Clinical & Experimental

Neuroimmunology
Clinical and Experimental Neuroimmunology (2018)
doi: 10.1111/cen3.12475

REVIEW ARTICLE

Neuroinflammation in mouse models of Alzheimer’s disease
Takashi Saito1,2

and Takaomi C. Saido1

1

RIKEN Center for Brain Science, Laboratory for Proteolytic Neuroscience, Wako, Japan, 2Department of Neuroscience and Pathobiology, ResearchInstitute of Environmental Medicine, Nagoya University, Wako, Japan

Keywords
Alzheimer’s disease; glial cell; mouse model;
neuroimmune communication;neuroinflammation
Correspondence
Takashi Saito and Takaomi C. Saido, Laboratory
for Proteolytic Neuroscience, RIKEN Center for
Brain Science, 2-1 Hirosawa, Wako-city, Saitama
351-0198, Japan.
Tel: +81-48-462-1111 (Ext. 7615)
Fax: +81-48-467-9716
Emails: takashi.saito.aa@riken.jp,
takaomi.saido@riken.jp
This is an open access article under the termsof the Creative Commons Attribution License,
which permits use, distribution andreproduction in any medium, provided theoriginal work is properly cited.
Received: 1 August 2018; accepted: 19 August
2018.

Abstract
Alzheimer’s disease (AD) is the most common type of neurocognitive disorder. Although both amyloid b peptide deposition and neurofibrillary tangle
formation in the AD brain have been established as pathological hallmarksof the disease, many other factors contribute in a complex manner to thepathogenesis of AD before clinical symptoms of the disease become apparent. Longitudinal pathophysiological processes cause patients’ brains toexist in a state of chronic neuroinflammation, with glial cells acting as key
regulators of the neuroinflammatory state. However, the detailed molecularand cellular mechanisms of glial function underlying AD pathogenesis
remain elusive. Furthermore, recent studies have shown that peripheral
inflammatory conditions affect glial cells in the brain through a process ofneuroimmune communication. Such disease complexities make it difficult
for the pathogenesis of AD to be understood, and impede the developmentof effective therapeutic strategies to combat the disease. Relevant AD animal models are thus likely to serve as a key resource to overcome many ofthese issues. Furthermore, as the pathogenesis of AD might be linked toconditions both within the brain as well as peripherally, it might become
necessary for AD to be studied as a whole-body disorder. The present
review aimed to summarize insights regarding current AD research, andshare perspectives for understanding glial function in the context of thepathogenesis of AD.

Introduction
Neurodegenerative disorders, such as Parkinson’s
disease, amyotrophic lateral sclerosis, Huntington’sdisease and Alzheimer’s disease (AD), are proving tobe the most difficult diseases to prevent or treat, andremain as unmet medical needs. AD is the primarycause of neurocognitive disorders in the elderly, andposes a huge socioeconomic burden for modern society. The number of patients with dementia is estimated to be >46 million people worldwide, and isincreasing unabated each year. To the present time,
only some symptomatic treatments have been foundto be effective. To overcome this impasse and todevelop effective treatments, elucidation of themolecular and cellular mechanisms underlying thepathogenesis of AD with a view to identifying druggable targets must be a priority.

Senile plaques composed of extracellular amyloidb peptide (Ab) and neurofibrillary tangles (NFT),
which are the aggregates of intracellular hyperphosphorylated tau protein, are hallmarks of the AD
brain.1 Ab deposition and NFT formation in the cortical region of the brain begin appearing 25–30 years
and 15 years, respectively, before the clinical onset
of AD (Fig. 1a).2 Ab is generated proteolytically fromamyloid precursor protein (APP) to subsequently
form oligomeric Ab, which aggregates into senile
plaques. Although microtubule-associated protein
tau stabilizes microtubules in the axon, pathologicaltau mislocalizes through an unknown mechanismand forms NFT aggregates in the neuronal dendrites
and cell body. These protein aggregates in the brain
environment induce the activation of microglia andastrocytes, which results in microgliosis and astrocytosis around the pathological structures.

© 2018 The Authors. Clinical and Experimental Neuroimmunology published by John Wiley & Sons Australia, Ltdon behalf of Japanese Society for Neuroimmunology

1Neuroinflammation in Alzheimer’s disease

Takashi Saito and Takaomi C. Saido(a)

Amyloidosis-associatedneuroinflammation Tauopathy-associatedneuroinflammation
Aβ

–30
(b)

NFTs

–20

–10

Onset of AD

0(Onset)Aβ/Iba1/GFAP+10

NFTs/Iba1/GFAPGlial cells are thus chronically activated in thebrain before the onset of AD,3 with the associatedchronic inflammation contributing to the pathogenesis of AD. In the AD brain, microgliosis and astrocytosis as a consequence of the presence of senile
plaques and NFTs can be detected immunohistochemically, with these glial cells showing a pathology-specific morphology (Fig. 1b). Although theextent of gliosis is correlated with cortical thickness
and neurodegeneration, the roles of different glial
cells in neurodegenerative processes remain
unclear.4 Relevant animal models are required forthese processes to be investigated in greater detail.
Animal models for AD and neuroinflammation
Animal models representing relevant pathologies
with as few artifactual anomalies as possible are necessary. To this end, a number of AD mouse models
have been developed,5 with APP overexpressing
mice, such as APP transgenic (APP Tg) mice, having
been used widely,6,7 although they are associatedwith considerable technical and physiological issues.
For example, amyloid plaques in some APP Tg mice,
particularly Tg2576 and APP23 mice, were found tobe very large in size and composed mainly of Ab40,8
making the plaques decidedly different from thoseseen in AD patients (Fig. 2). These findings were
due to technical limitations associated with the animal models, which were based on an APP overexpression paradigm. To overcome these drawbacks,
2(years)Figure 1 (a) Time-course of Alzheimer’s disease (AD) progression. Amyloid b peptide (Ab)deposition begins >25 years before the onset
of AD and is followed by neurofibrillary tangles(NFT) formation. This leads to neurodegeneration and neuronal cell death. Both amyloidassociated and tauopathy-associated neuroinflammation might facilitate AD pathogenesis.
(b) Immunohistochemical staining of gliosis in
the human AD brain. 1-Fluoro-2,5-bis(3-carboxy-4-hydroxystyryl)benzene (blue fluorescence) binds to b-sheet structures, such as
dense-cored Ab plaques (left panel) and NFTs
(right panel), respectively, with ionized calcium
binding adaptor molecule 1 (Iba1)-positive
microgliosis shown in red and glial fibrillaryacid protein (GFAP)-positive astrocytosis ingreen. Scale bar, 20 lm.

we created two strains of App knock-in (KI) mice,9
named AppNL-F KI and AppNL-G-F KI. AppNL-F KI miceharbor the Swedish mutation (NL) and the Iberianmutation (F), whereas AppNL-G-F KI mice also harbor
the Arctic mutation (G). Both App KI mouse strains
showed relevant amyloid deposition composed ofpathological Ab42, similar to that in AD patients(Fig. 2).9 Advantages associated with using the App
KI strains have been described,10,11 with thesemouse strains showing fewer artifactual anomalies
compared with APP overexpressing mice.12,13 However, we did not observe NFT in the App KI mice
during their lifespan, suggesting that the mice mightalso be useful as preclinical AD mouse models toinvestigate the pathological role of amyloidosis andamyloid-associated neuroinflammation. Hama et al.
succeeded in using 3-D visualization of resting andactivated microglia in the brains of App KI mice andAD patients using an optical clearing technique, andshowed that microglia are frequently associated withdiffuse plaques in the AD brain.14 Zhang et al. further reported that App KI mice show mushroom
spine loss,15 which could reflect microglia-mediatedsynapse loss in AD.16 Furthermore, Castillo et al.
reported amyloidosis-dependent transcriptomic profiles in 3xTg AD mice17 and AppNL-G-F KI mice.18 In
contrast to 3xTg AD mice, AppNL-G-F KI mice express
genes in common with AD patients, such as neuroinflammation-related genes (C4a/C4b, Cd74, Ctss,
Gfap, Nfe212, Phyhd1, S100b, Tf, Tgfbr2 and Vim) andAD risk factor genes (Abi3, Apoe, Bin2, Cd33, Ctsc,© 2018 The Authors. Clinical and Experimental Neuroimmunology published by John Wiley & Sons Australia, Ltdon behalf of Japanese Society for Neuroimmunology

Takashi Saito and Takaomi C. Saido

Neuroinflammation in Alzheimer’s disease

APP23

AD

AppNL-F KI

AppNL-G-F KI

Figure 2 Pathological differences in amyloidosis between mouse models and human brain
tissue. Double staining for Ab (anti-Ab antibody: 82E1, red) and ionized calcium binding
adaptor molecule 1-positive microgliosis(green) was carried out using brain sections
obtained from amyloid precursor protein (APP)
23 mice, App knock-in mice and post-mortem
brain tissue from an Alzheimer’s disease (AD)patient. Scale bar, 25 lm. F, Iberian mutation;
G, Arctic mutation; NL, Swedish mutation.

Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2
and Tyrobp).18 Thus, App KI mice might overcome
some of the previous limitations associated with
APP overexpression-based mouse models, andcould thus serve as a useful research tool for further
investigations.
Various tauopathy mouse models have also been
generated,19 with most tau transgenic models harboring tau mutations known to be associated withfrontotemporal dementia with parkinsonism linked
to chromosome 17 (FTDP-17), and not associatedwith AD.20 The mutations accelerate the self-aggregation of tau or give rise to an isoform shift from 3repeat to 4-repeat tau. In any case, tau transgenic
mice containing FTDP-17 mutations form NFT without amyloid plaque deposition, meaning that thesemouse models might contribute to elucidation of therole of tauopathy-associated neuroinflammation. The
microglial phenotype changes from a ramified typeto an amoeboid type during the development of
tauopathy in rTg4510 mice.21 P301S-tau Tg miceshow reactive gliosis before tau aggregation, whereas
immunosuppression of P301S-tau Tg mice with
FK506 attenuates tau pathology.22 In another scenario, amyloid deposition exacerbates NFT formationin JNPL3 transgenic mice.23 Although the pathomolecular mechanisms linking Ab deposition to NFT
formation, or NFT formation to neurodegenerationand neuronal cell death remain unclear, these outcomes suggest that neuroinflammation could link
amyloid pathology and NFT formation as an important pathophysiological event in the development of
AD. To further elucidate a pathological role of neuroinflammation in AD, different strategies using
immune challenge-based models and neurotoxininduced AD models have been used.24 In virtually
all scenarios considered, animal models will be indispensable for elucidating the molecular and cellularmechanisms of AD pathogenesis, and for developing
effective strategies to prevent and treat the disease.
Neuroinflammatory glial responses (relevance tothe brain’s microenvironment)
Microglia, the principal innate immune cells in thebrain, carry out macrophage-like phagocytic actions
to remove pathogens and to protect neurons fromtoxic species. However, microglia produce andrelease molecules, such as reactive oxygen species
and nitric oxide, that are neurotoxic.25 They also

© 2018 The Authors. Clinical and Experimental Neuroimmunology published by John Wiley & Sons Australia, Ltdon behalf of Japanese Society for Neuroimmunology

3Neuroinflammation in Alzheimer’s disease

Takashi Saito and Takaomi C. Saido

generate pro-inflammatory cytokines and chemokines in response to danger signals, and communicate
with astrocytes.26 To this end, the dysregulation of
microglial activity has been associated with AD
pathogenesis in the aged brain.27 Recently, it wasreported that TREM2, as well as CD36 and thereceptor for advanced glycation end-products, work
as Ab sensor molecules and activate microglia.28 A
consistent and elevated expression of TREM2 wasdescribed in AppNL-G-F KI mice.18 Activated microglia
also produce the pro-inflammatory cytokines CCL3/
MIP-1a and interleukin (IL)-6,28 the latter being a
key component of the senescence-associated secretory phenotype,29 which might provide a pathophysiologicalconnection
betweencellular/tissue
senescence and age-related chronic diseases in thebrain, including AD. Furthermore, pro-inflammatory
gene polymorphisms, including CCL3/MIP-1a andIL-6, have been identified as risk factors for AD.30
The genetic modulation of inflammation-related
factors has been investigated in various transgenic
models of AD.31 These studies commonly showedthat the modulation of inflammatory factors alters
amyloid pathology and tau phosphorylation in themouse models used. Interestingly, the inflammasome, a key inflammatory signaling platform in
immune cells that activates IL-1b and IL-18 through
NLRP3/ASC/Caspase1 activation,32 in microglia
might contribute to AD pathogenesis in APP/PS1
mice.33,34 To this end, microglia-derived ASC (a constituent of the inflammasome) has been shown toregulate amyloidosis in APPswe/PSEN1dE9 mice.35
Modulation of glial function through the manipulation of cytokines/chemokines and their receptors has
also been investigated.31,36 These studies provided
evidence that the microglial fractalkine receptor(CX3CR1) could potentially exacerbate tau pathology and neuronal cell death,37,38 and that microglia
also expand tau propagation through the exosome.27,39 These findings support the notion thatreactive microglial neuroinflammation accelerates
AD pathogenesis, particularly by linking tau pathology with neurodegeneration.
Astrocytes serve multiple functions, including providing support to endothelial cells that form neurovascular units in the blood–brain barrier, supplying
nutrients to the central nervous system, maintaining
the extracellular balance of electrolytes and water,and repairing or remodeling tissue during the processof traumatic brain injury or neuroinflammation. As
shown in Figure 1b, reactive astrocytes can be
typically observed in the vicinity of amyloid plaque(plaque-associated astrocytes). Although the primary4function of the plaque-associated astrocytic response
remains unclear, deletion of the glial filament proteins glial fibrillary acid protein and vimentin in
APP/PS1 mice increased the number of dystrophic
neurites,40,41 whereas astrocyte-producing kallikreinrelated peptidase 7 contributed to Ab degradation.42,43 Astrocytes also contribute to the clearanceof Ab and other debris from the brain through astrocytic transport, the so-called “glymphatic system”.44
As the glymphatic system is comparable with thelymphatic system in peripheral organs, astrocytes
might act as a gateway from the brain to the bloodvessels. Recently, phagocytic astrocytes wereobserved at ischemic sites of the brain.45 Astrocytic
phagocytosis has been suggested to engulf anddegrade plaque-associated synaptic dystrophies in
APP/PS-1 mice and AD brain.46 Furthermore, neurotoxic A1 astrocytes are induced by activated microglia;47 to this end, a glucagon-like peptide-1 receptor
agonist was postulated to act as a potential neuroprotective agent through the suppression of A1 astrocytes in a mouse model of Parkinson’s disease.48
Although further classification of astrocyte cell types
is required, plaque-associated reactive astrocytes
could protect neurons surrounding amyloid plaquesin the early stages of AD pathogenesis. While these
glial cells thus serve as “guardians” of the brain
microenvironment, any dysregulation of glial communication could lead to a neurotoxic state.
The receptivity and responsiveness of glial cells aredifferent with respect to amyloid plaques comparedwith NFT in the AD brain. Plaque-associated astrocytes surround amyloid plaques, whereas microglia
attack the inside of the plaques. However, microglia
are unable to reach the inside of amyloid plaques in
APP23 mouse brains due to the unphysiologicallylarge size of these plaques (Fig. 2). Consequently,
the microglial response in APP Tg mice is likely to bedifferent from that in App KI mice and in the AD
brain. The morphological pattern of reactive astrocytes and microglia in response to FSB-positive NFT(ghost tangles) was different from that in response
to Ab deposition (Fig. 1b). Regulation of the glial
response might therefore change markedly depending on the pathological stage of tauopathy.21,49 However, it is still unclear which glial cells, astrocytes or
microglia, recognize these abnormal protein aggregates as danger signals, and how this is achieved,
especially considering that the communication
between astrocytes and microglia is regulated bypathology-associated cytokines/chemokines.
In summary of the above literature, the cytokines
induced by amyloidosis are different from those© 2018 The Authors. Clinical and Experimental Neuroimmunology published by John Wiley & Sons Australia, Ltdon behalf of Japanese Society for Neuroimmunology

Takashi Saito and Takaomi C. Saido

induced by tauopathy in the different mouse models,meaning that it might be possible to distinguishamyloidosis-associated glial responses (neuroinflammation) from tauopathy-associated neuroinflammation, as shown in Figure 1a.18,31,36–38 Indeed, in amanner similar to that describing amyloidosis andtauopathy in the AD brain, glial pathology in amyloidosis mouse models is different from that intauopathy mouse models. Furthermore, at the stage
when both amyloid and tau pathologies exist, dysregulation of glial communication in the brain
microenvironment along with the long-lasting
abnormal activation of glial cells might facilitate thepathogenesis of AD.
Neuroinflammation and the interaction between
brain and peripheral tissue (whole-bodymacroenvironment)
Evidence from epidemiological studies pointed to apossible link between the use of non-steroidal antiinflammatory drugs (NSAIDs) and a decreased riskof AD in people with rheumatoid arthritis.50 Subsequently, the long-term use of NSAIDs was found topotentially protect individuals against AD, but notagainst vascular dementia.51 A number of studies
using different AD mouse models also suggested that
NSAIDs improve Ab-mediated brain dysfunction.
Although the protective mechanisms by which
NSAIDs exert their effects remain unclear, inflammation in the brain and/or periphery could be
involved in the pathogenesis of AD. In contrast to
the epidemiological evidence, a recent meta-analysis
on the effects of NSAID treatment reported no beneficial effect on AD.52 These conflicting results suggestthat NSAIDs do not improve AD pathogenesis
directly in the brain, but that systemic inflammation,such as that seen with rheumatoid arthritis, might
affect the brain pathologically. Recent evidence alsosuggests that inflammatory diseases, such as osteoporosis,53 diabetes,54 cancer55 and infection,56 are
possibly implicated in brain disorders, and that these
diseases could affect brain function through immune
responses elicited in the periphery; that is, throughneuroimmune communication. Furthermore, treatment strategies against such diseases might influence
brain function and the macroenvironment, asreported for cancer-related cognitive impairment57
or HIV-associated neurocognitive disorder,58 possibly
leading to the onset of brain disorders. Recently,
accumulating evidence has suggested a role ofperipheral immune cells, particularly CD4+ T cells,in the central nervous system. CD4+ T cells have

Neuroinflammation in Alzheimer’s disease

been suggested to affect the activation of microglia,
and to alter the Ab burden in APP Tg mice and AD
patients.59–61 Thus, future investigations need toclarify the role of both tissue resident immune cells
and circulating immune cells in the pathogenesis ofAD.
Interestingly, gut microbiota and associatedmetabolites have been described to influence brain
dysfunction62,63 and to modulate the host immune
system.64 This “gut–brain axis” has consequently
received attention in several research fields. While it
was reported that factors, such as obesity,65 exercise,65 diet/nutrition,65 circadian rhythm,66 sleep,67
stress68 and aging,69 modulate gut microbiotic conditions, such factors might also affect brain function
and brain disorders. The body’s macroenvironment,
particularly the role played by inflammatory factors
and immune cells including microglia and astrocytes,
almost certainly contributes to the correct physiological functioning of the brain, as well as to the pathogenesis of brain disorders when this environment isdisturbed. Taken together, these observations shed
new light on the notion that the pathogenesis of AD
might be linked not only to conditions within thecentral nervous system, but also to peripheral conditions, thus making it a whole-body disorder. To further investigate such whole-body interactions,studies using relevant animal models and the in vivo
imaging of neuroinflammation will be critical tounderstanding the mechanisms underlying AD and
to predicting therapeutic outcomes.70
Conclusion
Numerous AD studies showing the time-course of
disease development and the complex nature ofpathological processes in the brain attest to the difficulty of elucidating the molecular and cellular mechanisms underlying AD pathogenesis. To promotefurther investigation, animal models will be critical if
progress is to be made. However, some AD mousemodels do not accurately or reproducibly reflect AD
in humans, and might thus need to be re-evaluatedas suitable models. As highlighted here, neuroinflammation is an important process in the pathogenesis of AD, and contributes a rate-limiting
component that potentially links Ab amyloidosis
with neurodegeneration and neuronal cell deaththrough tauopathy. However, the pathological rolesof neuroinflammation based on the brain microenvironment, as well as that contributed by the wholebody macroenvironment, remain elusive. Understanding glial cell interactions associated with AD© 2018 The Authors. Clinical and Experimental Neuroimmunology published by John Wiley & Sons Australia, Ltdon behalf of Japanese Society for Neuroimmunology

5Neuroinflammation in Alzheimer’s disease

Takashi Saito and Takaomi C. Saido

and other neurodegenerative disorders according to
the newly coined term “gliostasis” (homeostasis of
glial cells) might serve as a promising starting point.
Relevant animal models will again be necessary toinitiate such studies, and will serve as a fundamental
research tool to elucidate the pathogenetic mechanisms underlying AD development and to develop
preventive or therapeutic interventions to combat
the disease.
Acknowledgments
We thank Naomi Mihira and Yukio Matsuba fortechnical assistance, and Yukiko Watanabe-Nagai forsecretarial assistance. This work was partially supported by AMED, under Grant Number JP18dm0107070h0003 (the Strategic Research Program forBrain Sciences; T.S.) and JP18dm027001 (Brain
Mapping by Integrated Neurotechnologies for Disease Studies [Brain/MINDS] T.C.S.); a grant-in-aid
for scientific research (B) (grant number: 26290019)
of the Ministry of Education, Culture, Sports,
Science and Technology (T.S.); JST PRESTO (T.S);
the Cell Science Research Foundation (T.S.); theAging Project of RIKEN (T.C.S.); and research grants
from RIKEN Center for Brain Science (T.C.S.). We
also thank Michael Patterson, Sciencedit, for editing
the English in our manuscript.
Conflict of interest
T.S. and T.C.S. serve as the advisor and CEO, respectively, for RIKEN BIO Co. Ltd., which sublicenses
animal models to for-profit organizations, the profits
from which are used for the identification of diseasebiomarkers.

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