Ligands of Receptor for Advanced Glycation End-Products Produced by Activated Microglia are Critical in Neurodegenerative Diseases
Myeongjoo Son1,2* Seyeon Oh2*, Sojung Lee1,2 and Kyunghee Byun1,2†
1Department of Anatomy and Cell Biology, Gachon University, Graduate School of Medicine, Incheon, Republic of Korea
2Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
- Corresponding Author:
- Kyunghee Byun
Department of Anatomy and Cell
Gachon University Graduate School of Medicine
21999, Republic of Korea
Tel: + 82-899-6511
Received date: March 17, 2017; Accepted date: April 03, 2017; Published date: April 10, 2017
Citation: Son M, Oh S, Lee S, Byun K (2017) Ligands of Receptor for Advanced Glycation End-Products Produced by Activated Microglia are Critical
in Neurodegenerative Diseases. J Alzheimers Dis Parkinsonism 7:318. doi:10.4172/2161-0460.1000318
Copyright: © 2017 Son M, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
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Receptor for advanced glycation end products (RAGE) and its ligands have been reported to be involved in the progressions of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Recently microglia activated by immunological stimuli, cytokines, or oxidative stress were reported to synthesize and secrete RAGE ligands including AGEs, HMGB1, and S100 in neurodegenerative diseases. Furthermore, RAGE/ligand binding has been implicated in neuroinflammation and in the progression of neurodegenerative diseases through a RAGEmediated pathway in neurons. A number of RAGE inhibitors, such as, antagonists, small RAGE inhibitors, anti-RAGE antibody, and soluble RAGE, have been shown to interfere with RAGE/ligand binding and to reduce RAGE ligand accumulation, microglia activation, and neuronal cell death in neurodegenerative diseases. Accordingly, RAGE inhibitors present an attractive therapeutic target in neurodegenerative diseases, and RAGE ligands might be useful diagnostic targets. Some human studies have shown RAGE ligand distributions in brain, serum, and cerebrospinal fluid are promising biomarkers for early disease detection and that these ligands might play important roles during early disease stages. Taken together, RAGE ligands and RAGE inhibitors appear to be good therapeutic and diagnostic candidates for neurodegenerative diseases.
Amyloid beta (Aβ); Advanced glycated end products
(AGEs); HMGB1; S100; Receptor of AGEs (RAGE); Microglia
activation; Alzheimer’s disease (AD); Parkinson’s disease (PD);
Diagnosis; Therapeutic effects
Relations between Microglial Activation and Neuronal
Cell Death in Neurodegenerative Diseases
Neurodegenerative diseases result from the progressive loss of
neuronal cell functions and structures, and Alzheimer’s disease (AD)
is a chronic type of neurodegenerative disease . The main causes of
AD have yet to be determined, although 1% to 5% of cases harbor a genetic mutation . Several studies have shown chronic inflammation
contributes to the pathology of AD [3,4] and which is known to be related
to microglia activation [5,6]. Although the cause of AD progression is
unclear, AD is characterized by inflammatory responses to amyloid-β
(Aβ), microglia activation, and astrocyte recruitment by Aβ deposits . Parkinson’s disease (PD) is occurs by loss of dopaminergic neurons in
the substantia nigra (SN) and by many other events and agents, such
as, genetic events or toxic drugs or chemicals, such as, 1-methyl-4-
phenyl-1,2,3-6 tetrahydropyridine or rotenone [8,9]. Pathologic changes
in the PD brain are closely related to microglial activation induced
inflammation, which accelerates dopamine (DA)-producing neuron
death. Interestingly, positron emission tomography (PET) studies
have shown noticeable microglial activation in the SN, putamen and
subcortical and cortical areas of the PD brain [10,11].
Molecular genetic studies are indispensable for understanding
the central role played by Aβ in the pathogenesis of AD. Amyloid
precursor protein (APP) mutation mouse models, such as, the PDAPP
, Tg2576 , APP23 , APP/presenilin (PS1) models or APP/
PS1/Tau mutation models, such as, the APP/PS1 , 3XFAD 
and 5XFAD  models. The 5XFAD model shows an amyloid plaque
formation, which exhibits neuron loss in cortical layer 5 and subiculum
from 9 months  and inn this model; microglia is activated in the
cortex (Figure 1), which is a region of neuronal death .
Genetic mutation animal models of PD have also been well
established, such as, the PINK1, PARKIN, DJ-1, PARK9, LRKK2 and
α-Synuclein models . Although genetic models generally show
features that appear in the PD, PINK1  and PARKIN  genetic
models do not exhibit DA related behavior abnormities and the DJ-1
, PARK9  and LRRK2 [24,25] models do not exhibit changes in
the number of DA-producing neurons in SN.
However, α-Synuclein genetic model exhibits hallmark pathologic
features of PD, including progressive loss of the DA-producing neurons
in the SN and reduced DA levels in the striatum  and formation
of Lewy bodies in old animals . In particular, α-synuclein has been
reported to be related to microglia activation in the SN and striatum
[27,28]. These observations suggest microglial activation is critical for
neuronal cell death.
Microglia can be activated by toxins, cytokines, injury, or inflammation [29,30] and their activation has also been reported
to be a key contributor [5,6,31]. Cytokines are involved in systemic
inflammation and in degenerative disease and can be produced by
neurons. In AD, amyloid β (Aβ), chromogranin A (CGA), interferon
gamma (IFN-γ), and matrix metalloproteinase-3 (MMP-3) are
candidate participants in neuronal apoptosis and microglial activation
[32-34] and the cytokines α-synuclein, CGA, IFN-γ, MMP-3, neuromelanin, and tumor necrosis factor alpha (TNF-α) are candidate
microglia activators in PD [35-41].
Figure 1: Microglia was activated in 5XFAD at 6 month. Activated microglia was determined by Iba1 staining and the number of Iba1 positive cells was counted. (A)
Boxed area image is enlarged to the upper panel in cortex of wild type (top row) and 5XFAD mice (bottom row). (B) Quantitation of Iba1 positive cell was counted per
mm2 in cortex. Scale bar; 100 μm. Statistical significance was marked with 2 symbols.
*; p<0.05 versus wild type, #; p<0.05 versus 1.5 month mice
Figure 2:RAGE ligands increased in 5XFAD at 6 month. The expression level of RAGE ligands including (A) AGE, (B) HMGB1, and (C) S100β was validated by Indirect
ELISA in cortex of wild type and 5XFAD. Ratios represented in the graphs represented fold levels to 1.5 month mice.
Statistical significance was marked with 2 symbols.
*; p<0.05 versus wild type, #; p<0.05 versus 1.5 month mice.
Secretion and Synthesis of RAGE Ligands by Activated
Microglia in AD and PD
RAGE ligands include advanced glycation end products (AGEs),
high mobility group box chromosomal protein 1 (HMGB1),
lipopolysaccharide (LPS), macrophage-1 antigen (Mac-1),
phosphatidylserine and S100/calgranulin and under pathologic
conditions activate microglia [42-46], which then secrete and synthesize
RAGE ligands, such as, AGEs, HMGB1 and S100β in AD  (Figure
2) and PD .
Advanced glycation end products (AGEs)
AGEs are considered to induce the development or support the
progression of neurodegenerative diseases and their toxic properties are
known to stem from oxidative stress and inflammation [48,49]. AGEs
localize in senile plaques and extracellular spaces in AD [50-52] and
AGE-albumin and RAGE binding stimulate the activations of diverse signaling cascades through MAPK (mitogen-activated protein kinases)
and bcl-2-like protein 4 (Bax) pathways that result in neuron apoptosis . In PD, AGEs act as major structural cross-linkers, and are
responsible for the formation of Lewy bodies in human dopaminergic
neurons . Furthermore, AGE-albumin and RAGE co-localization
promote MAPK and Bax mediated DA-producing neuron apoptosis
in the SN of Rotenone-exposed mice  in a manner similar to that
observed in AD .
High mobility group box 1 protein (HMGB1)
Activated microglia secretes HMGB1 during inflammation in
neurodegenerative diseases  and this secretion is increased by Aβ
and promotes neuronal cell death. Furthermore, microglial infiltration
and secretion of soluble HMGB1 are significantly elevated in the AD
hippocampus and promote neuronal cell death, synaptic destruction
and behavioral deficits . The interaction between HMGB1 and
RAGE activates the NF-κB (nuclear factor kappa-light-chain-enhancer
of activated B cells) pathway and leads to neuronal cell death via
an autoregulatory loop, which exacerbates neurodegeneration and neuroinflammation in AD . HMGB1 is also released by microglia
under inflammatory conditions, and in PD, binds to microglial Mac-1.
Furthermore, these activities activate the NF-κB pathway and NADPH
(nicotinamide adenine dinucleotide phosphate) oxidase .
The S100 protein family
This low-molecular-weight protein family consists of approximately
25 proteins, which are involved in the regulation of protein
phosphorylation, calcium homeostasis, transcription factors, and
inflammatory response . S100β is found in degenerative cells of AD
and PD , and it has been reported S100β overexpression ameliorates
AD-like pathology and enhances microgliosis and astrogliosis .
S100 proteins have also been reported to cause neuronal cell death via
TNF-α and NF-κB in PD .
In the 5XFAD model, microglia activation increased at 6 months
and significantly increased RAGE ligand levels at 6 months versus
1.5 months, and these ligands can promote neuron cell death at 9 or
12 months (Figure 2) . Interestingly, in PD, secreted α-synuclein
can activate microglia directly and LRRK2 has been related with the
regulation of microglia activation in PD .
RAGE ligands are secreted and synthesized by activated microglia
and accelerate neurodegenerative diseases via RAGE pathway (Figure
3). In particular, JNK and MAPK play important roles in neuronal cell
death and seem to be induced by NF-κB in the presence of inflammation.
RAGE Ligands and RAGE as Potential Therapeutic and
Diagnostic Targets in AD and PD
RAGE/ligand binding leads to neuronal cell death, and thus, the
inhibition of this binding considered an important strategy for treating
neurodegenerative diseases [29,47]. Furthermore, anti-RAGE therapy
using an antagonist, small molecule RAGE inhibitors, soluble RAGE
(sRAGE) or anti-RAGE antibody has been reported to protect neurons
[63-66]. In AD, FPS-ZM1 (a high-affinity RAGE-specific inhibitor) was
found to specifically bind to the V domain of RAGE, to cross the Blood-Brain-Barrier (BBB), and to inhibit Aβ-induced cellular stress , and
FPS-ZM1 protected neurons from mitochondrial injury and oxidative
stress by reducing RAGE/ligand binding directly or reducing Aβ levels
indirectly in brain [67-69]. In addition, a number of RAGE inhibitors
are undergoing clinical trials for the treatment of AD. Azeliragon
(TTP488), which was developed by vTv Therapeutics (formerly
TransTech Pharma), is a candidate for the treatment of mild AD and is
currently the subject of a phase 3 clinical trial . TransTech Pharma
also developed PF-04494700, which inhibits RAGE/Aβ-42 binding.
This agent, which is administered orally, crosses the BBB and helps
reduce Aβ accumulation and spatial memory defects .
Some evidence indicates sRAGE and anti-RAGE antibody block
RAGE/ligand binding in AD. sRAGE is a splice variant of RAGE that
binds RAGE ligands more effectively than RAGE, and thus, downregulates
the RAGE-mediated pathway. sRAGE and anti-RAGE
antibody act by inhibiting Aβ uptake and RAGE/ligand binding [29,63],
but sRAGE also reduces cell death of DA-producing neuron through
MAPK phosphorylation, Bax expression in PD . RAGE ligands can
also be used to support diagnoses of AD or PD. Generally, MRI and
cerebrospinal fluid (CSF) biomarkers related to AD, do not provide
evidence of neurodegenerative change or amyloid clearance [71,72].
However, it has been reported that some RAGE ligands might be useful
diagnostic targets. In the human AD brain, AGEs are distributed in
neuron cytoplasm in the hippocampus and para-hippocampal gyrus
and in one study, serum and CSF levels of AGEs were suggested as
biomarkers for the early detection of AD . Furthermore, AGE
accumulation has been observed in incidental Lewy Body diseases (a
presymptomatic PD state) as well as in the Lewy bodies of PD patients
. These studies suggest AGEs/RAGE binding plays an important
role during the early stages of neurodegenerative diseases .
The role played by activated microglia in neuronal cell death has
been well established in neurodegenerative diseases. Microglia activated
by immunological stimuli, oxidative stress or cytokines secrete and synthesize RAGE ligands, such as, AGEs, HMGB1 and S100β, and these
ligands trigger deleterious, RAGE mediated, signaling, which results in
neuron death in AD and PD. A number of RAGE inhibitors, including
antagonists, small molecule RAGE inhibitors, sRAGE and anti-RAGE
antibody have been demonstrated to ameliorate the pathologic processes
of AD and PD. Moreover, RAGE ligands in serum or CSF can be used
diagnostically to detect the presence of AD and PD. Furthermore,
evidence at hand indicates RAGE inhibitors and RAGE ligands are good
therapeutic and diagnostic candidates in AD and PD [74-81].
Figure 3:Cell specific ligands for RAGE and their signaling pathways in AD and PD. (A) RAGE and its ligands mediated neuronal cell death and autophagy via MAPK/
BAX and JAK/STAT pathways and also induced inflammation and oxidative stress via the NF-κB pathway in AD. (B) The RAGE/RAGE ligand interactions induced
DA-producing neuron cell death and inflammation via the NF-κB pathway in PD.
Myeongjoo Son and Seyeon Oh have equally contributed.
This work was supported by the National Research Foundation of Korea (grant
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