Received: 17 January 2023

Revised: 2 February 2023

Accepted: 8 February 2023

DOI: 10.1111/cen3.12745

INVITED REVIEWMultifactorial glial responses and their contributions
to Alzheimer's disease continuum
Masanori Hijioka 1|

Tatsuya Manabe 1

1
Department of Neurocognitive Science,
Institute of Brain Science, Nagoya City
University Graduate School of Medical
Sciences, Nagoya, Japan2
Department of Neuroscience andPathobiology, Research Institute ofEnvironmental Medicine, Nagoya University,
Nagoya, Japan| Takashi Saito 1,2

Abstract
Alzheimer's disease (AD) is the most common neurocognitive disorder. Various
factors are intricately intertwined before clinical symptoms appear, although bothamyloid-β peptide deposition and neurofibrillary tangle formation (i.e. pathologicalhallmarks of the AD brain) are established. Among such factors, glial responses havebeen increasingly recognized as important roles in the progression of these patholo-

Correspondence
Masanori Hijioka, PhD, Tatsuya Manabe, PhD
and Takashi Saito, PhD, Department of
Neurocognitive Science, Institute of Brain
Science, Nagoya City University Graduate
School of Medical Sciences, 1,Kawasumi,
Mizuho-cho, Mizuho-ku Nagoya 467-8601,
Japan.
Email: mhijioka@med.nagoya-cu.ac.jp,
t.manabe@med.nagoya-cu.ac.jp andsaito-t@med.nagoya-cu.ac.jp

gies and viewed as one component of the AD continuum. However, the detailed
molecular and cellular mechanisms of glial function underlying AD pathogenesis
remain to be elucidated. Recent studies showed that peripheral immunity, gut microbiota or environmental factors influence brain pathophysiologies through communication with glial cells in the brain. This disease complexity makes understanding AD
etiology difficult and hinders the development of effective therapeutic strategies totackle this disease. Conversely, aged patients often suffer from multiple – not a single– diseases as multimorbidity, and AD pathogenesis might be related to pathologies

Funding information
Hori Sciences and Arts Foundation; Japan
Agency for Medical Research andDevelopment; Japan Society for the Promotionof Science; Moonshot Research andDevelopment Program; Toyoaki ScholarshipFoundation; Moonshot R&D, Grant/Award
Number: JPMJMS2024; AMED, Grant/Award
Numbers: JP21dk0207050h001,
JP21gm1210010s0102; MEXT/JSPS
KAKENHI, Grant/Award Numbers: 22K20688,
22K06865, 20H03564; Research in Nagoya
City University, Grant/Award Number:
20211011|

caused by other diseases. Hence, investigating AD as a systemic disease has become
critical for identifying therapeutic interventions. This review aimed to summarize current knowledge on AD research and share perspectives for understanding glial functions regarding AD pathophysiology.
KEYWORDS

Alzheimer's disease continuum, Alzheimer's disease, astrocyte, brain–periphery interaction, glial
response, microglia, multimorbidity

I N T RO DU CT I O N

reduce disease progression. Conversely, clinical trials with anti-tau
antibodies against AD or anti-synuclein antibodies against Parkinson's

Alzheimer's disease (AD) is a common cause of neurocognitive disor-disease therapies have been inconclusive at present,3,4 and so far,der in the elderly and imposes tremendous social issues on modern

strategies targeting the upstream of the amyloid cascade appear to besociety. However, a definitive solution to AD has yet to be estab-promising. However, clarifying the molecular and cellular mechanisms

lished. Recently, interventions with anti-amyloid antibodies, such as

underlying AD pathogenesis, and developing fundamental disease-aducanumab1 and lecanemab,2 are effective in some patients withmodifying drugs is necessary to fully prevent and treat AD.

early AD. This implies that a proof of concept has been obtained that

Recent discoveries of many plasma and cerebrospinal fluid

amyloid-β (Aβ) removal therapy from the preclinical stage might

biomarkers identified that pathological changes that characterize AD
occur sequentially in an overlapping manner before the clinical onset.5,6

Review in Clinical and Experimental Neuroimmunology

Clin Exp Neuroimmunol. 2023;1–10.

AD is now referred to as a continuum rather than a discrete disease
wileyonlinelibrary.com/journal/cen3© 2023 Japanese Society for Neuroimmunology.

1

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HIJIOKA ET AL.

entity by covering both biological and clinical stages of AD during dis-consequent inflammatory burden is likely to accumulate and become

ease progression (Figure 1a).7 This so-called “AD continuum” is based

diverse over the disease progression, highlighting that further insights

on the amyloid cascade hypothesis where senile plaque formation repre-

into the AD pathogenesis can be provided by untangling the mixed

sents a primary hallmark of AD.8 Particularly, familial AD mutations on

inflammatory environment in the AD brain. Even more complicated,

the APP (amyloid precursor protein) and PSEN1/2 (presenilin-1/2) genes

other mediators can also modulate the glial reactivity and possiblystrongly drive Aβ production and plaque formation in the brain, causing

affect the AD pathogenesis (for instance, adaptive immune cells in the9the earlier onset of AD. In addition, genetic risk factors of AD also

brain, altered gut microbiota and co-existing brain or systemic pathol-

involve abnormal Aβ metabolism that in turn aids plaque formation.5

ogy; Figure 1b). The present review outlines how glia play key roles in

Subsequently, the appearance of neurofibrillary tangles (i.e. the accumu-

the development of the AD continuum, and how peripheral mediators

lation of hyperphosphorylated tau) finally leads to neurodegeneration.8

or multimorbidity might influence the continuums of AD pathology

Although the pathological cascade of the AD continuum is sup-and glial reactivity.

ported by the genetical,9,10 pathological11 and live-imaging studies,12
the underlying mechanisms that connect each pathology remain elusive. Current evidence hints at the role of the glial cell population,
because these cells can respond and contribute to the development

2 | G L I A L CE L L N E T W O R K
IN THE AD CONTINUUM

of pathological hallmarks of AD. Importantly, inflammation that differs
in degree and elicited molecular pathways should also occur continu-

Recently, glial cells have been recognized to play a major role in theously at distinct levels of the AD continuum (Figure 1a). The

pathogenesis of neurodegenerative disorders, including AD.13 In

(a)

(b)

F I G U R E 1 The complex inflammatory
milieu along with the Alzheimer's disease(AD) continuum. (a) The pathologicaltrajectory of AD is best described by atemporal continuity of pathologicalhallmarks, whereby aggregates of
β-amyloid (Aβ) and later
hyperphosphorylated tau protein
accumulate in the brain, followed byneuronal cell death (black lines).
Traditionally, inflammatory responses
have been simplified as“neuroinflammation” and integrated into
the “AD continuum” as an additional facetof AD pathology. Nevertheless, every
sequence of AD pathology is known tostimulate the glial cells differently.
Amyloid pathology first elicits theAβ-related inflammation (red line),
whereas tau accumulation andneurodegeneration generate overlapping,but different, inflammatory signatures or
glial cell behavior at the middle (blue line)
and late spectrum (purple line) of the AD
continuum. This results in mixed glial
responses and creates a heterogeneous
inflammatory environment in the brain.
(b) Glial response to the AD continuum
can be intensified by peripheral mediators(such as the infiltrated T cells and altered
gut microbiota) and co-existing chronic
diseases (including stroke, sepsis andchronic kidney disease [CKD]).

3

HIJIOKA ET AL.

particular, factors expressed in glial cells, such as triggering receptors

but not restricted to, interleukin-1β [IL-1β], IL-6 and tumor necrosis

expressed on myeloid cells 2 (TREM2), have emerged as a focus offactor) in the AD brain at post-mortem.31 Notably, nuclear factor-κBattention, following the genome-wide association study of rare vari-(NF-κB) is a well-established upstream transcriptional factor forants of AD.14 TREM2 is expressed specifically in microglia, and is the

inflammation initiation and cooperates with an inflammatory platform,

initiator of glial responses by binding to various ligands, including

termed inflammasome.32,33 In particular, the NOD-, LRR- and pyrin

Aβ.15 Deletion of TREM2 function was shown to reduce microglial

domain-containing 3 (NLRP3) inflammasome appears to contribute to16

This has led to aAβ and tau pathogenesis.34,35 Recently, neuronal cell death by pyrop-

growing interest in the diversity of microglial functions. Previously,

tosis (an inflammatory cell death downstream of the NLRP3 inflamma-

microglial subtypes were limited to the classical classification of M1some) has been found to be involved in the AD brain through theand M2,17 but recent RNAseq analyses have shown that microglia canactivation of the NLRP3 inflammasome exclusively in microglia (butbe classified into a variety of types. In particular, functional analysis ofneither in astrocytes nor neurons).36 Conversely, NLRP3 inflamma-

TREM2-expressing disease-associated microglia has become a hotsome might not be involved in the early stage of amyloidosis, andtopic.18 These results showed that microglial abnormalities affectfurther scrutiny is needed under chronic conditions as a non-other glial cells, such as astrocytes and oligodendrocytes.19 Further-

inflammatory response of glial cells (in preparation). Furthermore, one

more, the diversity of gene expression signatures of microglia, astro-of the inflammasome components, including apoptosis-associatedcytes and oligodendrocytes in the brains of patients with AD has been

speck-like protein containing a caspase activation and recruitment

shown.20,21 Conversely, RNAseq analysis has been carried out in vari-

domain (ASC), can form speck-like aggregates by itself and contribute

ous AD model mice. Such datasets from 5FAD mice (Gene Expres-to pathological deterioration,37 and act as a cross-seed for Aβ.38 Addi-

phagocytosis and accelerate Aβ accumulation.

sion Omnibus database [GSE150934]),

22

APP/PS1 mice (the dataset

tionally, NF-κB is activated and involved in the expression of cyto-

will be deposited soon), 3Tg-AD mice (GSE92926),23 AppNL-G-F

kines in astrocytes derived from induced pluripotent stem cells ofknock-in mice (GSE127893)23–26 and rTg4510 (the dataset will bepatients with AD,39 suggesting that NF-κB is a common pro-deposited soon)25 are available. Interestingly, microglial proprieties in

inflammatory regulator in both microglia and astrocytes. Research on

the Aβ and tau pathology models appear to differ, suggesting the exis-

drug development targeting NF-κB is underway, and future trends aretence of pathology-specific microglial subtypes.13 Gene expression in

attracting attention.40 Of note, other investigators reported the roles

the amyloidosis model also shows the presence of model-specificof oxidative stress involving reactive oxygen species,41,42 metal/lipid

microglial subtypes, but gene expression in the disease-associatedmetabolism43,44 and aging,45 thus clarification of how these factors

microglia appears to be similar. However, the direct extrapolation of

are intricately intertwined would provide more insights into AD

the gene expression profiles of microglia to humans might be debat-

pathogenesis.

able. Additionally, RNAseq analysis showed that the genetic back-The amyloid cascade hypothesis proposes that Aβ accumulation

ground of the model mice also results in microglial diversity, and rare

triggers the formation of tau pathology. For example, the formation ofvariants found in genome-wide association study (such as ApoE,

neurofibrillary tangles in tau transgenic (Tg) JNPL3 mice is accelerated

TREM2 and Sorl1) seem to be affected by the genetic background ofby the coexistence of Aβ accumulation.46 Furthermore, treatment

27

model mice.

Both differences between models, and between

with immunosuppressive agents including FK506 suppressed the tau

humans and animal models (including sex differences in glial cells)

pathology formation in P301S-Tau-Tg mice,47 suggesting that glial

28

should be considered.

Capturing the pathophysiology in the AD

cells are involved in tau pathology formation. Conversely, non-brain from the analysis using animal models of AD is important while

pathological neurofibrillary tangles, which are confined to the entorhi-

considering these factors. Additionally, the aspect of homeostatic

nal cortex until Braak stages I–II, seem to spread and expand

microglial dysfunction is important.25,29 In particular, not only theextensively in the brain after Braak stages III–IV, when Aβ pathology

massive activation of glial cells, as characterized by disease-associatedspreads into the entorhinal cortex and hippocampus according tomicroglia, but also a decreased maintenance of homeostatic function

Braak's classification of AD pathology.48 Additionally, the early symp-

for the brain environment preservation, are thought to be extremely

toms of dementia are evident around Braak stages III–IV, and this tau

important in the onset of diseases. The diversity of other brain cells

propagation is hotly debated as having important implications for(e.g. astrocytes) needs to be taken into account, similar to microglial

pathogenesis and dementia symptoms. Interestingly, tau propagation

subtypes.

was accelerated in mice with Aβ pathology,49 and even more exagger-

Whereas inflammatory responses are generally important defense

ated in tau-humanized MAPT knock-in mice when tau seeds extracted

responses for the body, chronically maintained inflammation caused

from patients with AD were inoculated into mice.50 Microglial contri-

by sustained glial activation is regarded as a pathological trigger forbution to the uptake and release of tau seed has been recently

various disorders. This chronic neuroinflammation is mediated by notreported using animal models.51 Consistently, positron emission

only microglia, but also other cell types that are simultaneously stimu-

tomography imaging studies in humans revealed that tau propagation

lated as a whole (namely, glial cell network responses). Epidemiologicalwas correlated with microglial activation along the Braak stage.52 Fur-studies have long suggested that anti-inflammatory drugs might bethermore, glial roles in neurodegeneration (that is, the final stage ofeffective for AD prevention and treatment.13,30 This is congruent with

the AD continuum) were recently documented as in pyroptosis,36

the increased expression of pro-inflammatory cytokines (including,necroptosis53 and phagoptosis,54 reflecting different glial responses to

4

HIJIOKA ET AL.

amyloid and tau pathology within the AD continuum.13 Together, themice).73,74 Depletion of T cells by administering anti-CD3 antibody res-glial cell network in the AD brain should be carefully investigated,cued the spatial memory deficits in these mice, hinting at the possible

because it is subtle and dynamic, transforming from moment to

involvements of T cells in synapses.75 Altogether, brain border manipu-

moment as the disease progresses in the AD continuum.

lations that prevent the T cell infiltration or dampen neurotoxic T cellfunction seem to be therapeutically beneficial for AD.
Gut microbiota alteration affects the physiology and AD pathology

3 | B RA I N– P E R I P H E R Y I N T E R A C T I O N S I N
AD PATHOGENESIS

in the brain.76 The gut microbiota is the microorganisms that live in thedigestive tracts, and its composition affects the metabolism of diet anddrugs, the immune cell regulation, and the brain function.77 The gut

Recent studies showed that the peripheral body environment could

microbiota regulates brain function through the parasympathetic

influence the central nervous system (CNS) in various ways. For thisnervous systems and sympathetic nervous systems in physiologicalreason, a more holistic research approach would enhance our under-

conditions in mice.78,79 Fecal microbiota transplantation from young

standing of AD pathology. Noteworthily, this particular viewpoint has

mice attenuates age-dependent learning impairment and microglial

therapeutical potential, because many CNS-targeting drugs have phar-phenotypic changes associated with aging.80 Gut microbiota-derived

macokinetic difficulties in crossing the blood–brain barrier (BBB). Sev-

N6-carboxymethyl lysine (a major advanced glycation end-product) is

eral of these peripheral targets highlighted previously include theaccumulated in the serum and brain of aged mice, and promotes micro-

brain border, adaptive immune system and intestinal microbiota.

glial reactive oxygen species production.81 Likewise, N6-carboxymethyl

Because the CNS was considered to be an immune-privileged
55

system,lysine and other advanced glycation end-products increase in diabetic

the majority of research focused on the brain resident

vasculature, and contribute to the development of atherosclerosis andimmune cells in the AD brain that could acquire the aggressive pheno-

increase the endothelial permeability to macromolecules.82 Diabetes

18,56

types.

Increasing lines of evidence highlighted the importance of

mellitus is associated with an increased risk of developing AD and cog-a tightly regulated CNS border where meningeal lymphatic vessels

nitive dysfunctions, and these findings suggest that the metabolic con-and skull bone marrow maintain the immune cell dynamics in thetrol system, including intestinal bacteria, plays an important role in AD

brain.57–60 This brain border is also known as the key component ofdevelopment.83 This is supported by previous findings in patients withthe glymphatic system that mediates clearance of toxic proteins in

AD where N6-carboxymethyl lysine levels were elevated or accumu-

AD.61 For example, extracellularly injected Aβ and tau can be removed

lated in plasma, neurons and endothelial cells in the brain.84,85 Indeed,

62–65

into the cerebrospinal fluid through aquaporin-4.

Meningeal lym-

the elimination of gut microbiota by rearing mice in a germ-free envi-

phatic vessel occlusion (through reactive oxygen species productionronment led to reductions of Aβ and tau phosphorylation in the brain

by Visudyne-mediated photoconversion) aggravated Aβ deposition inof 3Tg mice.86 The authors also suggested that this germ-free effectthe meningeal lymphatic vessels and brain parenchyma of 5FAD

was masked by fecal transplantation from patients with AD, but not

65

healthy controls.86 In contrast, fecal transplantation from the wild-type

Lymphocyte infiltration into the brain parenchyma also contributes

mice ameliorated Aβ and tau pathologies in ADLPAPT mice (novelto the pathogenesis of AD. A multifactorial data-driven analysis based

APP-Tg mice with MAPT mutations).87 One of the possible mediatorson the multimodal brain images and biomarkers showed that vascular

might be short-chain fatty acids that are known to be derived from gut

dysregulation was an early pathological event during disease progres-microbiota, and microglial contributions have been suspected. Supple-

sion.66 The leaky BBB in patients with early AD was associated withmenting short-chain fatty acids in APP/PS1 mice increased the Aβ plaquecognitive decline.67 More T cells were observed in the hippocampus ofload and changed the microglial transcriptomic signature.88 Conversely,

patients with AD than in those with other cognitive impairments andgut microbiota depletion by an antibiotic cocktail (ABX) reduced Aβ load

mice.

68

Of note, Down syndrome is pathologically related toin APP/PS1 mice, which was diminished by microglial depletion withAD, because the trisomy of chromosome 21 produces an extra copy ofmental diseases.

colony-stimulating factor 1 receptor inhibitor.89 Interestingly, Aβ or phos-

the APP gene.

69,70

The highest T cell infiltration was recorded in thosephorylated tau deposition attenuation by ABX treatment was observedwith Down syndrome possessing AD pathology, substantiating theonly in male mice, reflecting possible sex differences in microglial

notion that the presence of T cells in the brain is correlated with amy-

responses.90,91 Overall, age- and disease-associated changes in gut micro-

68

loid pathology.

In support, compromised BBB integrity and robust

CD8+ T cell extravasation were found in APP/PS1 mice.71,72 The roles

biota composition and metabolism might serve as therapeutic targets for
AD, although detailed mechanisms remain to be elucidated.

of these infiltrating T cells are as yet unclear, but the transcriptomic
analysis showed the involvement in synaptic plasticity dysfunction.72
These results collectively suggest that amyloid pathology impairs vascular functions, which in turn leads to T cell extravasation and T cell-

4 | MULTIMORBIDITY
IN AD PATHOGENESIS

mediated neuronal damage. Meanwhile, the detection of extravascular
CD3+ T cells was also correlated with tau protein accumulation.71

Age serves as an unambiguous risk factor for AD, but also for various

T cells were observed in the brain of multiple models of tauopathy,

other diseases, raising the awareness of the concept of “multimorbid-

which lack Aβ deposition (for example, THY-Tau22 mice and rTg4510

ity” – the presence of two or more chronic diseases in the same5

HIJIOKA ET AL.

individual.92,93 Notably, multimorbidity was documented in 43% of

as potential mechanisms for increased tau phosphorylation.103,106

patients at the time of dementia diagnosis, with a linear correlation

Nevertheless, others argued that leptin reduced tau phosphoryla-

between the number of conditions and dementia risk when elderlytion112 and hypoxia promoted autophagy.113 These inconsistencies

individuals (n = 206 960) were followed up for up to 15 years.

obscured the current understanding of how tau phosphorylation

Another prospective cohort study of middle-aged individuals

increased post-stroke, warranting further investigations in the future.

(n = 10 095) showed that the onset of multimorbidity, especially

Furthermore, not all patients with stroke manifest cognitive

before the age of 55 years, doubled the risk of subsequent dementia

decline during the recovery, and this differentiation has been pro-during the follow up over 32 years.95 The top five chronic conditions

posed by pre-existing amyloid pathology upon stroke onset. Patientsassociated with dementia were Parkinson's disease, mental disorders,

who were positive for Pittsburgh compound B in the brain at the time

stroke, chronic kidney disease (CKD) and depression among the 13 dis-of stroke diagnosis presented a progressive deterioration of cognitive

94

95

whereas other stud-functions over 3 years, whereas negative patients did not.114 Intrigu-

ies indicated hypertension, coronary heart disease, diabetes andingly, recent preclinical findings suggested that stroke lesion was

pain.94,96 Additionally, a recent population-based study (n = 989 800)

exaggerated in the presence of Aβ, as evidenced by twice larger

highlighted the importance of infection due to a twofold increase ininfarct sizes in APP-Tg mice than wild-type mice after middle cerebral

eases that defined multimorbidity in this study,

97

These lines of evi-artery occlusion.115,116 One could speculate plausibly that tissue dam-dence delineate possible, albeit probably multilayered, interactions

age is more pronounced in patients with AD after stroke onset, con-

between multimorbidity and dementia. In this context, multimorbidity

tributing to worsening brain atrophy and cognitive decline throughis likely to accelerate or worsen the progression of AD pathology,

exaggeration of glial responses.

dementia incidence in elderly survivors of sepsis.

because AD is characterized by a pathological trajectory overOur understanding of stroke–AD multimorbidity is also largely

decades.5 Here, we concentrate on three chronic conditions that can

restricted to ischemic stroke and can be strengthened by considering

frequently shape multimorbidity in patients with AD and relate to glial

intracerebral hemorrhage. This underestimation might be due to the

responses to the co-existing pathology.

less common onset of hemorrhagic stroke than ischemic stroke in the

Stroke confers well-acknowledged risks for subsequent dementia,

general population117 and patients with AD.118 Nevertheless, patients

because post-stroke dementia represents one of the major vascular cog-with ischemic stroke frequently showed hemorrhagic transformation

nitive impairments that occur within 6 months post-stroke.98 Indeed, a(accounting for 27%),119 and elevated BBB permeability was detected5-year longitudinal study of 2080 patients with varying stroke severityat the very early stages of AD before cognitive decline.120 Evaluation

confirmed a 50-fold increase in dementia among those with severeof hemorrhagic stroke in patients with AD and the relevant animal

stroke and an acceleration of the estimated onset by 25 years.99

models is currently sparse, and this will be another focus of future

Although conflicting evidence is available,100 elderly patients with ische-research in this field.

mic stroke showed higher retention of Aβ positron emission tomography

Elderly patients with sepsis (that is, life-threatening organ dysfunc-

radiotracer, Pittsburgh compound B, in the ipsilateral peri-infarct region

tions caused by dysregulated host responses to infections) can irrevers-

with neocortical retention remaining normal.101 Congruently, ischemic

ibly impair cognitive functions in those who survived sepsis throughstroke (modeled by middle cerebral artery occlusion and bilateral carotid

systemic inflammation.33 Brain structural changes in the medial tempo-

artery stenosis) in APP-Tg mice worsened the amyloid pathology102,103

ral lobe – the brain region vulnerable to AD – and altered cognition

104

Meanwhile,

were documented in those who survived sepsis and COVID-19 infec-

patients with ischemic stroke had a heightened binding of tau positrontion.121–123 Notably, falls that necessitate hospitalization wereor induced de novo leptomeningeal Aβ deposition.
18

emission tomography tracer ( F-THK-5451) in the peri-ischemic andrecorded in one-third of patients with dementia,124 and patients withremote areas 3 months post-stroke.105 In line with this, 3Tg-AD mice

AD had a threefold higher risk of hip fracture, which could cause sepsis

manifested increased levels of tau phosphorylation after bilateral carotidin the elderly after the surgery.125,126 This is corroborated by motor

103,106

artery stenosis and unilateral carotid artery occlusion.

dysfunctions in patients with mild cognitive impairment and AD, as wellPrevious studies indicated the involvement of several signaling

as mouse models.127–130 Studies investigating the effects of systemic

pathways in the aggravation of amyloid and tau pathology. Notably,

inflammation on AD pathology were flourishing, and reported multifac-

stroke can induce acute cerebral hypoxia in patients and animal

torial mechanisms that drove these changes. For instance, intraperito-

models.107,108 Tissue reperfusion has frequently failed due to persis-

neal injection of Gram-negative bacterial cell wall component,

tent occlusion of the capillaries by clogged neutrophils (“no-reflow”

lipopolysaccharide, increased Aβ deposition in APP-Tg mice and App

phenomenon) even after a clot removal and recanalization of occluded

knock-in mice.131,132 The same was true for APP-Tg mice that under-

109

vessels.

On this ground, hypoxia-related pathways (for example,

went cecal ligation and puncture that simulated polymicrobial infec-

hypoxia-inducible factor 1) are likely to be activated, thereby modulat-

tion.133 Proposed mechanisms that enhance amyloid pathology

ing both amyloid and tau pathology. To illustrate, hypoxia-inducible

include: (i) reduction of Aβ phagocytosis by microglia, possibly due tofactor 1α upregulated β-secretase enzyme 1, and promoted Aβ pro-microglial migration toward blood vessels;131–134 (ii) secretion of glia-

duction in APP-Tg mice and 3Tg-AD mice after hypoxia and bilateralderived proteins that can cross-seed Aβ peptides (as exemplified bycarotid artery stenosis, respectively. 103,110,111 Meanwhile, activated

ASC specks);37,131 and/or (iii) upregulation of cytokine-responsive pro-

leptin signaling and impaired autophagy activity have been suggested

teins

that

regulate

APP

processing(e.g.

interferon-induced

6

HIJIOKA ET AL.

transmembrane protein 3).135 Likewise, systemic lipopolysaccharide

22K06865, and 22K20688), Grant-in-aid for Research in Nagoya

injection into Tau-Tg mice acutely boosted tau phosphorylation andCity University (Grant Number 2021101), the Hori Sciences & Arts

136

chronically exacerbated neuronal loss in the cortex.

A similar

Foundation and Toyoaki Scholarship Foundation.

increase in tau phosphorylation in the hippocampus was found after
biweekly injections of lipopolysaccharide in young and aged 3Tg AD

CONFLIC T OF INTER E ST STATEMENT

mice.137,138 Some reasoned alteration of cyclin-dependent kinase

The authors declare no conflict of interest.

5 and glycogen synthase kinase 3β activities at different ages of
mice,137,138 whereas others pointed to different kinases, such as p38

DISCLOS URE OF ETHICAL STATEMENTS

mitogen-activated protein kinase.139 Importantly, the effects of sys-

Approval of the research protocol: N/A.

temic inflammation are not limited to the amyloid and tau pathology,

Informed Consent: N/A.

hence adding a further complexity of its consequences. For example,

Registry and the Registration No. of the study/trial: N/A.

systemic inflammation can decrease the number of synapses in the

Animal Studies: N/A.

hippocampus,140,141 generate long-lasting innate immune memory inmicroglia that modulates amyloid pathology,142 dampen neurogenesis
in the hippocampus143 and increase the BBB permeability.144
Finally, emerging evidence has implicated the association of CKD
144,145

with mild cognitive impairment and dementia.

At present, AD

neuropathology exacerbation by persistent renal dysfunctions in

OR CID
Masanori Hijioka

https://orcid.org/0000-0001-6912-3496

Tatsuya Manabe

https://orcid.org/0000-0002-1424-5688

Takashi Saito

https://orcid.org/0000-0002-9659-9251

patients is unknown, but likely, because the uremic toxins in the blood
include pro-inflammatory cytokines that can elicit systemic inflamma146

tion (e.g., IL-1β, IL-6, IL-8 and tumor necrosis factor).

In support, uni-lateral nephrectomy for 6 months worsened Aβ pathology, promoted
tau phosphorylation and augmented spatial memory deficits in APP-Tg
mice.147 The underlying mechanism remains unexplored, but AD
pathology aggravation might be mediated through systemic inflammation or, alternatively, hypertension in view of the intermittent link
between CKD and cardiovascular disease.148 Prolonged angiotensin II
infusion accelerated Aβ deposition in APP-Tg mice,149 and augmented
tau phosphorylation in the cortex of wild-type mice.150 However, neuroinflammatory responses to CKD and their contributions to AD
pathology exacerbation remain unclear, thus requiring more investigations to address the CKD–AD cross-talks in the future.

5|

C O N CL U S I O N

The present review has outlined the recent findings on the pathological roles of glial cells in the AD continuum. To develop preventive,
disease-modifying and ultimately curative therapies, it is essential todecipher the whole spectrum of AD pathogenesis with a particularfocus on the immune responses. Glial cells are indeed responsive toboth amyloid and tau pathologies and, consequently, shape uniquetranscriptional signatures that govern their functions. Likewise, altered
gut microbiota, stroke and systemic inflammation modified both glial
phenotypes and AD pathology in mouse models, and likely, in patientswith AD. Still, trends in research fields that are relatively novel tend toconcentrate on non-glial cells, and more detailed examinations of glial
populations are strongly encouraged in the future.
ACKNOWLEDGMENTS
This work was partially supported by JST (Moonshot R&D; Grant
Number JPMJMS2024), AMED (JP21gm1210010s0102 and JP21dk
0207050h001), MEXT/JSPS KAKENHI (Grant Numbers: 20H03564,

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How to cite this article: Hijioka M, Manabe T, Saito T.
Multifactorial glial responses and their contributions to
Alzheimer's disease continuum. Clin Exp Neuroimmunol. 2023.
https://doi.org/10.1111/cen3.12745