-kB activation
(Yamazaki et al., 2009). Direct evidence for a proinflammatory ac-
tion of ATF6 in brain pathology, however, is still lacking.
In parallel to the three UPR branches, recent work has revealed
another potential feed-forward mechanism linking inflammation
and stress signaling through eIF2a phosphorylation in AD. In cell
culture and in AD mouse models, we demonstrated that microglia-
derived TNF-a drives cognitive and non-cognitive aspects of AD
(Ledo et al., 2016, 2013). Moreover, we showed that, downstream of
TNFR1 signaling, activation of PKR and eIF2a phosphorylation in
neurons is required for AD-related memory deficits (Lourenco et al.,
2013). Given that eIF2a phosphorylation may induce NF-kB acti-
vation (Deng et al., 2004), leading to further TNF-a expression
(Chung et al., 2009), chronically activated UPR or ISR in AD could
form a self-activating loop. Of relevance to this proposed mecha-
nism, it was recently shown that systemic inflammation induces
TNF-a expression in a PKR-dependent manner in the mouse brain
(Carret-Rebillat et al., 2015).
A second pathway that may reciprocally link ER stress and
inflammation in AD is oxidative signaling. The ER lumen is a strong
oxidative environment, where the ratio of GSH to GSSH is one to
two orders of magnitude lower than in the rest of the cell
(Chakravarthi et al., 2006; Hwang et al., 1992). This environment is
required for proper oxidative folding of proteins, and reductive
signals have long been known to induce ER stress by impairing
protein folding (DuRose et al., 2006). More recently, however,
oxidative insults, which may result from prolonged UPR activation,
have also been shown to elicit ER stress (Eletto et al., 2014). A key
player in this oxidative regulatory mechanism is nitric oxide (NO), a
proinflammatory mediator deeply involved in AD pathogenesis
(Uehara et al., 2006), as discussed below.
 L.E. Santos, S.T. Ferreira / Neuropharmacology xxx (2017) 1e11 5

Fig. 1. e Common pathways link ER stress and the UPR to neuroinflammation in Alzheimer's disease and other disorders. UPR pathways converge on increased production of
inflammatory cytokines through the NF-kB pathway. These mechanisms have been observed in AD and in several conditions, including metabolic disorders (type 2 diabetes,
obesity), depression, traumatic brain injury (TBI), infections and, notably, aging. These conditions are considered risk factors for AD and share ER stress and neuroinflammation as
drivers of symptoms. Inflammatory mediators such as TNF-a may result from prolonged UPR activation, and further activate UPR pathways and the cellular integrated stress
response, e.g., via activation of PKR. Additionally, S-nitrosylation, a protein modification prominently found in AD and metabolic disorders, modulates ER stress sensors such as PERK
and IRE-1, leading to a dysfunctional UPR. These mechanisms amount to an ER stress-inflammation loop, that may underlie the connection between AD and its comorbidities.

6. Nitric oxide regulation of the UPR
NO is a highly diffusible signaling molecule, produced in vivo by
NO synthase (NOS), an enzyme found throughout the brain in both
constitutively expressed and inducible isoforms. While neuronal
NOS (nNOS) is typically found in select neurons and has numerous
physiological roles, inducible NOS (iNOS) is expressed by activated
astrocytes and microglia, downstream of proinflammatory signals
(Pacher et al., 2007).
Due to its chemical nature, NO defies typical ligand-receptor
paradigms. While soluble guanylyl cyclase may be deserving of
the ‘NO-receptor’ moniker, many of the effects of NO, both physi-
ological and pathological, are mediated by protein modification. In
pathology, reactions between NO or NO-derived molecules and
biological targets are part of what is termed nitrative stress (Foster
et al., 2009; Jaffrey et al., 2001; Pacher et al., 2007).
In AD, as in virtually any CNS pathology, levels of NO-related
protein modifications are found to be increased, particularly at in-
flammatory loci. Post mortem assessment of AD brains showed that
dysmorphic neurons, those found near amyloid deposits or con-
taining Tau tangles, have increased immunoreactivity for nitrated
tyrosine (3-NT; Good et al., 1996; Butterfield et al., 2001). Being a
largely irreversible protein modification, 3-NT is useful as a marker
of nitrative stress, and is a common consequence of iNOS expres-
sion during inflammation. Glial iNOS was further shown to be
increased around neurofibrillary tangles and amyloid lesions in AD
brains, as well as in Ab-stimulated glial cultures, in the latter case in
an NF-kB dependent manner (Akama and Van Eldik, 2000; De La
Monte et al., 2000; Pacher et al., 2007). Notably, 3-NT is also
found increased in the CSF of AD patients, and its buildup is an early
event, detected in those diagnosed with mild cognitive impair-
ment, a preliminary condition that often progresses to AD
(Butterfield et al., 2007; Pacher et al., 2007; Reed et al., 2009;
Reynolds et al., 2006; Tohgi et al., 1999).
Several pathways that result in iNOS expression involve NF-kB
activation, as it is one of the transcription factors driving the iNOS
gene in mice and humans (Aktan, 2004). Although it is reasonable
to assume that prolonged ER stress will at some point lead to iNOS
expression through NF-kB and/or other pro-inflammatory path-
ways, few reports have examined this directly, and the diversity of
experimental models and approaches employed do not yet warrant
definite conclusions in this regard (Guo et al., 2010; Hosoi et al.,
2013). On the other hand, NO-induced ER stress and activation of
UPR pathways is well-established, having been described in
numerous cell types (Oyadomari et al., 2001; Gotoh et al., 2002;
Nakato et al., 2015). Events downstream of activated IRE-1 (Kim
et al., 2010; Meares et al., 2011), ATF6 (Xu et al., 2004), PERK, and
PKR (Tong et al., 2011) have been observed in response to NO do-
nors, while NOS inhibitors were proposed to reduce ischemic
damage by mitigating the UPR-CHOP pathway (Iadecola et al., 1997;
Kim et al., 2008; Kohno et al., 1997). Nitration of tyrosines on sarco/
endoplasmic reticulum Caþþ-ATPase (SERCA), a calcium pump
present in the ER membrane and involved in regulation of luminal
calcium stores (Dickhout et al., 2005; Mekahli et al., 2011), is one of
the mechanisms mediating this link.
Most notably, recent work showed that cysteine S-nitrosylation,
another NO-related modification involved in AD pathology
(Nakamura et al., 2013), is a powerful modulator of ER stress.
Nakato et al. (2015) showed that the ribonuclease activity of IRE1 is
inhibited by S-nitrosylation, while PERK activity is increased by the
same mechanism. Further, site-directed mutagenesis of a target
cysteine residue on IRE1 rendered cells resistant to NO-induced
death (Nakato et al., 2015). This work built upon a seminal report
by the same group, which showed that protein disulphide isom-
erase (PDI), a major ER chaperone, may also be functionally down-
regulated by S-nitrosylation, with negative implications to ER stress
and brain disease (Uehara et al., 2006).
Finally, although S-nitrosylation of UPR sensors has not yet been

Please cite this article in press as: Santos, L.E., Ferreira, S.T., Crosstalk between endoplasmic reticulum stress and brain inflammation in
Alzheimer's disease, Neuropharmacology (2017), https://doi.org/10.1016/j.neuropharm.2017.11.016
6 L.E. Santos, S.T. Ferreira / Neuropharmacology xxx (2017) 1e11
directly observed in AD patients or models, it was recently
described in mouse models of obesity (Yang et al., 2015). That study
reported that iNOS-mediated nitrosylation of IRE-1 was involved in
several aspects of the obese phenotype, such as glucose intolerance,
and used a nitrosylation-resistant IRE-1 variant to provide evidence
for a causal link (Yang et al., 2015). These results underscore a
possible role of ER stress, and particularly its regulation by NO, in
the link between AD and inflammation-driven metabolic disorders,
such as type 2 diabetes and obesity.
7. Potential therapeutic approaches targeting ER stress/
inflammation in AD
Microglia are central to the inflammatory hypothesis of AD. As
such, they have long been targets of potential therapeutic ap-
proaches, which sought to curb overall microglial responses, or
shift them towards a more benign inflammatory profile (Choi et al.,
2007; Fan et al., 2017; Kobayashi et al., 2013; Ledo et al., 2016;
Mandrekar and Landreth, 2010; Spangenberg et al., 2016). How-
ever, as noted above, these approaches have had only limited suc-
cess, in part due to the complexity of inflammatory responses and
the challenges in pharmacologically isolating their maladaptive
aspects (Jiang et al., 2015; Wang et al., 2015). Additionally, it is
increasingly clear that ER stress and inflammation coexist in the AD
brain, and are intertwined. The involvement of secreted cytokines
and, particularly, of NO, which readily crosses biological mem-
branes, means that ER stress and inflammation may interact with
each other even across individual cells and different cellular types.
ER stress and modulation of UPR sensors may also play a direct
role in microglial priming. Although the concept of ‘ER stress
priming’ (i.e., lasting changes in ER stress proteins following an
insult) is itself virtually unexplored, Kim et al. (2014) showed that
chemical induction of ER stress is sufficient to prime myeloid
lineage cells to release IL-1b upon a subsequent stimulus. Other
reports further suggest that ER stress may function as a key inter-
mediate in toll-like receptor-mediated inflammatory priming
(Lebeaupin et al., 2015; Rao et al., 2014). Notably, the recent
observation that systemic LPS administration requires PKR
expression to increase hippocampal levels of TNF-a, IL-6 and Iba-1
(a microglial marker) in mice strongly supports a role for the in-
tegrated stress response system in microglial priming (Carret-
Rebillat et al., 2015). Given the increasingly recognized relevance
of microglial priming events in long-term epidemiological con-
nections between AD and other co-morbidities, including mood
alterations (Santos et al., 2016), involvement of ER stress in this
process may represent new therapeutic targets. Thus, anti-
inflammatory approaches known to effectively modulate the UPR
may hold promise in the so far disappointing landscape of AD
clinical trials.
Recent work from our group points to TNF-a as a prominent
target candidate in this regard. The human monoclonal antibody
Infliximab, which neutralizes TNF-a and has been in use for auto-
immune and inflammatory diseases since the late 1990s, was suc-
cessful in preventing eIF2a phosphorylation and memory loss in a
mouse model of AD (Lourenco et al., 2013). Further, Infliximab
prevented depressive-like behavior, a common non-cognitive
symptom of AD that is recapitulated in AbO-infused mice (Ledo
et al., 2016), suggesting a broad range of effects. These findings
are supported by pre-clinical studies showing that interference
with TNF-a signaling using thalidomide attenuates cognitive defi-
cits in rodent models of AD (Alkam et al., 2008; Gabbita et al., 2012;
He et al., 2013; Tweedie et al., 2012). The concept of neutralizing
TNF-a in AD patients is not new, and was pointed out in early case
reports employing Infliximab (Shi et al., 2011) and Etanercept, a
decoy TNFR-Fc fusion protein also in clinical use for chronic
Please cite this article in press as: Santos, L.E., Ferreira, S.T., Crosstalk between endoplasmic reticulum stress and brain inflammation in
Alzheimer's disease, Neuropharmacology (2017), https://doi.org/10.1016/j.neuropharm.2017.11.016
systemic inflammatory disease (Tobinick and Gross, 2008). Eta-
nercept has further been tested in recent clinical trials in AD
(NCT01068353, NCT01716637, NCT00203359, NCT00203320;
ClinicalTrials.gov). Although a recent phase 2 trial of Etanercept
showed promising trends in terms of mood, cognition, and daily
functioning, no statistically significant results were found in that
study, possibly due to the small sample size (41 patients divided
between treated and control groups) (Butchart et al., 2015). The
drug, however, was confirmed to be well-tolerated, and larger trials
are warranted.
Another cytokine antibody currently in clinical use for periph-
eral inflammatory diseases is Canakinumab, which targets IL-1b.
Given the evidence for IL-1b involvement in AD-related inflam-
mation, including increased expression in patient brains, correla-
tion to amyloid deposition and polymorphisms linked to higher
incidence of AD, Canakinumab may be a promising approach for
treating AD (Hallegua and Weisman, 2002). Not unlike TNF-a, IL-1b
expression is regulated by NF-kB, and it may be induced by ER
stress (Kim et al., 2014). Non-antibody alternatives, such as the drug
Anakinra, an IL-1 receptor antagonist, also exist for neutralizing IL-
b signaling. Albeit at relatively low concentrations, Anakinra has
been reported to reach the CNS following intravenous adminis-
tration (Galea et al., 2011; Goldbach-Mansky, 2011), while brain
bioavailability remains a challenge for large, immunoglobulin-
based molecules such as Infliximab or Canakinumab (Hallegua
and Weisman, 2002; Tweedie et al., 2007). For those larger mole-
cules, beneficial effects in brain disease following peripheral
administration could stem from lower levels of circulating cyto-
kines, leading to a “sink effect” that would reduce CNS concentra-
tions (Dantzer and Kelley, 2007; Ferreira et al., 2014). Notably,
neither Anakira nor Canakinumab have yet been clinically tested in
AD.
As noted above, a recent meta-analysis of the literature on over a
dozen different drugs showed that the use of NSAIDs in AD pre-
vention is currently supported by observational studies, but this
support could not be confirmed by randomized trials (Wang et al.,
2015). Such results highlight our incomplete understanding of the
mechanism of action of these drugs in AD. For instance, the effects
of NSAIDs in ER stress are particularly complex. While several au-
thors have shown that NSAIDs induce apoptosis through UPR
activation, others have described protective mechanisms, including
CHOP inhibition, with outcomes appearing to depend greatly on
the drugs and model organism used (Hosoi et al., 2009; Kitamura,
2008; Tsutsumi et al., 2006, 2004; Yamazaki et al., 2006). Perhaps
a deeper understanding of the role of NSAIDs in ER stress will allow
for a better selection of candidate drugs. Not all NSAIDs affect ER
stress in the same manner (Kitamura, 2008), and this may deci-
sively influence future choices of drugs and treatment regimens.
Minocycline, a tetracycline antibiotic with interesting anti-
inflammatory properties, has been suggested as a promising
approach to modulate microglia in AD. This is largely due to the
selectivity it shows towards neurotoxic inflammatory profiles of
microglia, while preserving more benign, phagocytic phenotypes,
which are essential for amyloid clearance (Kobayashi et al., 2013;
Santos et al., 2016). In mouse models of AD, minocycline was
shown to block AbO-mediated TNF-a release from microglia,
positively impacting behavior (Ledo et al., 2016) and memory
(Biscaro et al., 2012; Garcez et al., 2017). Most notably, Choi et al.
(2007) showed that, while preventing neuronal death and mem-
ory impairment in transgenic and AbO-infused mouse models of
AD, minocycline attenuated the upregulation of p-eIF2a observed
in those mice. Whether direct or indirect, such an effect of mino-
cycline on the UPR/ISR lends additional support to its use as a po-
tential anti-AD drug. The MADE (Minocycline in AD Efficacy,
ISRCTN16105064) trial is a phase 2, randomized, placebo controlled
 L.E. Santos, S.T. Ferreira / Neuropharmacology xxx (2017) 1e11
trial, currently ongoing with around 500 recruited patients, which
may soon shed light on the potential of minocycline in AD.
Interestingly, treatment with serotonin (5-HT) reduced TNF-a
release in cultured primary microglia exposed to AbOs and in the
brains of AbO-infused mice, and prevented behavioral deficits
associated with AD in mice (Ledo et al., 2016). Indeed, 5-HT is
known to bind microglial receptors and to have anti-inflammatory
properties, which have been proposed as part of the mechanism of
action of serotonergic antidepressants (Walker, 2013). Among these
drugs are the widely prescribed selective 5-HT reuptake inhibitors
(SSRIs), which, in the past decade, have been proposed as modu-
lators of a number of AD-related mechanisms, from amyloid pro-
cessing to its inflammatory response (e.g., Cirrito et al., 2011; Ledo
et al., 2013). Intriguingly, SSRIs were suggested to be promoters of
CHOP-mediated apoptosis (Glo € ckel et al., 2008); however, as shown
by Zschocke et al. (2011) and, more recently, by Omi et al. (2014),
these results may differ amongst neural cell populations, or may
not apply to all SSRIs. Similarly to NSAIDs, pre-selecting SSRIs on
the basis of their modulation of the stress response may help
improve their outcomes as prospective AD therapies.
8. Conclusion
Although the UPR is a vital response mechanism that evolved to
protect cells from stressors, its prolonged activation is known to
underlie pathology. Since the first description of an ER stress sensor
25 years ago (Cox et al., 1993; Morl et al., 1993), several lines of
evidence have linked aberrant UPR to neurodegeneration and, in
particular, to AD (e.g., Ma et al., 2013; Lourenco et al., 2013; Duran-
Aniotz et al., 2017; Hetz and Mollereau, 2014; Hoozemans et al.,
2005). Given the extensive links between inflammation and ER
stress described above, it may no longer be possible to consider any
inflammatory hypothesis of disease without taking ER stress into
account, and vice-versa. From early microglial priming to late
neuronal death, UPR responses are part of the mechanisms by
which inflammation influences AD incidence and progression.
Novel pharmacological approaches targeting the inflammatory
component of AD may be more likely to succeed if they can prove
effective in controlling a dysfunctional UPR, thus breaking the ER
stress-inflammation loop.
Acknowledgements
Work in the authors' laboratory is supported by grants from the
National Institute for Translational Neuroscience/Brazil, Coor-
denaça~o de Aperfeiçoamento de Pessoal de Nível Superior, Con-
selho Nacional de Desenvolvimento Científico e Tecnolo ! gico and
Fundaça~o Carlos Chagas Filho de Amparo a # Pesquisa do Estado do
Rio de Janeiro. L.E.S. is a postdoctoral fellow supported by CAPES.
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