Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

Review Article

Inflammation as a central mechanism in Alzheimer’s disease

Jefferson W. Kinneya,*, Shane M. Bemillerb, Andrew S. Murtishawa,
Amanda M. Leisganga, Arnold M. Salazara, Bruce T. Lambb
a
Department of Psychology, University of Nevada Las Vegas, Las Vegas, NV, USA
b
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by

cognitive decline and the presence of two core pathologies, amyloid b plaques and neurofibrillary
tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged
as a third core pathology in AD. The sustained activation of the brain’s resident macrophages
(microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau
pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we
provide an overview of inflammation in AD and a detailed coverage of a number of
microglia-related signaling mechanisms that have been implicated in AD. Additional information
on microglia signaling and a number of cytokines in AD are also reviewed. We also review the
potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.
Ó 2018 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access
article under the CC BY-NC-ND license ([Link]
Keywords: Alzheimer’s disease; Inflammation; Microglia; Cytokines; Microglia receptors

1. Overview (NFTs). Ab pathology arises from the improper cleavage

of the amyloid precursor protein (APP) resulting in Ab
Alzheimer’s disease (AD) is a neurodegenerative disorder
monomers that aggregate forming oligomeric Ab and
that is the most common cause of dementia and is
eventually aggregating into Ab fibrils and plaques [4]. The
characterized by the decline in cognitive and function and
function of APP is unknown but is believed to have a role
neuronal loss. AD currently affects over 5 million
in cell health and growth [5]. Critical aspects of
Americans [1] and is expected to become increasingly
understanding the onset of Ab pathology rests on knowing
prevalent with the rise in life expectancy. It is estimated
the mechanisms of the generation of Ab monomers, their
that by 2050, 13.8 million Americans will be living with
clearance, and their aggregation into oligomeric Ab.
AD [2]. The financial burden imposed by AD currently Normal processing of the APP sequence consists of
exceeds $230 billion and is expected to reach $1.1 trillion
nonamyloidogenic proteolysis of APP via a-secretase and
by 2050 [3]. Given the clinical and financial burden
l-secretase, producing soluble fragments [6]. When APP
associated with AD, the identification of novel mechanisms
is cleaved by l-secretase and erroneous b-secretase, it leads
responsible for pathogenesis, as well as novel therapeutic
to insoluble amyloid b peptides that aggregate in the brain to
targets, is urgently needed.
form b-amyloid plaques [4,7–17]. The precise role of Ab in
AD is characterized by two core pathologies, the presence
AD pathology remains an open question as Ab plaques may
of b-amyloid (Ab) plaques and neurofibrillary tangles
accumulate up to 10 years before any observable AD
symptoms or diagnosis.
The second core pathology, NFT, arises from the
hyperphosphorylation of tau, a microtubule-associated pro-
The authors have declared that no conflict of interest exists.
tein that stabilizes microtubules [18–27]. Phosphorylation
*Corresponding author. Tel.: 1702-895-4766; Fax: 1702-895-0195.
E-mail address: [Link]@[Link] of tau serves a necessary role in intracellular trafficking to

[Link]
2352-8737/Ó 2018 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http://
[Link]/licenses/by-nc-nd/4.0/).
576 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

remove tau from microtubules, allowing transport, followed nized that a sustained immune response is a central feature
by dephosphorylation to return tau to the microtubule [28]. of neurodegenerative disorders [71–77].
In AD, tau protein is phosphorylated at multiple sites The presence of a sustained inflammatory response in the
resulting in the removal of tau from the microtubule and brain of patients with AD was, at one point, thought to be
causing the collapse of microtubule structures and disruption reactive to the neuronal loss occurring in the disorder.
in a number of cellular processes ranging from protein However, substantial body of research has now
trafficking to overall cellular morphology [29–31]. In demonstrated that a persistent immune response in the brain
addition, the hyperphosphorylated tau (ptau) aggregates is not only associated with neurodegeneration but it also
into paired helical fragments that eventually form facilitates and exacerbates both Ab and NFT pathologies.
neurofibrillary tangles [20,24,25,32,33]. The accumulation Furthermore, it has been suggested that the inflammatory
of ptau tangles and the compromised cellular function response may provide a link between the initial Ab
leads to loss of neuronal function, and ultimately pathology and the later development of NFT [78–83]. In
apoptosis [30]. the succeeding sections, we highlight some of the recent
Despite extensive and productive research investigating data indicating the role of inflammation in AD, as well as
the mechanisms responsible for both core pathologies, as data indicating inflammation may be a central mechanism
well as approaches aimed at the prevention of Ab plaques driving Ab pathology and progression.
and NFT, there remains no treatment that effectively alters This review highlights the research supported by the
either pathology in clinical populations [34]. Furthermore, National Institutes of General Medical Sciences (NIGMS)
there exists a considerable gap in the understanding of AD through Center for Biomedical Research Excellence
pathogenesis given these two pathological features. As (COBRE) awards that develop the national research
stated previously, patients may exhibit Ab plaque pathol- infrastructure.
ogy for up to or greater than a decade before any overt
diagnosis of AD [35,36]. For NFT, the overall tangle
2. Inflammation in AD
load is correlated with cognitive decline in AD; however,
the appearance of NFT appears to occur before the Many studies now point to the involvement of
inauguration of AD pathology in clinical populations and neuroinflammation playing a fundamental role in the
preclinical animal models [37–39]. The combination of progression of the neuropathological changes that are
the aforementioned gaps in the pathophysiology of AD observed in AD. Since the 1980s, there have been reports
suggests that other pathological mechanisms may be of immune-related proteins and cells located within close
driving both the onset of the disorder, as well as the proximity to b-amyloid plaques [43,84]. Beginning in the
progression of the disease. 1990s, several large epidemiological and observational
Over the last 10 years, a third core feature of AD has studies were published indicating that anti-inflammatory
emerged that may provide insight into AD pathogenesis, treatments used in diseases, such as rheumatoid arthritis,
as well as provide a link between the other two core showed protective qualities against developing AD,
pathologies. A number of investigations initially demonstrating as much as a 50% reduction in the risk for
demonstrated that in addition to Ab plaques and NFT, the developing AD in patients who are long-term nonsteroidal
brains of patients with AD exhibited evidence of a sustained anti-inflammatory drug (NSAID) users [77,85–87]. These
inflammatory response [40–50]. The inflammatory response studies lead to studies utilizing animal transgenic AD
has now been observed in multiple studies of postmortem models demonstrating that NSAIDs can reduce AD
tissues of AD patient samples [51–57] and is routinely pathology [88]. Human trials of NSAIDS showed variable
observed in preclinical model systems of AD. outcomes with no convincing evidence of benefit using the
Acute inflammation in the brain is a well-established trial methods of the time [89].
defense against infection, toxins, and injury, but when a These various epidemiological studies and observational
disruption in the equilibrium of anti-inflammatory and studies serve as the bedrock of support for neuroinflamma-
pro-inflammatory signaling occurs, as seen in AD, it results tion playing a major role in developing sAD. Unlike other
in chronic inflammation (neuroinflammation) [58–61]. This risk factors and genetic causes of AD, neuroinflammation
chronic neuroinflammation is attributed to activated is not typically thought to be causal on its own but rather a
microglia cells and the release of numerous cytokines. The result of one or more of the other AD pathologies or risk
presence of a sustained immune response in the brain is factors associated with AD and serves to increase the
not exclusive to AD. A number of studies have severity of the disease by exacerbating b-amyloid and tau
demonstrated elevated markers of inflammation in the pathologies [90,91].
brain of patients with Parkinson’s disease (PD) [62–66], Brain inflammation appears to have a dual function,
and traumatic brain injury associated with chronic playing a neuroprotective role during an acute-phase
traumatic encephalopathy (CTE) [67–70], amyotrophic response, but becomes detrimental when a chronic response
lateral sclerosis (ALS) [70], and Multiple Sclerosis (MS) is mounted [92]. Chronically activated microglia release a
[71] to name a few key examples. It is increasingly recog- variety of proinflammatory and toxic products, including
 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590 577

reactive oxygen species, nitric oxide, and cytokines. In exacerbation of AD pathology, likely as a result of
deceased patients suffering from recent head trauma, there sustained activation of microglia in a feed forward loop,
is an increase in cerebral Ab deposits 1–3 weeks postinjury, referred to as reactive microgliosis. This results in an
and it has been shown that elevated levels of interleukin 1 accumulation of Ab and sustained pro-inflammatory
(IL-1) are responsible for the increased APP production cytokine singling beginning to damage neurons
and Ab load [93,94]. In addition, elevated levels of IL-1b [118,121,122]. The sustained activation also results in a
has been shown to increase the production of other decrease in microglia efficiency for binding and
cytokines, including IL-6, which in turn has been shown to phagocytosing Ab and decreases in Ab degrading enzyme
stimulate the activation of CDK5, a kinase known to activity of microglia leading, in turn, to a reduced ability
hyperphosphorylate tau [95]. The neuroinflammation to break down the Ab plaques [123,124]. However, data
observed in AD appears to serve a primary role in indicate that the microglial capacity for producing
exacerbating Ab burden and tau hyperphosphorylation, pro-inflammatory cytokines is unaffected [118]. These
suggesting that this dual role could be a leading link between data demonstrate a unique feature of pathogenesis in that
these seemingly disparate core AD pathologies. The overall clearance of Ab becomes compromised while
mounted immune response via the brain’s resident immune activation continues simultaneously. The continued
macrophage (microglia) is now a central tenant in the release of pro-inflammatory cytokines and associated
investigation of AD. neurotoxins from microglia serves to exacerbate the
neuroinflammation and contribute to neurodegeneration,
leading to the activation of yet more microglia.
2.1. Microglia
As the microglia are involved in clearance of Ab, they
Microglia are the resident immune cells within the central release a number of proinflammatory cytokines that recruit
nervous system (CNS) [96]. In a healthy brain, microglia are additional microglia to plaques [125–127], resulting in a
in an inactive, “resting” state and are described characteristic halo of activated microglia surrounding
morphologically as ramified cells with small somas plaques [112,128]. More recent data indicate that as
[97,98]. In this state, the cell somas are stationary, while microglia become less able to clear Ab, peripheral
the cell processes extend and retract, surveying their macrophages may be recruited to Ab plaque deposition in
environment and communicating with neurons and other an effort to clear Ab [129]. The recruitment of peripheral
glia cells [99–101]. Overall surveillance of the macrophages into the brain likely exacerbates the effects
surrounding neuronal environment is accomplished via a of sustained inflammation and thus AD pathology. Some
large number of signaling mechanisms [99,102]. This of the most compelling data for the importance of
includes surveillance of the local neuronal milieu via inflammation in AD pathogenesis and the regulation of the
numerous receptors for classical neurotransmitters [103], immune response comes from the recent demonstration
receptors for numerous cytokines and chemokines that a mutation in the Triggering Receptor Expressed on
[104–106], and a number of receptors, such as fractalkine Myeloid Cells 2 (TREM2) confers a greater likelihood of
(CX3CR1), that bind ligands constitutively released in developing AD [129–132]. A rare missense mutation
healthy neuronal environments [107]. When microglia in TREM2 results in a substantial elevated risk of AD
recognize a threat to the CNS, such as invasion, injury, or [133–136].
disease, it leads to microglial activation, causing a
morphological change resulting in retraction of processes,
3. The role of TREM2 in Alzheimer’s disease pathology
enlargement of the cell, and migration [99,108–111].
Transitioning into an activated state may be triggered by Recent identification of a number of genetic variants of
alterations in any number of the aforementioned TREM2 has ignited a flurry of research into the mechanistic
mechanisms involved in surveillance. contributions of this critical innate immune-regulating
In AD, it is hypothesized that the primary driver of receptor to the pathogenesis of AD and numerous other
activation of microglia is the presence of Ab. Activated neurodegenerative diseases. Original interest in the role of
microglia respond to Ab resulting in migration to the TREM2 and neurodegeneration was generated in the early
plaques and phagocytosis of Ab [108,112,113]. A number 2000s, when associations were identified between TREM2
of investigations have demonstrated that activated loss of function mutations and polycystic lipomembranous
microglia phagocytose Ab [114–117]; however, these osteodysplasia with sclerosing leukoencephalopathy
microglia become enlarged and after prolonged periods are (PLOSL), or Nasu-Hakola disease [137–139]. This rare
no longer able to process Ab [114,118]. Early in AD but aggressive neurodegenerative disorder is characterized
pathogenesis, the mounted immune response results in by abnormal bone cysts and early-onset dementia with
clearance of Ab and has been demonstrated to exert profound frontal lobe degeneration and is also associated
positive effects on AD-related pathologies in animal models’ with mutations in TYROBP, the intracellular signaling
systems [77,119,120]. However, prolonged activation of the coreceptor for TREM2 [140–142]. In 2012, two
immune response has been demonstrated to result in an independent studies reported strong associations between
578 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

the R47H variant of TREM2 and late-onset AD [133,136]. increased cleaved caspase-3 activation, resulting in
The conferral of 2–4.5 fold increased risk of developing enhanced myeloid cell death [151]. Utilizing super
late onset AD (LOAD) in carriers of the R47H allele resolution microscopy, Yuan et al. further demonstrated
positions TREM2 as the strongest associated risk gene that haploinsufficiency of TREM2 in mice or humans
behind only apolipoprotein E-ε4 (ApoE4), and further harboring the R47H mutation results in altered plaque
implicates innate immunity as a key component to the compaction with much more diffuse and fibrillar plaques
pathogenesis of AD [143,144]. In addition to the R47H present, and fewer thioflavin S1 dense core plaques [152].
variant, the R62H TREM2 mutation has been associated In this situation, more neurotoxic oligomeric and fibrillar
increased risk of LOAD. Using a variety of approaches Ab may be present leading to increased neuronal dystrophy
with cell and rodent models along with human patient and death. Along with plaque compaction issues, microglia
tissue and data, great strides have been made to elucidate and macrophages lacking TREM2 have been shown to have
the mechanistic contributions of TREM2 in the context decreased capacity to phagocytose and clear Ab, apoptotic
of AD. cells, as well as other proteins and complexes
Early studies addressing the contributions of TREM2 to [131,153,154]. TREM2-deficient myeloid cells also
AD pathology utilized the APP/PS1 and 5XFAD mouse exhibit increased numbers of autophagy-associated
models of Ab pathology along with human AD brain tissues. phagolysosomes reflective of aberrant mTOR activation
Initial characterization of TREM2 in AD revealed resulting in dysregulated metabolic homeostasis within the
strongly upregulated protein and transcripts on neuritic context of Ab pathology [155].
plaque-associated macrophages in the brain, but not within More recently, the contributions of TREM2 to tau
microglia or myeloid cells distal to Ab deposits in amyloid pathology have been addressed by the Lamb and Holtzman
mice and human AD brain tissues [129,145]. Further groups. Utilizing hTau mice harboring the entire human
characterization of these plaque-associated cells using flow tau gene on a complete murine tau knockout background,
cytometry revealed cell surface signatures consistent with Bemiller et al. demonstrated that TREM2 deficiency
peripheral macrophages, including high expression of worsens cortical soluble and insoluble tau pathology at
CD45, Ly6c, and CD11 b, although subsequent studies 6-months of age [156]. This worsening was accompanied
utilizing parabiosis failed to detect these infiltrates by the presence of morphologically dystrophic microglia
[129,132,146]. Several studies have identified increased and widespread neuronal stress kinase hyperactivation,
TREM2 expression in human AD blood, further suggesting including within ERK-, JNK-, and GSK3b-associated
roles for peripheral TREM2 in modifying disease pathways. The Holtzman group recently reported mitigated
outcomes [147–149]. neuroinflammation, astrocytosis, and reduced neurodegen-
Next, the mechanistic roles of TREM2 were explored in eration at advanced ages in the PS19 mouse model of
the context of amyloid pathology using APP/PS1 and tauopathy, an aggressive model of tauopathy harboring the
5XFAD mice, along with various cellular models. Both hap- FTD-associated P301S 4R familial tau mutation [157].
loinsufficiency and complete deletion of Trem2 dramatically Similar to TREM2 signaling in the context of amyloid
reduces the number of plaque-associated macrophages pathology, there appear to be disease stage-specific
throughout all time points of disease in Ab-bearing mice contributions of TREM2, which normally are protective in
[129,150]. Interestingly, this decrease in plaque-associated early stages of disease by facilitating clearance of
macrophages reduces hippocampal plaque load at intracellular and extracellular pathological tau species and
4-months of age but ultimately exacerbates pathological damaged neuronal debris, but transformation to becoming
outcomes by the 8-month time point [146]. This pathogenic during neurodegenerative phases of disease
phenomenon was accompanied by decreases in where inflammation, astrocytosis, and aberrant synaptic
inflammatory cytokines including IL1b, IL6, and TNFa as and neuronal engulfment dominate.
well as decreased astrocytosis as measured by GFAP and The nuanced roles of TREM2 in promoting neurodegen-
S100b later in mid-late stages of pathology. This suggests eration can be attributed to three key aspects as currently
that TREM2 alters the inflammatory milieu not only through understood within the context of AD: (1) regulation of
macrophage-mediated responses but also through alterations phagocytic and autophagic processes; (2) myeloid cell
in astrocyte activation. survival and proliferation; and (3) regulation of
Given the profound loss of plaque-associated inflammation. Recent studies by the Amit, Colonna, and
macrophages in TREM2-deficient amyloid mice, myeloid Schwartz groups highlighted distinct activation patterns for
cell survival and proliferation were of interest in these what have been termed “damage-associated microglia”
models. It has been shown that TREM2-deficient mice [158]. In these studies, the authors demonstrate distinct
have dramatically decreased numbers of proliferating myeloid activation patterns, which initially are independent
plaque-associated macrophages as measured by of TREM2 activation, but later rely on TREM2-dependent
proliferation markers Ki67, and BrdU in aging APPPS1 pathways to convert to a neurodegenerative transcriptional
and 5XFAD mice [146,151]. In addition, it was shown by program altering phagocytosis and lipid metabolism. These
the Colonna lab that TREM2 deficiency results in studies have further highlighted the disease stage-specific
 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590 579

responses to pathology along with the incredible heterogene- hippocampal-dependent learning [175]. Conversely in
ity of cells involved in neurodegenerative processes. amyloidogenic AD models, deleting CX3CR1-attenuated
neuronal loss and microglial activation with no impact on
amyloidogenesis in 3XTg mice [166] but reduced b-amyloid
4. Additional microglial receptors
deposition in both the APP/PS1 and R1.40 mouse models
In addition to the TREM2 receptor, a number of other [167].
microglia-specific receptors have been explored in the Studies investigating alterations in CX3CL1-CX3CR1
investigation of the exaggerated immune response in AD. signaling in humans are rare compared with in-vitro and
animal studies; however, the emerging human literature
suggests that the fractalkine pathway may play an important
4.1. CX3CR1 and AD
role in AD pathogenesis. Cortical levels of fractalkine are
To limit the activated role of microglia under resting, reduced in the brains of healthy elderly adults with no
basal conditions in the brain, neurons release a variety of history of dementia or other neurodegenerative disorders
inhibitory factors, including CX3CL1, a chemokine when compared with the brains of healthy, middle-aged
frequently referred to as fractalkine [107]. CX3CL1 consists adults, suggesting a potential age effect that may be
of a chemokine domain attached to a mucin-rich stalk on the associated with altered surveillance by fractalkine receptors
extracellular domain and is synthesized as a membrane- and inflammation [176]. Plasma levels of soluble fractalkine
anchored protein that may be cleaved into a soluble form are elevated in patients with both mild cognitive impairment
[159,160]. CX3CL1 binds to its obligate receptor, (MCI) and AD [177]. In addition, these same researchers
CX3CR1, on the surface of microglia [161]. Originally found higher levels of plasma in individuals with
identified on lymphocytes, CX3CR1 is involved with mild-moderate AD than in patients with severe AD and the
immune regulation on other tissues, including bone, kidney, highest levels in MCI patients, which is considered a key
and in the cardiovascular system [162–164]. Despite the turning point from normal aging into AD pathogenesis.
widespread distribution of CX3L1/CX3CR1 signaling Since inflammation often precedes AD pathology, plasma
throughout the body, CX3CR1 has been most extensively levels of CX3CL1 could potentially be a useful systemic
studied in microglia [165–167], which have an expression biomarker. Postmortem analyses show modest reductions
of CX3CR1 nearly .1000-fold higher when compared of CX3CR1 and markedly lower levels of CX3CL1 in the
with both peripheral myeloid cells and other CNS cell types, hippocampus of AD brains compared with age-matched
including both neurons and astrocytes [168,169]. Unlike nondemented controls [178].
other promiscuous chemokines, CX3L1 is the exclusive
ligand for CX3CR1, binding rapidly and with a high
4.2. Alternative receptors on microglia
affinity [170]. CX3CL1 is a pleiotropic protein involved in
the abatement of microglia under basal conditions but also
regulates microglial activity by influencing migration and 4.2.1. GABA and GABAB
proliferation in injury conditions [171]. In the central nervous system, gamma-aminobutyric acid
Numerous studies demonstrate that CX3CL1 can (GABA) is the primary inhibitory neurotransmitter released
dose-dependently reduce the expression of nitric oxide, IL- by neurons. Neurons produce GABA by conversion of
6, and TNFa following stimulation by lipopolysaccharide glutamate to GABA via glutamate decarboxylases (GADs),
and suppress neuronal death induced by microglial which is released in response to neuronal activity. The
activation [172,173]. CX3CR1-mediated neuronal signaling released GABA binds to a fast-acting chloride channel
to microglia can be disrupted by replacing CX3CR1 with a (GABAA) resulting in rapid hyperpolarization or binding
green fluorescent protein (GFP) reporter gene that leads to to a receptor coupled to a metabotropic G-protein coupled
systemic inflammation and exacerbated microglial receptor (GABAB) that results in a slow inhibitory
neurotoxicity in a variety of animal models, including PD postsynaptic current (IPSC) [179]. As alterations in
ALS [165,174]. GABAergic signaling have been reported in AD
However, the role of fractalkine signaling in AD [180–184], and GABA plays a central role in learning and
pathogenesis appears to be complex and is not well memory [185,186], there has been interest in its role in
understood. One of the pathogenic hallmarks of AD is AD. GABA also plays a role in regulation of immune
aberrant microglial activation, making the CX3CL1- signaling [186]. Microglia express GABAB receptors [187]
CX3CR1 pathway an ideal candidate for investigations of that are in Gi/o subclass of GPCR receptors. Activated
AD pathophysiology. The effect of CX3CR1 deficiency in microglia exhibit an upregulation of GABAB
mouse models of AD has been discordant, depending on receptors compared with resting microglia [187]. GABA
the type of models and methods used. For and GABAB also have anti-inflammatory properties.
example, CX3CR1 deletion in a tau transgenic mouse led Studies have demonstrated that when GABA is released
to increased tau phosphorylation and aggregation, by astrocytes into the extracellular fluid, it inhibits inflam-
increased microglial activation, and exacerbated deficits in matory responses of activated microglia and astrocytes
580 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

[186,188,189]. GABA has also been demonstrated to microglial activation, and improved performance in
decrease the release of pro-inflammatory cytokines, TNFa cognitive tasks [196]. High levels of soluble TNFR1 and
and IL-6, by activated astrocytes and microglia via GABAB TNFR2 can be detected in cerebrospinal fluid (CSF) of
[186]. In an LPS-induced inflammatory response, activation patients diagnosed with MCI who progress to AD on a
of the GABAB receptor reduces the release of IL-12 from 6-year follow-up [197].
microglia [187]. By utilizing baclofen, a GABAB receptor Increased levels of TNF-a have been reported in both the
agonist, intracellular inflammatory pathways were reduced brains and plasma of patients with AD [198]. Ab can directly
by 40–60% [186]. These data clearly indicate GABAB on stimulate microglia production of TNF-a through activation
microglia serve an anti-inflammatory role [187] suppressing of the transcription factor NFkB [199]. In addition,
proinflammatory signaling. In addition, astrocytes TNF-a can increase Ab burden through the upregulation
synthesize GABA via monoamine oxidase B (MAOB) of b-secretase production and increased g-secretase activity
[190], and it has been demonstrated that reactive astrocytes [11,200].
release large quantities of GABA [186,191] in what is
hypothesized to help regulate microglia function. The 4.3.2. Pro-inflammatory signaling: IL-1b
aforementioned data indicate a pathway that is likely IL-1b has been described as a “master regulator” within
involved in the regulation of microglia function. The the brain inflammatory cascade due to its integral role in
expressed GABAB receptors on microglia likely serve a regulating the expression of other proinflammatory
role in surveillance of neuronal function as GABA cytokines, including TNF-a and IL-6, and that disruptions
released from local synapses bind to GABAB on microglia to IL-1b can delay the onset of neuroinflammation and
to suppress pro-inflammatory signaling in a similar fashion neurodegeneration [201].
to the fracktalkine ligand and receptor. Furthermore, when IL-1 is a proinflammatory cytokine that is upregulated
microglia and astrocytes move into a more active state, early in AD development and is considered crucial for
GABA release from astrocytes appears to be a mechanism b-amyloid plaque deposition [41]. IL-1b is similarly
to regulate and suppress pro-inflammatory signaling in elevated in both MCI and AD patients compared with
microglia. If GABAergic tone is compromised in AD, this controls, suggesting that increased IL-1b production begins
suggests the loss of a mechanism to regulate microglia early and remains elevated as the disease progresses [202].
function. This mechanism is currently the focus of research Specific IL-1b polymorphisms resulting in higher IL-1b
in our Center of Biomedical Research Excellence (COBRE) production are linked to increased AD risk [203]. Increased
award, in particular, the investigation of changes in levels of IL-1b have been detected in the prefrontal cortex
GABAergic signaling in AD, as well as the role of GABAB and hippocampus in brain tissue of patients with AD
on microglia. [204]. IL-1b-mediated actions are through binding to the
The impact of the TREM2 mutation and other alterations IL-1 receptor, which is expressed throughout the brain but
in microglia receptors that alter microglia activation lead to can be found in greatest concentration in the dentate gyrus
the upregulation of a number of pro- and anti-inflammatory and pyramidal cells in the hippocampus, which are key areas
cytokines that regulate the immune response. The evaluation in the early development of AD pathology [205].
of these cytokines has become a central part of AD IL-1b regulates the synthesis of APP, increased APP
inflammation investigations. secretion from glial cells, and amyloidogenic processing of
APP through the activation of protein kinase C and increased
g-secretase activity [11,206]. The ability of IL-1b to
4.3. Specific cytokine signaling in AD
increase Ab burden and plaque deposition creates a
self-sustaining cycle wherein the increase of Ab load results
4.3.1. Pro-inflammatory signaling: TNF-a in further microglia activation and IL-1b production
TNF-a is one of the more important proinflammatory [207,208].
cytokines in AD, playing a central role in both initiation
and regulation of the cytokine cascade during a response 4.3.3. Pro-inflammatory signaling: IL-6
to an inflammatory challenge [41,192]. TNF-a increases IL-6 is an important, multifunctional cytokine that
vascular endothelial adhesion molecules, allowing can be considered proinflammatory or anti-inflammatory
leukocytes and immune cells to migrate into areas under depending on the amount and condition in which it was
duress [193]. released [209]. IL-6 is crucial for normal homeostasis of
TNF-a exerts its biological functions by binding to neuronal tissue, and removal of this signaling pathway leads
two main receptors, TNFR1 and TNFR2 [194]. The to reduced microglial activation, yet overproduction of IL-6
overexpression of TNFR1 in mouse hippocampal tissue leads to chronic neuroinflammation and neurodegeneration
was necessary for the activation of NFkB- and Ab-induced [210].
neuronal apoptosis [195]. Conversely, mice lacking Elevated levels of peripheral IL-6 during late midlife
TNFR1 crossed with the APP23 transgenic AD model have been reported to effectively predict cognitive decline
exhibit reduced plaque deposition, mitigated hippocampal in a 10-year longitudinal study [211]. IL-6 is elevated in
 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590 581

the CSF and serum of AD patients and is considered a have been unsuccessful, and in some studies even
significant contributor to neuroinflammation observed in exacerbated the disease [225]. Alternative studies have
LOAD [212,213]. supported this claim, by demonstrating that IL-10 can
Studies have demonstrated that IL-6 staining in the promote neuroinflammation and cause dysfunction of
hippocampus and cortex is strongly associated with Ab microglia. In early AD, microglia perform their role of
plaques, which is absent in age-matched controls activation, migration, and phagocytosis to alleviate the
[214,215]. Ab has been shown to stimulate the synthesis disease, but as the disease progresses, these functions are
and release of IL-6 by glial cells [207]. Activation of IL-6 inhibited. A study by Guillot-Sestier et al. (2015) suggests
receptors, which show a regional distribution strongest in that this microglia inhibition is related to IL-10.
the hippocampus and cortex, has been shown to enhance Il10-deficient APP/PS1 mice (APP/PS11IL-102/2)
APP transcription and expression, as does the IL-6/soluble showed a reduction of Ab in the cerebrum and an increase
IL-6 receptor complex, which can be readily found in serum in the amount of activated microglia surrounding the
and CSF [216]. IL-6 has also been demonstrated to result in remaining Ab, suggesting an increase in microglia migration
the hyperphosphorylation of several tau epitopes by and phagocytosis [226]. This study also demonstrated that
increasing CDK5 activity via the CDK5 activator p35, APP/PS11IL-102/2 mice have reduced synaptic loss and
potentially serving as an important bridge between the behavioral impairments in comparison with APP/PS11IL-
core AD pathologies [95]. 101/1 mice. Research also shows that a polymorphism of
IL-10 increases the risk of developing AD in some
4.3.4. Pro-inflammatory signaling: NFkB populations [227,228].
The transcription factor NFkB is considered a primary
regulator of inflammatory responses by responding to 4.3.6. Anti-inflammatory signaling: TGF-b1
proinflammatory stimuli, such as TNF-a or IL-1 [217]. Transforming growth factor-b (TGF-b) is involved in the
Activated NFkB is predominately found in neurons and glial regulation of cell growth, cell differentiation, and
cells that are surrounding Ab plaques and is central to immunosuppression. Studies have shown that TGF-b is
reactive gliosis observed in AD brains [218]. elevated in CSF, serum, and brain microvascular endothelial
NFkB has been shown to play an important role in cells of patients with AD [229,230]. Grammas et al.
regulating b-site APP cleaving enzyme 1 (BACE1) demonstrates that this increase of TGF-b in endothelial
transcription, as numerous NFkB binding sites have been cells also provokes the release of pro-inflammatory
identified near the BACE1 promoter [219]. In addition, Ab cytokines, IL-1b and TGF-a, promoting an inflammatory
has been shown to stimulate cytokine production through response [230]. Within this family of cytokines, the most
the NFkB-dependent pathway, resulting in a cyclical loop abundant isoform is TGF-b1, which is secreted by astrocytes
of exacerbating pathology [199]. and is a ligand for receptors found on neurons, astrocytes,
Both in vitro and in vivo studies demonstrate and microglia [231]. TGF-b1 is neuroprotective against
that utilizing an NFkB inhibitor, such as 6-amino-4(4- Ab production, deposition, and damage, regulates
phenoxyphenylethylamino) quinazoline, can reduce neuroinflammation, and inhibits the pathway for the
TNF-a-induced BACE1 transcription, resulting in lower tau-phosphorylating enzyme, GSK-3b [232]. It is also
Ab burden [196,220]. Certain NSAIDS, such as responsible for causing an increase in the expression of
flurbiprofen and indomethacin, have been shown to reduce Bcl-2 and Bcl-xl, anti-apoptotic proteins. The quantity of
NFkB activity, which subsequently results in lower levels TGF-b1 in plasma has been shown to be decreased in
of Ab1–40 and Ab1–42 [221,222]. patients with AD [233,234]. When Ab oligomers are
injected into the hippocampus of mice, decrease in
4.3.5. Anti-inflammatory signaling: IL-10 synaptic protein levels and atrophy of astrocytic processes
Interleukin 10 (IL-10) is an anti-inflammatory cytokine occur. However, intracerbroventricular infusion of 10 ng
that is found in healthy brain tissue but is upregulated in TGF-b1 30 minutes before an injection of 10 pmol Ab
patients with AD [223]. There is a correlation between oligomers resulted in reduced levels of the proteins,
IL-10 levels and the progression of AD, suggesting that drebrin, PSD-95, and synaptophysin, and strengthening of
IL-10 could serve as a biomarker for AD diagnosis and/or astrocytic processes [235]. Also, mice that were
progression. IL-10 is released by both microglia and intracerebroventricularly injected with Ab failed to spend
astrocytes in response to the increase in pro-inflammatory more time with a novel object in a novel object recognition
cytokines to attempt to maintain homeostasis in the immune test, whereas the mice previously injected with TGF-b1 did
system [224]. IL-10 has been shown to inhibit not show memory impairments [235]. TGF-b1 deficiency
pro-inflammatory cytokines, including IL-1a, IL-1b, also causes impairment in the TGF-b1/Smad signaling
TNF-a, IL-6, and the chemokine MCP-1 [223]. These pathway. The disruption of this pathway contributes to the
findings suggest that increases in IL-10 may also be a ectopic phosphorylation of Smad2/3, which has been found
possible therapeutic target to manage chronic inflammation, in the hippocampal cytoplasm of neurons attached to NFT
though clinical trials involving anti-inflammatory agents and within Ab plaques. There is a negative correlation
582 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

between TGF-b1 mRNA levels and NFT, suggesting that from binding within the hippocampus to protect against
TGF-b1 deficiency advances tau pathology, causing further AD-related synaptic deterioration [259], and the alterations
impairment of the TGF-b1/Smad pathway [232]. These in insulin signaling (including insulin receptor resistance)
studies demonstrate how disruption of TGF-b1 signaling results in cerebrospinal fluid levels of Ab being higher in
contributes to the AD pathogenesis. patients with T2DM than nondiabetic controls [260].
The aforementioned studies demonstrate a number of Insulin resistance that arises from DM is proposed to
specific roles for inflammatory mechanisms altered in AD, manifest from a prolonged, mild state of inflammation
as well as a number of mechanisms that are likely related to occurring within peripheral tissue. Adipose tissue has been
AD pathogenesis. Given the very strong relationship between shown to recruit macrophage and stimulate the secretion of
the missense mutation in TREM2 and the risk for developing numerous proinflammatory cytokines, including TNF-a,
AD, a number of other known risk factors for AD for which IL-1b, and IL-6, which are then easily distributed throughout
the mechanism underlying the risk is not known have now the rest of the body causing systemic inflammation
been hypothesized to be linked to inflammation. [261–263]. TNF-a is, in turn, a potent inducer of insulin
resistance occurring within adipose tissue [261,264].
Numerous studies have demonstrated the correlation
4.4. Relevance of inflammation and risk factors for AD
between peripheral inflammation and cognitive deficits,
A number of risk factors have been identified that confer particularly with MCI and AD [265,266]. A meta-analysis
greater risk for developing AD. These include age [236], of 40 studies revealed that peripheral cytokines, including
cardiovascular changes [237], traumatic brain injury TNF-a, IL-1b, and IL-6, and TGF-b are higher in patients
[94,238–240], and metabolic disorders such as diabetes. with AD [267]. Whether the peripheral inflammation is
Interestingly, each of the aforementioned risk factors also arising from adiposity or another source, proinflammatory
is associated with an immune response, including in the cytokines can cross the blood-brain barrier, which triggers
brain. This has led to hypotheses that elevated brain-specific inflammatory responses [268,269]. Systemic
inflammation and/or inflammatory signaling may be inflammation is also a primary cause of damage to the
increasing the risk [241]. As mechanisms are numerous, blood-brain barrier, allowing entry of peripheral immune
we have explained one example below in more detail. cells into the brain. Decreased blood-brain barrier integrity
can be observed in rodents that feed on high-fat, high-energy
4.4.1. Diabetes mellitus (DM), AD, and inflammation diets, leading to increased blood-brain barrier permeability,
In addition to the aforementioned pathological hallmarks, excessive microglial activation, and hippocampal-dependent
AD is also characterized by abnormal metabolic changes. learning deficits [270–272]. Compromised blood-brain
Decreased cerebral glucose metabolism is now considered barrier integrity can also allow chronic, low-grade systemic
a distinct characteristic of the AD brain [242–244]. The inflammation, as observed in obesity and T2DM, to induce
association between T2DM and AD is well established, central inflammation.
along with other neurodegenerative diseases, including Microglia are primed in AD brains to be more susceptible
vascular dementia and PD [245–247]. One of the first key to secondary inflammatory insults, resulting in an
studies, the 1999 Rotterdam Study, found that type-2 diabetes exacerbated inflammatory response [273]. High-fat chow
mellitus (T2DM) could double the risk for the development can be used in the APP/PS1 mouse model to induce systemic
of AD [248]. Since that seminal Rotterdam Study, numerous inflammation that results in profound neuroinflammation
studies have since substantiated this finding that T2DM and accelerated AD-pathology, including Ab and tau
nearly doubles the risk for AD [249,250], including that hyperphosphorylation, and central insulin resistance [274].
T2DM serves as a useful predictor for the development of The mechanism of neuronal insulin resistance appears to
AD in a 12-year longitudinal study [251,252]. be similar with Ab oligomers inducing microglial activation,
The defining characteristics of T2DM are impairments in which in turn release numerous pro-inflammatory cytokines,
insulin signaling and hyperglycemia [253,254], which including TNF-a [275]. Although activation of microglia by
appear to be the main contributing factors increasing the Ab is an adaptive physiological response to reducing Ab
risk for AD. Impairments in brain insulin signaling as seen burden through phagocytosis, chronic inflammation leads
in T2DM has been found to get progressively worse as the to exacerbated AD pathology and metabolic abnormalities,
pathology advances in patients with AD, corresponding to which in turn further exacerbate pathogenesis. These data
increased levels of amyloid peptides and, in particular, are providing evidence for links between molecular
neuroinflammation [255,256]. pathways and biochemical abnormalities associated with
A considerable literature has demonstrated that inflammatory mechanisms shared between AD and DM.
alterations in insulin levels and insulin receptor resistance
(in particular in T2DM) within the brain impact survival 4.4.2. APOE and inflammation
and function of both neurons and glial cells that are Apolipoprotein (ApoE) is produced primarily peripher-
dependent on intact insulin signaling [257,258]. Insulin is ally within the liver and by astrocytes within the CNS. While
even neuroprotective by preventing b-amyloid oligomers the main roles of ApoE involve cholesterol transport,
 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590 583

regulation of lipid transport, and aid of injury repair within Neither funding source was involved in the report
the brain, ApoE plays a role in glucose metabolism preparation or interpretation of data.
[276,277]. Owing to the ApoE-ε4 allele representing the
strongest genetic risk factor for late-onset AD (LOAD),
present in nearly w40% of all patients with AD [278], and
RESEARCH IN CONTEXT
the increasing risk that metabolic disturbances play in
dementia progression, the links between ApoE-ε4, glucose
metabolism, and recently inflammation are important to
understanding the shared underlying mechanisms between 1. Systematic review: Inflammation in Alzheimer’s
these risk factors. disease (AD) has emerged as a central pathology
A recent investigation has highlighted a particularly that likely plays a role in onset and progression
important aspect of ApoE risk in AD as it is related to of the disease. Numerous investigations have
inflammation. Krasemann et. al., (2017) identified a role highlighted that the sustained inflammation in the
for ApoE signaling in the regulation of microglia phenotype brain accelerates other core pathologies, making
in response to amyloid b, as well as in other inflammatory mechanisms viable targets for
neurodegenerative disorders [279]. Even more compelling therapeutic development as well. In the below
is that TREM2 signaling appears to mediate a return to review, we highlight a number of the inflammatory
nonpathogenic and reduced phagocytosis of neurons by mechanisms that have been implicated in AD
microglia. This suggests a completely novel interaction pathogenesis. We also highlight links between risk
between one of the major risk factors for developing AD factors for AD and potential interactions with
and microglia function. Additional studies are required to inflammatory mechanisms.
determine the relationship between ApoE and inflammation, 2. Interpretation: In the present review we provide
but this may serve as another example of the central role of coverage of the interactions of inflammatory
inflammation driving AD pathology. ApoE-ε4 appears to signaling and the progression of AD. We also discuss
synergistically combine with other AD risk factors, a number of possible mechanisms that may account
including cardiovascular disease, atherosclerosis, and for connections between altered inflammatory
type-2 diabetes [280]. As each of these other risk factors signaling and the changes observed in AD.
includes an evoked immune response in the brain the
possibility exists that inflammation may be the common 3. Future directions: This review highlights several
thread for increased risk. emerging mechanisms that may provide a better
understanding of AD pathogenesis as well as may
serve as novel therapeutic targets for treatment
5. Summary and/or onset of AD.
The aforementioned sections highlight the central role that
investigations of inflammation in AD has taken in the last
decade and highlight a number of interrelated mechanisms
that may contribute to AD pathogenesis. As the literature
demonstrating the role of inflammation in accelerating core References
AD pathologies increases, so should the investigations of
therapeutic approaches targeting the sustained inflammatory [1] Prince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M.
response. In addition, extensive investigations in AD patient World Alzheimer Report 2016: Improving Healthcare for People Living
populations as well as pre-clinical model systems needs to With Dementia: Coverage, Quality and Costs Now and in the Future.
London: Alzheimer’s Disease International; 2016.
further evaluate microglia signaling cascades and numerous
[2] Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the
receptors that have not yet been well characterized. Given United States (2010–2050) estimated using the 2010 census.
recent hypothesis that extend beyond the findings of Neurology 2013;80:1778–83.
inflammation exacerbating AD pathologies to suggestions [3] Alzheimer’s Impact Movement. Alzheimer’s Disease Caregivers
that the inflammatory response evoked by Ab may serve to Factsheet. Chicago, IL: Alzheimer’s Association; 2017.
[4] Selkoe DJ. Normal and abnormal biology of the beta-Amyloid
seed the onset of tau pathology, the identification of how
Precursor Protein. Annu Rev Neurosci 1994;17:489–517.
the microglia response is regulated and how to modify the [5] O’Brien RJ, Wong PC. Amyloid precursor protein processing and
response has become an important topic in potential Alzheimer’s disease. Annu Rev Neurosci 2011;34:185–204.
treatments of AD. [6] Anderson JP, Chen Y, Kim KS, Robakis NK. An alternative secretase
cleavage produces soluble Alzheimer amyloid precursor protein
containing a potentially amyloidogenic sequence. J Neurochem
Acknowledgments 1992;59:2328–31.
[7] Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M,
This work was supported by a COBRE grant from the Eikelenboom P, Grubeck-Loebenstein B. Costimulatory Effects of
NIH/MIGMS (P20GM109025) and Keep Memory Alive. Interferon-g and Interleukin-1b or Tumor Necrosis Factor a on the
584 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

Synthesis of Ab1-40 and Ab1-42 by Human Astrocytes. Neurobiol [29] Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B,
Dis 2000;7:682–9. Mandelkow E-M, et al. Overexpression of Tau Protein Inhibits
[8] Busciglio J, Gabuzda DH, Matsudaira P, Yankner BA. Generation of Kinesin-dependent Trafficking of Vesicles, Mitochondria, and
beta-amyloid in the secretory pathway in neuronal and nonneuronal Endoplasmic Reticulum: Implications for Alzheimer’s Disease.
cells. Proc Natl Acad Sci 1993;90:2092–6. J Cell Biol 1998;143:777–94.
[9] Butterfield DA, Swomley AM, Sultana R. Amyloid b-Peptide (1–42)- [30] Gong C-X, Iqbal K. Hyperphosphorylation of microtubule-
Induced oxidative stress in Alzheimer disease: Importance in disease Associated protein Tau: A promising therapeutic target for Alzheimer
pathogenesis and progression. Antioxid Redox Signal 2012;19:823–35. disease. Curr Med Chem 2008;15:2321–8.
[10] Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, [31] Guo T, Noble W, Hanger DP. Roles of tau protein in health and
Ostaszewski BL, et al. Amyloid b-peptide is produced by cultured disease. Acta Neuropathol 2017;133:665–704.
cells during normal metabolism. Nature 1992;359:322–5. [32] Lippens G, Sillen A, Landrieu I, Amniai L, Sibille N, Barbier P, et al.
[11] Liao Y-F, Wang B-J, Cheng H-T, Kuo L-H, Wolfe MS. Tumor Necrosis Tau Aggregation in Alzheimer’s Disease. Prion 2007;1:21–5.
Factor-a, Interleukin-1b, and Interferon-g Stimulate g-Secretase-  c G, Babic Leko M, Wray S, Harrington C, Delalle I, Jovanov-
[33] Simi
mediated Cleavage of Amyloid Precursor Protein through a Milosevic N, et al. Tau Protein Hyperphosphorylation and aggrega-
JNK-dependent MAPK Pathway. J Biol Chem 2004;279:49523–32. tion in Alzheimer’s disease and other tauopathies, and possible neu-
[12] Murphy MP, LeVine H. Alzheimer’s disease and the b-Amyloid roprotective strategies. Biomolecules 2016;6.
peptide. J Alzheimer’s Dis 2010;19:311. [34] Cummings J, Aisen PS, DuBois B, Fr€olich L, Jack CR, Jones RW,
[13] Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, et al. Drug development in Alzheimer’s disease: the path to 2025.
Mahmoudi J. Amyloid-Beta: A crucial factor in Alzheimer’s disease. Alzheimers Res Ther 2016;8:39.
Med Princ Pract 2015;24:1–10. [35] Hardy J, Selkoe DJ. The Amyloid hypothesis of Alzheimer’s disease:
[14] Selkoe DJ. Physiological production of the b-amyloid protein and the Progress and problems on the road to therapeutics. Science 2002;
mechanism of Alzheimer’s disease. Trends Neurosci 1993;16:403–9. 297:353–6.
[15] Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, et al. [36] Morris GP, Clark IA, Vissel B. Inconsistencies and controversies
Production of the Alzheimer amyloid beta protein by normal surrounding the amyloid hypothesis of Alzheimer’s disease. Acta
proteolytic processing. Science 1992;258:126–9. Neuropathol Commun 2014;2.
[16] Stockley JH, O’Neill C. Understanding BACE1: essential protease [37] Guillozet AL, Weintraub S, Mash DC, Mesulam MM. Neurofibrillary
for amyloid-b production in Alzheimer’s disease. Cell Mol Life Sci tangles, amyloid, and memory in aging and mild cognitive
2008;65:3265. impairment. Arch Neurol 2003;60:729–36.
[17] Wilson CA, Doms RW, Lee VM. Intracellular APP processing and A [38] Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ,
beta production in Alzheimer disease. J Neuropathol Exp Neurol et al. Correlation of Alzheimer disease neuropathologic changes
1999;58:787–94. with cognitive status: A review of the literature. J Neuropathol Exp
[18] Alonso AC, Grundke-Iqbal I, Iqbal K. Alzheimer’s disease Neurol 2012;71:362–81.
hyperphosphorylated tau sequesters normal tau into tangles of [39] Nelson PT, Braak H, Markesbery WR. Neuropathology and cognitive
filaments and disassembles microtubules. Nat Med 1996;2:783–7. impairment in Alzheimer disease: A complex but coherent
[19] Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally relationship. J Neuropathol Exp Neurol 2009;68:1–14.
phosphorylated tau in the breakdown of microtubules in Alzheimer [40] Akama KT, Eldik LJV. b-Amyloid Stimulation of Inducible
disease. Proc Natl Acad Sci U S A 1994;91:5562–6. Nitric-oxide Synthase in Astrocytes Is Interleukin-1b- and Tumor
[20] Alonso A del C, Grundke-Iqbal I, Barra HS, Iqbal K. Abnormal Necrosis Factor-a (TNFa)-dependent, and Involves a TNFa
phosphorylation of tau and the mechanism of Alzheimer neurofibril- Receptor-associated Factor- and NFkB-inducing Kinase-dependent
lary degeneration: Sequestration of microtubule-associated proteins Signaling Mechanism. J Biol Chem 2000;275:7918–24.
1 and 2 and the disassembly of microtubules by the abnormal tau. [41] Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al.
Proc Natl Acad Sci U S A 1997;94:298–303. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000;
[21] Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, 21:383–421.
et al. Accumulation of abnormally phosphorylated t precedes the [42] Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE.
formation of neurofibrillary tangles in Alzheimer’s disease. Brain Inflammatory mechanisms in Alzheimer’s disease: Inhibition of
Res 1989;477:90–9. b-Amyloid-Stimulated proinflammatory responses and neurotoxicity
[22] Braak H, de Vos RA, Jansen EN, Bratzke H, Braak E. by PPARg agonists. J Neurosci 2000;20:558–67.
Neuropathological hallmarks of Alzheimer’s and Parkinson’s [43] Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ,
diseases. Prog Brain Res 1998;117:267–85. et al. Brain interleukin 1 and S-100 immunoreactivity are
[23] Iqbal K, Zaidi T, Wen G, Grundke-Iqbal I, Merz P, Shaikh S, et al. elevated in Down syndrome and Alzheimer disease. Proc Natl
Defective brain microtubule assembly in Alzheimer’s disease. Lancet Acad Sci U S A 1989;86:7611–5.
1986;328:421–6. [44] Griffin WST, Sheng JG, Roberts GW, Mrak RE. Interleukin-1 expression
[24] Iqbal K, Liu F, Gong C-X, Grundke-Iqbal I. Tau in Alzheimer disease in different plaque types in Alzheimer’s disease: Significance in plaque
and related tauopathies. Curr Alzheimer Res 2010;7:656–64. evolution. J Neuropathol Exp Neurol 1995;54:276–81.
[25] K€opke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I. [45] McGeer PL, Akiyama H, Itagaki S, McGeer EG. Immune system
Microtubule-associated protein tau. Abnormal phosphorylation of a response in Alzheimer’s disease. Can J Neurol Sci 1989;16:516–27.
non-paired helical filament pool in Alzheimer disease. J Biol Chem [46] McGeer PL, McGeer EG. The inflammatory response system of
1993;268:24374–84. brain: implications for therapy of Alzheimer and other
[26] Schmitt H, Gozes I, Littauer UZ. Decrease in levels and rates of neurodegenerative diseases. Brain Res Rev 1995;21:195–218.
synthesis of tubulin and actin in developing rat brain. Brain Res [47] Mrak RE, Griffin WST. Common inflammatory mechanisms in Lewy
1977;121:327–42. Body disease and Alzheimer disease. J Neuropathol Exp Neurol
[27] Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein 2007;66:683–6.
factor essential for microtubule assembly. Proc Natl Acad Sci U S A [48] Mrak RE, Sheng JG, Griffin WST. Glial cytokines in Alzheimer’s
1975;72:1858–62. disease: Review and pathogenic implications. Hum Pathol 1995;
[28] Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both 26:816–23.
physiological and pathological conditions. Physiol Rev 2004; [49] Tuppo EE, Arias HR. The role of inflammation in Alzheimer’s
84:361–84. disease. Int J Biochem Cell Biol 2005;37:289–305.
 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590 585

[50] Walters A, Phillips E, Zheng R, Biju M, Kuruvilla T. Evidence for [72] Amor S, Peferoen LAN, Vogel DYS, Breur M, Valk P, Baker D, et al.
neuroinflammation in Alzheimer’s disease. Prog Neurol Psychiatry Inflammation in neurodegenerative diseases – an update. Immu-
2016;20:25–31. nology 2014;142:151–66.
[51] Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, [73] Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neuro-
Tenner AJ, et al. Extensive innate immune gene activation degenerative diseases. Immunology 2010;129:154–69.
accompanies brain aging, increasing vulnerability to [74] Cappellano G, Carecchio M, Fleetwood T, Magistrelli L, Cantello R,
cognitive decline and neurodegeneration: a microarray study. Dianzani U, et al. Immunity and inflammation in neurodegenerative
J Neuroinflammation 2012;9:179. diseases. Am J Neurodegenerative Dis 2013;2:89–107.
[52] Gomez-Nicola D, Boche D. Post-mortem analysis of [75] Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms
neuroinflammatory changes in human Alzheimer’s disease. Underlying Inflammation in Neurodegeneration. Cell 2010;
Alzheimers Res Ther 2015;7. 140:918–34.
[53] Sudduth TL, Schmitt FA, Nelson PT, Wilcock DM. [76] Griffin WST. Inflammation and Neurodegenerative Diseases. Am J
Neuroinflammatory phenotype in early Alzheimer’s disease. Clin Nutr 2006;83:470S–4.
Neurobiol Aging 2013;34:1051–9. [77] Wyss-Coray T, Yan F, Lin AH-T, Lambris JD, Alexander JJ,
[54] Janssen B, Vugts DJ, Funke U, Molenaar GT, Kruijer PS, van Quigg RJ, et al. Prominent neurodegeneration and increased plaque
Berckel BNM, et al. Imaging of neuroinflammation in Alzheimer’s formation in complement-inhibited Alzheimer’s mice. Proc Natl
disease, multiple sclerosis and stroke: Recent developments in Acad Sci U S A 2002;99:10837–42.
positron emission tomography. Biochim Biophys Acta 2016; [78] Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W.
1862:425–41. Astrocytes are important mediators of Ab-induced neurotoxicity
[55] Knezevic D, Mizrahi R. Molecular imaging of neuroinflammation in and tau phosphorylation in primary culture. Cell Death Dis 2011;
Alzheimer’s disease and mild cognitive impairment. Prog 2:e167.
Neuropsychopharmacol Biol Psychiatry 2018;80:123–31. [79] Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipo-
[56] Lagarde J, Sarazin M, Bottlaender M. In vivo PET imaging of polysaccharide-Induced inflammation exacerbates tau pathology by
neuroinflammation in Alzheimer’s disease. J Neural Transm (Vienna) a Cyclin-Dependent Kinase 5-Mediated pathway in a transgenic
2018;125:847–67. model of Alzheimer’s disease. J Neurosci 2005;25:8843–53.
[57] Zimmer ER, Leuzy A, Benedet AL, Breitner J, Gauthier S, [80] Kitazawa M, Yamasaki TR, Laferla FM. Microglia as a potential
Rosa-Neto P. Tracking neuroinflammation in Alzheimer’s bridge between the amyloid b-Peptide and tau. Ann N Y Acad Sci
disease: the role of positron emission tomography imaging. J 2004;1035:85–103.
Neuroinflammation 2014;11:120. [81] Ma Q-L, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, et al.
[58] Ferreira ST, Clarke JR, Bomfim TR, De Felice FG. Inflammation, b-Amyloid oligomers induce phosphorylation of tau and inactivation
defective insulin signaling, and neuronal dysfunction in Alzheimer’s of insulin receptor substrate via c-Jun N-Terminal kinase signaling:
disease. Alzheimers Dement 2014;10:S76–83. Suppression by Omega-3 fatty acids and curcumin. J Neurosci
[59] Grammas P. Neurovascular dysfunction, inflammation and 2009;29:9078–89.
endothelial activation: Implications for the pathogenesis of [82] Nisbet RM, Polanco J-C, Ittner LM, G€otz J. Tau aggregation and its
Alzheimer’s disease. J Neuroinflammation 2011;8:26. interplay with amyloid-b. Acta Neuropathol 2015;129:207–20.
[60] Meraz-Rıos MA, Toral-Rios D, Franco-Bocanegra D, Villeda- [83] Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, et al.
Hernandez J, Campos-Pe~na V. Inflammatory process in Alzheimer’s Amyloid-b and tau synergistically impair the oxidative phosphoryla-
Disease. Front Integr Neurosci 2013;7. tion system in triple transgenic Alzheimer’s disease mice. Proc Natl
[61] Rubio-Perez JM, Morillas-Ruiz JM. A Review: Inflammatory process Acad Sci 2009;106:20057–62.
in Alzheimer’s disease, role of cytokines. ScientificWorldJournal [84] Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of
2012;2012. immune system-associated antigens by cells of the human central
[62] Herrero M-T, Estrada C, Maatouk L, Vyas S. Inflammation in nervous system: relationship to the pathology of Alzheimer’s disease.
Parkinson’s disease: role of glucocorticoids. Front Neuroanat 2015;9. Neurobiol Aging 1988;9:339–49.
[63] Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson’s disease [85] Beard CM, Waring SC, O’Brien PC, Kurland LT, Kokmen E.
and its potential as therapeutic target. Transl Neurodegener 2015; Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease:
4:19. a case-control study in Rochester, Minnesota, 1980 through 1984.
[64] Crotti A, Glass CK. The choreography of neuroinflammation in Mayo Clinic Proc 1998;73:951–5.
Huntington’s disease. Trends Immunol 2015;36:364–73. [86] Breitner JC, Gau BA, Welsh KA, Plassman BL, McDonald WM,
[65] Ellrichmann G, Reick C, Saft C, Linker RA. The role of the immune Helms MJ, et al. Inverse association of anti-inflammatory treatments
system in Huntington’s disease. Clin Dev Immunol 2013;2013. and Alzheimer’s disease: initial results of a co-twin control study.
 Lahiri N, Andre R, Magnusson-
[66] Silajdzic E, Rezeli M, Vegvari A, Neurology 1994;44:227–32.
Lind A, et al. A critical evaluation of inflammatory markers in [87] Rich JB, Rasmusson DX, Folstein MF, Carson KA, Kawas C,
Huntington’s Disease plasma. J Huntington’s Dis 2013;2:125–34. Brandt J. Nonsteroidal anti-inflammatory drugs in Alzheimer’s
[67] Breunig J, Guillot-Sestier M-V, Town T. Brain injury, neuroinflam- disease. Neurology 1995;45:51–5.
mation and Alzheimer’s disease. Front Aging Neurosci 2013;5. [88] McGeer PL, McGeer EG. NSAIDs and Alzheimer disease:
[68] Faden AI, Loane DJ. Chronic neurodegeneration after traumatic Epidemiological, animal model and clinical studies. Neurobiol Aging
brain injury: Alzheimer disease, chronic traumatic encephalopathy, 2007;28:639–47.
or persistent neuroinflammation? Neurotherapeutics 2015; 
[89] Miguel-Alvarez M, Santos-Lozano A, Sanchis-Gomar F, Fiuza-
12:143–50. Luces C, Pareja-Galeano H, Garatachea N, et al. Non-steroidal
[69] Ling H, Hardy J, Zetterberg H. Neurological consequences of anti-inflammatory drugs as a treatment for Alzheimer’s disease:
traumatic brain injuries in sports. Mol Cell Neurosci 2015; a systematic review and meta-analysis of treatment effect. Drugs
66:114–22. Aging 2015;32:139–47.
[70] McCombe P, Henderson R. The role of immune and inflammatory [90] McGeer PL, Rogers J. Anti-inflammatory agents as a therapeutic
mechanisms in ALS. Curr Mol Med 2011;11:246–54. approach to Alzheimer’s disease. Neurology 1992;42:447–9.
[71] Chen W-W, Zhang X, Huang W-J. Role of neuroinflammation [91] Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D. Inflammation
in neurodegenerative diseases (Review). Mol Med Rep 2016; in Alzheimer’s disease: relevance to pathogenesis and therapy.
13:3391–6. Alzheimer’s Res 2010;2:1.
586 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

[92] Kim YS, Joh TH. Microglia, major player in the brain inflammation: [114] Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al.
their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med Peripherally administered antibodies against amyloid beta-peptide
2006;38:333–47. enter the central nervous system and reduce pathology in a mouse
[93] Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, model of Alzheimer disease. Nat Med 2000;6:916–9.
et al. Interleukin 1 regulates synthesis of amyloid beta-protein [115] Simard AR, Soulet D, Gowing G, Julien J-P, Rivest S. Bone
precursor mRNA in human endothelial cells. Proc Natl Acad Sci marrow-derived microglia play a critical role in restricting senile
1989;86:7606–10. plaque formation in Alzheimer’s disease. Neuron 2006;49:489–502.
[94] Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, [116] Tamboli IY, Barth E, Christian L, Siepmann M, Kumar S, Singh S,
Drosdick D, et al. Documented head injury in early adulthood and et al. Statins promote the degradation of extracellular amyloid
risk of Alzheimer’s disease and other dementias. Neurology 2000; b-Peptide by microglia via stimulation of exosome-associated
55:1158–66. insulin-degrading Enzyme (IDE) secretion. J Biol Chem 2010;
[95] Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB. 285:37405–14.
Interleukin-6 induces Alzheimer-type phosphorylation of tau protein [117] Yuyama K, Sun H, Mitsutake S, Igarashi Y. Sphingolipid-modulated
by deregulating the cdk5/p35 pathway. Exp Cell Res 2004; exosome secretion promotes clearance of amyloid-b by microglia. J
295:245–57. Biol Chem 2012;287:10977–89.
[96] Sarma JD. Microglia-mediated neuroinflammation is an amplifier of [118] Hickman SE, Allison EK, Khoury JE. Microglial dysfunction and
virus-induced neuropathology. J NeuroVirology 2014;20:122–36. defective b-amyloid clearance pathways in aging Alzheimer’s dis-
[97] Glenn JA, Jordan FL, Thomas WE. Further studies on the ease mice. J Neuroscience 2008;28:8354–60.
identification of microglia in mixed brain cell cultures. Brain Res [119] Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C,
Bull 1989;22:1049–52. Levites Y, Verbeeck C, et al. Massive gliosis induced by
[98] Glenn JA, Ward SA, Stone CR, Booth PL, Thomas WE. interleukin-6 suppresses Ab deposition in vivo: evidence against
Characterisation of ramified microglial cells: detailed morphology, inflammation as a driving force for amyloid deposition. FASEB J
morphological plasticity and proliferative capability. J Anat 1992; 2010;24:548–59.
180:109–18. [120] Shaftel SS, Kyrkanides S, Olschowka JA, Miller JH, Johnson RE,
[99] Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP O’Banion MK. Sustained hippocampal IL-1b overexpression medi-
mediates rapid microglial response to local brain injury in vivo. Nat ates chronic neuroinflammation and ameliorates Alzheimer plaque
Neurosci 2005;8:752–8. pathology. J Clin Invest 2007;117:1595–604.
[100] Eyo UB, Dailey ME. Microglia: Key elements in neural development, [121] Meda L, Cassatella MA, Szendrei GI, Otvos L, Baron P, Villalba M,
plasticity, and pathology. J Neuroimmune Pharmacol 2013;8:494–509. et al. Activation of microglial cells by beta-amyloid protein and inter-
[101] Nolte C, Moller T, Walter T, Kettenmann H. Complement 5a controls feron-gamma. Nature 1995;374:647–50.
motility of murine microglial cells in vitro via activation of an [122] Sheng JG, Zhou XQ, Mrak RE, Griffin WST. Progressive neuronal
inhibitory G-protein and the rearrangement of the actin cytoskeleton. injury associated with amyloid plaque formation in Alzheimer dis-
Neuroscience 1996;73:1091–107. ease. J Neuropathol Exp Neurol 1998;57:714–7.
[102] Madry C, Attwell D. Receptors, ion channels, and signaling [123] Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD,
mechanisms underlying microglial dynamics. J Biol Chem 2015; Bernhardt U, et al. Functional impairment of microglia coincides
290:12443–50. with beta-amyloid deposition in mice with Alzheimer-Like pathol-
[103] Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. ogy. PLoS One 2013;8:e60921.
Trends Neurosci 2007;30:527–35. [124] Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P.
[104] Cross AK, Woodroofe MN. Chemokines induce migration and changes Characterization of the microglial phenotype under specific
in actin polymerization in adult rat brain microglia and a human fetal pro-inflammatory and anti-inflammatory conditions: Effects of
microglial cell line in vitro. J Neurosci Res 1999;55:17–23. oligomeric and fibrillar amyloid-b. J Neuroimmunol 2009;210:3–12.
[105] Flynn G, Maru S, Loughlin J, Romero IA, Male D. Regulation of che- [125] Bhaskar K, Maphis N, Xu G, Varvel NH, Kokiko-Cochran ON,
mokine receptor expression in human microglia and astrocytes. J Weick JP, et al. Microglial derived tumor necrosis factor-a drives
Neuroimmunol 2003;136:84–93. Alzheimer’s disease-related neuronal cell cycle events. Neurobiol
[106] Lee YB, Nagai A, Kim SU. Cytokines, chemokines, and cytokine Dis 2014;62.
receptors in human microglia. J Neurosci Res 2002;69:94–103. [126] Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory
[107] Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, cytokines released from microglia in neurodegenerative diseases.
et al. Role for neuronally derived fractalkine in mediating Brain Res Bull 2012;87:10–20.
interactions between neurons and CX3CR1-expressing microglia. [127] Yates SL, Burgess LH, Kocsis-Angle J, Antal JM, Dority MD,
Proc Natl Acad Sci U S A 1998;95:10896–901. Embury PB, et al. Amyloid b and amylin fibrils induce increases in
[108] Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, et al. proinflammatory cytokine and chemokine production by THP-1 cells
Dynamics of the Microglial/Amyloid interaction indicate a role in and murine microglia. J Neurochem 2000;74:1017–25.
plaque maintenance. J Neurosci 2008;28:4283–92. [128] Wisniewski HM, Moretz RC, Lossinsky AS. Evidence for induction
[109] Brierley JB, Brown AW. The origin of lipid phagocytes in the central of localized amyloid deposits and neuritic plaques by an infectious
nervous system: II. The adventitia of blood vessels. J Comp Neurol agent. Ann Neurol 1981;10:517–22.
1982;211:407–17. [129] Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML,
[110] Graeber MB, Tetzlaff W, Streit WJ, Kreutzberg GW. Microglial cells et al. TREM2 deficiency eliminates TREM21 inflammatory
but not astrocytes undergo mitosis following rat facial nerve macrophages and ameliorates pathology in Alzheimer’s disease
axotomy. Neurosci Lett 1988;85:317–21. mouse models. J Exp Med 2015;212:287–95.
[111] Mrak RE. Microglia in Alzheimer Brain: A neuropathological [130] Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G,
perspective. Int J Alzheimer’s Dis 2012. et al. TREM2 deficiency exacerbates tau pathology through
[112] Baik SH, Kang S, Son SM, Mook-Jung I. Microglia contributes to dysregulated kinase signaling in a mouse model of tauopathy. Mol
plaque growth by cell death due to uptake of amyloid b in the brain Neurodegener 2017;12.
of Alzheimer’s disease mouse model. Glia 2016;64:2274–90. [131] Savage JC, Jay T, Goduni E, Quigley C, Mariani MM, Malm T, et al.
[113] Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Nuclear Receptors License Phagocytosis by Trem21 Myeloid Cells
Jucker M. Association of Microglia with Amyloid Plaques in Brains in Mouse Models of Alzheimer’s Disease. J Neurosci 2015;
of APP23 Transgenic Mice. Am J Pathol 1999;154:1673–84. 35:6532–43.
 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590 587

[132] Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, [152] Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al.
et al. TREM2 lipid sensing sustains microglia response in an Alz- TREM2 haplodeficiency in mice and humans impairs the microglia
heimer’s disease model. Cell 2015;160:1061–71. barrier function leading to decreased amyloid compaction and severe
[133] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, axonal dystrophy. Neuron 2016;90:724–39.
Majounie E, et al. TREM2 Variants in Alzheimer’s Disease. N [153] Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R,
Engl J Med 2013;368:117–27. et al. TREM2 regulates microglial cell activation in response to
[134] Hickman SE, Khoury JE. TREM2 and the neuroimmunology of Alz- demyelination in vivo. Acta Neuropathol 2015;129:429–47.
heimer’s disease. Biochem Pharmacol 2014;88:495–8. [154] Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y,
[135] Jin SC, Carrasquillo MM, Benitez BA, Skorupa T, Carrell D, Patel D, Gilfillan S, et al. TREM2 sustains microglial expansion during aging
et al. TREM2 is associated with increased risk for Alzheimer’s dis- and response to demyelination. J Clin Invest 2015;125:2161–70.
ease in African Americans. Mol Neurodegener 2015;10. [155] Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A,
[136] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Beatty WL, et al. TREM2 Maintains Microglial Metabolic Fitness
Snaedal J, et al. Variant of TREM2 associated with the risk of Alz- in Alzheimer’s Disease. Cell 2017;170:649–663.e13.
heimer’s disease. N Engl J Med 2013;368:107–16. [156] Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G,
[137] Paloneva J, Mandelin J, Kiialainen A, Bohling T, Prudlo J, Hakola P, et al. TREM2 deficiency exacerbates tau pathology through dysregu-
et al. DAP12/TREM2 deficiency results in impaired osteoclast differ- lated kinase signaling in a mouse model of tauopathy. Mol Neurode-
entiation and osteoporotic features. J Exp Med 2003;198:669–75. gener 2017;12:74.
[138] Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, [157] Leyns CEG, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina
Adolfsson R, et al. Mutations in two genes encoding different sub- Serrano J, et al. TREM2 deficiency attenuates neuroinflammation and
units of a receptor signaling complex result in an identical disease protects against neurodegeneration in a mouse model of tauopathy.
phenotype. Am J Hum Genet 2002;71:656–62. Proc Natl Acad Sci U S A 2017;114:11524–9.
[139] Paloneva J, Kestila M, Wu J, Salminen A, Bohling T, [158] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-
Ruotsalainen V, et al. Loss-of-function mutations in TYROBP Szternfeld R, Ulland TK, et al. A Unique Microglia Type Associated
(DAP12) result in a presenile dementia with bone cysts. Nat with Restricting Development of Alzheimer’s Disease. Cell 2017;
Genet 2000;25:357–61. 169:1276–1290.e17.
[140] Kaneko M, Sano K, Nakayama J, Amano N. Nasu-Hakola disease: [159] Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, et al. A
The first case reported by Nasu and review. Neuropathology 2010; new class of membrane-bound chemokine with a CX3C motif. Na-
30:463–70. ture 1997;385:640–4.
[141] Bird TD, Koerker RM, Leaird BJ, Vlcek BW, Thorning DR. Lipo- [160] Umehara H, Bloom E, Okazaki T, Domae N, Imai T. Fractalkine and
membranous polycystic osteodysplasia (brain, bone, and fat disease): vascular injury. Trends Immunol 2001;22:602–7.
a genetic cause of presenile dementia. Neurology 1983;33:81–6. [161] Sheridan GK, Murphy KJ. Neuron-glia crosstalk in health and dis-
[142] Sessa G, Podini P, Mariani M, Meroni A, Spreafico R, Sinigaglia F, ease: fractalkine and CX3CR1 take centre stage. Open Biol 2013;
et al. Distribution and signaling of TREM2/DAP12, the receptor sys- 3:130181.
tem mutated in human polycystic lipomembraneous osteodysplasia [162] Landsman L, Bar-On L, Zernecke A, Kim K-W, Krauthgamer R,
with sclerosing leukoencephalopathy dementia. Eur J Neurosci Shagdarsuren E, et al. CX3CR1 is required for monocyte homeostasis
2004;20:2617–28. and atherogenesis by promoting cell survival. Blood 2009;
[143] Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, 113:963–72.
Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E [163] Lionakis MS, Swamydas M, Fischer BG, Plantinga TS, Johnson MD,
allele epsilon 4 with late-onset familial and sporadic Alzheimer’s dis- Jaeger M, et al. CX3CR1-dependent renal macrophage survival pro-
ease. Neurology 1993;43:1467–72. motes Candida control and host survival. J Clin Invest 2013;
[144] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, 123:5035–51.
Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 [164] Ponzetta A, Sciume G, Benigni G, Antonangeli F, Morrone S,
allele and the risk of Alzheimer’s disease in late onset families. Sci- Santoni A, et al. CX3CR1 regulates the maintenance of KLRG11
ence 1993;261:921–3. NK Cells into the bone marrow by promoting their entry into circu-
[145] Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, et al. lation. J Immunol 2013;191:5684–94.
Altered microglial response to A beta plaques in APPPS1-21 mice [165] Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM,
heterozygous for TREM2. Mol Neurodegener 2014;9. Dijkstra IM, et al. Control of microglial neurotoxicity by the fractal-
[146] Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, kine receptor. Nat Neurosci 2006;9:917–24.
Ransohoff RM, et al. Disease Progression-Dependent Effects of [166] Fuhrmann M, Bittner T, Jung CKE, Burgold S, Page RM,
TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease. J Mitteregger G, et al. Microglial Cx3cr1 knockout prevents neuron
Neurosci 2017;37:637–47. loss in a mouse model of Alzheimer’s disease. Nat Publishing Group
[147] Tan YJ, Ng ASL, Vipin A, Lim JKW, Chander RJ, Ji F, et al. Higher 2010;13:411–3.
peripheral TREM2 mRNA levels relate to cognitive deficits and hip- [167] Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM,
pocampal atrophy in Alzheimer’s disease and amnestic mild cogni- et al. CX3CR1 deficiency alters microglial activation and reduces
tive impairment. J Alzheimers Dis 2017;58:413–23. beta-amyloid deposition in two Alzheimer’s disease mouse models.
[148] Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, Am J Pathol 2010;177:2549–62.
et al. CD33 modulates TREM2: convergence of Alzheimer loci. Nat [168] Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang L-C,
Neurosci 2015;18:1556–8. Means TK, et al. The microglial sensome revealed by direct RNA
[149] Hu N, Tan MS, Yu JT, Sun L, Tan L, Wang YL, et al. Increased sequencing. Nat Neurosci 2013;16:1896–905.
expression of TREM2 in peripheral blood of Alzheimer’s disease pa- [169] Nishiyori A, Minami M, Ohtani Y, Takami S, Yamamoto J,
tients. J Alzheimers Dis 2014;38:497–501. Kawaguchi N, et al. Localization of fractalkine and CX3CR1 mRNAs
[150] Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, et al. in rat brain: does fractalkine play a role in signaling from neuron to
Altered microglial response to Abeta plaques in APPPS1-21 mice microglia? FEBS Lett 1998;429:167–72.
heterozygous for TREM2. Mol Neurodegener 2014;9:20. [170] Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M,
[151] Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. et al. Identification and molecular characterization of fractalkine re-
TREM2-mediated early microglial response limits diffusion and ceptor CX3CR1, which mediates both leukocyte migration and adhe-
toxicity of amyloid plaques. J Exp Med 2016;213:667–75. sion. Cell 1997;91:521–30.
588 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

[171] Limatola C, Ransohoff RM. Modulating neurotoxicity through [194] Granic I, Dolga AM, Nijholt IM, van Dijk G, Eisel ULM. Inflamma-
CX3CL1/CX3CR1 signaling. Front Cell Neurosci 2014;8:229. tion and NF-kappaB in Alzheimer’s disease and diabetes. J Alz-
[172] Zujovic V, Benavides J, Vige X, Carter C, Taupin V. Fractalkine mod- heimers Dis 2009;16:809–21.
ulates TNF-a secretion and neurotoxicity induced by microglial acti- [195] Li R, Yang L, Lindholm K, Konishi Y, Yue X, Hampel H, et al. Tumor
vation. Glia 2000;29:305–15. necrosis factor death receptor signaling cascade is required for
[173] Mizuno T, Kawanokuchi J, Numata K, Suzumura A. Production and amyloid-beta protein-induced neuron death. J Neurosci 2004;
neuroprotective functions of fractalkine in the central nervous sys- 24:1760–71.
tem. Brain Res 2003;979:65–70. [196] He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, et al.
[174] Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Deletion of tumor necrosis factor death receptor inhibits amyloid b
Sher A, et al. Analysis of Fractalkine Receptor CX3CR1 function generation and prevents learning and memory deficits in Alzheimer’s
by targeted deletion and green fluorescent protein reporter gene inser- mice. J Cell Biol 2007;178:829–41.
tion. Mol Cell Biol 2000;20:4106–14. [197] Buchhave P, Zetterberg H, Blennow K, Minthon L, Janciauskiene S,
[175] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Hansson O. Soluble TNF receptors are associated with A^Io2 meta-
Ransohoff RM, Lamb BT. Regulation of tau pathology by the micro- bolism and conversion to dementia in subjects with mild cognitive
glial fractalkine receptor. Neuron 2010;68:19–31. impairment. Neurobiol Aging 2010;31:1877–84.
[176] Fenn AM, Smith KM, Lovett-Racke AE, Guerau-de-Arellano M, [198] Chang R, Yee K-L, Sumbria RK. Tumor necrosis factor a Inhibition
Whitacre CC, Godbout JP. Increased micro-RNA 29b in the aged for Alzheimer’s Disease. J Cent Nervous Syst Dis 2017;9.
brain correlates with the reduction of insulin-like growth factor-1 117957351770927.
and fractalkine ligand. Neurobiol Aging 2013;34:2748–58. [199] Combs CK, Karlo JC, Kao SC, Landreth GE. b-Amyloid stimulation
[177] Kim T-S, Lim H-K, Lee JY, Kim D-J, Park S, Lee C, et al. Changes in of microglia and monocytes results in TNFalpha-dependent expres-
the levels of plasma soluble fractalkine in patients with mild cogni- sion of inducible nitric oxide synthase and neuronal apoptosis. J Neu-
tive impairment and Alzheimer’s disease. Neurosci Lett 2008; rosci 2001;21:1179–88.
436:196–200. [200] Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM,
[178] Cho S-H, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, et al. Gendelman HE, et al. Interferon-gamma and tumor necrosis factor-
CX3CR1 protein signaling modulates microglial activation and pro- alpha regulate amyloid-beta plaque deposition and beta-secretase
tects against plaque-independent cognitive deficits in a mouse model expression in Swedish mutant APP transgenic mice. Am J Pathol
of Alzheimer disease. J Biol Chem 2011;286:32713–22. 2007;170:680–92.
[179] Padgett CL, Slesinger PA. GABAB receptor coupling to G-proteins [201] Basu A, Krady JK, Levison SW. Interleukin-1: A master regulator of
and ion channels. Adv Pharmacol 2010;58:123–47. neuroinflammation. J Neurosci Res 2004;78:151–6.
[180] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. [202] Forlenza OV, Diniz BS, Talib LL, Mendonça VA, Ojopi EB,
Cell 2016;164:603–15. Gattaz WF, et al. Increased serum IL-1beta level in Alzheimer’s dis-
[181] Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, et al. ease and mild cognitive impairment. Demen Geriatr Cogn Disord
GABA from reactive astrocytes impairs memory in mouse models 2009;28:507–12.
of Alzheimer’s disease. Nat Med 2014;20:886. [203] Di Bona D, Plaia A, Vasto S, Cavallone L, Lescai F, Franceschi C,
[182] Kim YS, Yoon B-E. Altered GABAergic signaling in brain disease at et al. Association between the interleukin-1b polymorphisms and
various stages of life. Exp Neurobiol 2017;26:122–31. Alzheimer’s disease: A systematic review and meta-analysis. Brain
[183] Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H. Implications of GABAer- Res Rev 2008;59:155–63.
gic Neurotransmission in Alzheimer’s disease. Front Aging Neurosci [204] Cacabelos R, Alvarez XA, Fernandez-Novoa L, Franco A,
2016;8. Mangues R, Pellicer A, et al. Brain interleukin-1 beta in Alzheimer’s
[184] Wu Z, Guo Z, Gearing M, Chen G. Tonic inhibition in dentate gyrus disease and vascular dementia. Methods Findings Exp Clin Pharma-
impairs long-term potentiation and memory in an Alzhiemer’s dis- col 1994;16:141–51.
ease model. Nat Commun 2014;5:4159. [205] Farrar WL, Kilian PL, Ruff MR, Hill JM, Pert CB. Visualization and
[185] Heaney CF, Kinney JW. Role of GABA(B) receptors in learning and characterization of interleukin 1 receptors in brain. J Immunol 1987;
memory and neurological disorders. Neurosci Biobehav Rev 2016; 139:459–63.
63:1–28. [206] Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA,
[186] Lee M, Schwab C, Mcgeer PL. Astrocytes are GABAergic cells that Gandy SE, et al. Cholinergic agonists and interleukin 1 regulate pro-
modulate microglial activity. Glia 2011;59:152–65. cessing and secretion of the Alzheimer beta/A4 amyloid protein pre-
[187] Kuhn SA, van Landeghem FK, Zacharias R, F€arber K, Rappert A, cursor. Proc Natl Acad Sci U S A 1992;89:10075–8.
Pavlovic S, et al. Microglia express GABA B receptors to modulate [207] Chong Y. Effect of a carboxy-terminal fragment of the Alzheimer’s
interleukin release. Mol Cell Neurosci 2004;25:312–22. amyloid precursor protein on expression of proinflammatory cyto-
[188] Carson MJ, Thrash JC, Walter B. The cellular response in neuroin- kines in rat glial cells. Life Sci 1997;61:2323–33.
flammation: The role of leukocytes, microglia and astrocytes in [208] Barger SW, Harmon AD. Microglial activation by Alzheimer amy-
neuronal death and survival. Clin Neurosci Res 2006;6:237–45. loid precursor protein and modulation by apolipoprotein E. Nature
[189] Karve IP, Taylor JM, Crack PJ. The contribution of astrocytes 1997;388:878–81.
and microglia to traumatic brain injury. Br J Pharmacol 2016; [209] Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and
173:692–702. anti-inflammatory properties of the cytokine interleukin-6. Biochim
[190] Yoon B-E, Woo J, Chun Y-E, Chun H, Jo S, Bae JY, et al. Glial Biophys Acta 2011;1813:878–88.
GABA, synthesized by monoamine oxidase B, mediates tonic inhibi- [210] Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6
tion. J Physiol 2014;592:4951–68. signaling in nervous tissue. Biochim Biophys Acta 2016;
[191] Le Meur K, Mendizabal-Zubiaga J, Grandes P, Audinat E. 1863:1218–27.
GABA release by hippocampal astrocytes. Front Comput Neuro- [211] Singh-Manoux A, Dugravot A, Brunner E, Kumari M, Shipley M,
sci 2012;6. Elbaz A, et al. Interleukin-6 and C-reactive protein as predictors of
[192] Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B, et al. cognitive decline in late midlife. Neurology 2014;83:486–93.
Elevated circulating tumor necrosis factor levels in Alzheimer’s dis- [212] Blum-Degena D, M€uller T, Kuhn W, Gerlach M, Przuntek H,
ease. Neurosci Lett 1991;129:318–20. Riederer P. Interleukin-1b and interleukin-6 are elevated in the cere-
[193] Perry R. The role of TNF and its receptors in Alzheimer’s disease. brospinal fluid of Alzheimer“s and de novo Parkinson’s disease pa-
Neurobiol Aging 2001;22:873–83. tients. Neurosci Lett 1995;202:17–20.
 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590 589

[213] Dursun E, Gezen-Ak D, Hanagası H, Bilgiç B, Lohmann E, Ertan S, [232] Caraci F, Spampinato S, Sortino MA, Bosco P, Battaglia G, Bruno V,
et al. The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and et al. Dysfunction of TGF-b1 signaling in Alzheimer’s disease: per-
alpha-2-macroglobulin serum levels in patients with early or late spectives for neuroprotection. Cell Tissue Res 2012;347:291–301.
onset Alzheimer’s disease, mild cognitive impairment or Parkinson”s [233] Juraskova B, Andrys C, Holmerova I, Solichova D, Hrnciarikova D,
disease. J Neuroimmunol 2015;283:50–7. Vankova H, et al. Transforming growth factor beta and soluble endo-
[214] Hampel H, Haslinger A, Scheloske M, Padberg F, Fischer P, Unger J, glin in the healthy senior and in Alzheimer’s disease patients. J Nutr
et al. Pattern of interleukin-6 receptor complex immunoreactivity be- Health Aging 2010;14:758–61.
tween cortical regions of rapid autopsy normal and Alzheimer’s dis- [234] Mocali A, Cedrola S, Della Malva N, Bontempelli M, Mitidieri VAM,
ease brain. Eur Arch Psychiatry Clin Neurosci 2005;255:269–78. Bavazzano A, et al. Increased plasma levels of soluble CD40,
[215] Huell M, Strauss S, Volk B, Berger M, Bauer J. Interleukin-6 is pre- together with the decrease of TGFb1, as possible differential markers
sent in early stages of plaque formation and is restricted to the brains of Alzheimer disease. Exp Gerontol 2004;39:1555–61.
of Alzheimers disease patients. Acta Neuropathol 1995;89:544–51. [235] Diniz LP, Tortelli V, Matias I, Morgado J, Araujo APB, Melo HM,
[216] Ringheim GE, Szczepanik AM, Petko W, Burgher KL, Zhu SZ, et al. Astrocyte transforming growth factor beta 1 protects synapses
Chao CC. Enhancement of beta-amyloid precursor protein transcrip- against Ab Oligomers in Alzheimer’s disease model. J Neurosci
tion and expression by the soluble interleukin-6 receptor/interleukin- 2017;37:6797–809.
6 complex. Brain Research. Mol Brain Res 1998;55:35–44. [236] Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB,
[217] Hayden MS, West AP, Ghosh S. NF-kB and the immune response. et al. Risk factors for Alzheimer’s disease: a prospective analysis
Oncogene 2006;25:6758–80. from the Canadian study of health and aging. Am J Epidemiol
[218] Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C. 2002;156:445–53.
Transcription factor NF-kB is activated in primary neurons by amy- [237] Kivipelto M1, Helkala EL, Laakso MP, H€anninen T, Hallikainen M,
loid b peptides and in neurons surrounding early plaques from pa- Alhainen K, et al. Midlife vascular risk factors and Alzheimer’s dis-
tients with Alzheimer disease. Proc Natl Acad Sci U S A 1997; ease in later life: longitudinal, population based study. BMJ 2001;
94:2642–7. 322:1447–51.
[219] Sambamurti K, Kinsey R, Maloney B, Ge Y-W, Lahiri DK. Gene [238] Mortimer JA, Van Duiin CM, Chandra V, Fratiglioni L, Graves AB,
structure and organization of the human beta-secretase (BACE) pro- Heyman A, et al. Head trauma as a risk factor for Alzheimer’s dis-
moter. FASEB J 2004;18:1034–6. ease: A collaborative re-analysis of case-control studies. Int J Epide-
[220] Tobe M, Isobe Y, Tomizawa H, Nagasaki T, Takahashi H, miol 1991;20:S28–35.
Fukazawa T, et al. Discovery of quinazolines as a novel structural [239] Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A.
class of potent inhibitors of NF-kappa B activation. Bioorg Med Head injury as a risk factor for Alzheimer’s disease: the evidence
Chem 2003;11:383–91. 10 years on; a partial replication. J Neurol Neurosurg Psychiatry
[221] Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, 2003;74:857–62.
et al. NSAIDs and enantiomers of flurbiprofen target gamma- [240] Thakur MK, Sivanandam TM. Traumatic brain injury: A risk factor
secretase and lower Abeta 42 in vivo. J Clin Invest 2003;112:440–9. of Alzheimer’s disease. Neurosci Biobehav Rev 2012;36:1376–81.
[222] Sung S, Yang H, Uryu K, Lee EB, Zhao L, Shineman D, et al. Mod- [241] Djordievic J, Sabbir MG, Albensi BC. Traumatic brain injury as a risk
ulation of nuclear factor-kappa B activity by indomethacin influences factor for Alzheimer’s disease: is inflammatory signaling a key
A beta levels but not A beta precursor protein metabolism in a model player? Curr Alzheimer Res 2016;13:730–8.
of Alzheimer’s disease. Am J Pathol 2004;165:2197–206. [242] Mosconi L. Brain glucose metabolism in the early and specific diag-
[223] Szczepanik AM, Funes S, Petko W, Ringheim GE. IL-4, IL-10 and nosis of Alzheimer?s disease. Eur J Nucl Med Mol Imaging 2005;
IL-13 modulate A beta(1–42)-induced cytokine and chemokine pro- 32:486–510.
duction in primary murine microglia and a human monocyte cell line. [243] Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E,
J Neuroimmunol 2001;113:49–62. Tremblay S, et al. Brain fuel metabolism, aging, and Alzheimer’s dis-
[224] D’Anna L, Abu-Rumeileh S, Fabris M, Pistis C, Baldi A, Sanvilli N, ease. Nutrition 2011;27:3–20.
et al. Serum Interleukin-10 Levels Correlate with Cerebrospinal Fluid [244] Chen Z, Zhong C. Decoding Alzheimer’s disease from perturbed ce-
Amyloid Beta Deposition in Alzheimer Disease Patients. Neuro- rebral glucose metabolism: Implications for diagnostic and therapeu-
Degenerative Dis 2017;17:227–34. tic strategies. Prog Neurobiol 2013;108:21–43.
[225] Michaud J-P, Rivest S. Anti-inflammatory Signaling in Microglia Ex- [245] Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC.
acerbates Alzheimer’s Disease-Related Pathology. Neuron 2015; Increased risk of type 2 diabetes in Alzheimer disease. Diabetes
85:450–2. 2004;53:474–81.
[226] Guillot-Sestier M-V, Doty KR, Gate D, Rodriguez J, Yan Leung BP, [246] Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk
Rezai-Zadeh K, et al. Il10 deficiency re-balances innate immunity to of dementia in diabetes mellitus: a systematic review. Lancet Neurol
mitigate Alzheimer-like pathology. Neuron 2015;85:534–48. 2006;5:64–74.
[227] Lio D, Licastro F, Scola L, Chiappelli M, Grimaldi LM, Crivello A, [247] Kloppenborg RP, van den Berg E, Kappelle LJ, Biessels GJ. Diabetes
et al. Interleukin-10 promoter polymorphism in sporadic Alzheimer’s and other vascular risk factors for dementia: Which factor matters
disease. Genes Immun 2003;4:234–8. most? A systematic review. Eur J Pharmacol 2008;585:97–108.
[228] Zhang Y, Zhang J, Tian C, Xiao Y, Li X, He C, et al. The -1082G/A [248] Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM.
polymorphism in IL-10 gene is associated with risk of Alzheimer’s Diabetes mellitus and the risk of dementia: The Rotterdam Study.
disease: a meta-analysis. J Neurol Sci 2011;303:133–8. Neurology 1999;53:1937–42.
[229] Chao CC, Hu S, Frey WH, Ala TA, Tourtellotte WW, Peterson PK. [249] Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, et al.
Transforming growth factor beta in Alzheimer’s disease. Clin Diagn Glucose tolerance status and risk of dementia in the community:
Lab Immunol 1994;1:109–10. the Hisayama study. Neurology 2011;77:1126–34.
[230] Grammas P, Ovase R. Cerebrovascular Transforming Growth Factor- [250] Huang C-C, Chung C-M, Leu H-B, Lin L-Y, Chiu C-C, Hsu C-Y,
b Contributes to Inflammation in the Alzheimer’s Disease Brain. Am et al. Diabetes Mellitus and the Risk of Alzheimer’s Disease: A
J Pathol 2002;160:1583–7. Nationwide Population-Based Study. PLoS One 2014;9:e87095–7.
[231] Masliah E, Ho G, Wyss-Coray T. Functional role of TGF beta in Alz- [251] Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, et al.
heimer’s disease microvascular injury: lessons from transgenic mice. Diabetes Mellitus and Risk of Developing Alzheimer Disease Results
Neurochem Int 2001;39:393–400. From the Framingham Study. Arch Neurol 2006;63:1551.
590 J.W. Kinney et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 575-590

[252] Cheng D, Noble J, Tang MX, Schupf N, Mayeux R, Luchsinger JA. [267] Swardfager W, Lanct^ot K, Rothenburg L, Wong A, Cappell J,
Type 2 diabetes and late-onset Alzheimer’s disease. Dement Geriatr Herrmann N. A Meta-Analysis of Cytokines in Alzheimer’s Disease.
Cogn Disord 2011;31:424–30. Biol Psychiatry 2010;68:930–41.
[253] Yalow RS, Berson SA. Immunoassay of endogenous plasma insulin [268] Gutierrez EG, Banks WA, Kastin AJ. Murine tumor necrosis factor
in man. J Clin Invest 1960;39:1157–75. alpha is transported from blood to brain in the mouse. J Neuroimmu-
[254] Bonadonna RC, De Fronzo RA. Glucose metabolism in obesity and nol 1993;47:169–76.
type 2 diabetes. Diabete & Metabolisme 1991;17:112–35. [269] Banks WA, Kastin AJ, Broadwell RD. Passage of Cytokines
[255] Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, la Monte across the Blood-Brain Barrier. Neuroimmunomodulation 1995;
de SM. Insulin and insulin-like growth factor expression and function 2:241–8.
deteriorate with progression of Alzheimer’s disease: link to brain re- [270] Davidson TL, Monnot A, Neal AU, Martin AA, Horton JJ, Zheng W.
ductions in acetylcholine. J Alzheimer’s Dis 2005;8:247–68. The effects of a high-energy diet on hippocampal-dependent discrim-
[256] Steen E, Terry BM, J Rivera E, Cannon JL, Neely TR, Tavares R, ination performance and blood–brain barrier integrity differ for diet-
et al. Impaired insulin and insulin-like growth factor expression induced obese and diet-resistant rats. Physiol Behav 2012;
and signaling mechanisms in Alzheimer’s disease – is this type 3 dia- 107:26–33.
betes? J Alzheimer’s Dis 2005;7:63–80. [271] Freeman LR, Granholm A-CE. Vascular changes in rat hippocampus
[257] la Monte de SM, Neely TR, Cannon J, Wands JR. Ethanol impairs following a high saturated fat and cholesterol diet. J Cereb Blood
insulin-stimulated mitochondrial function in cerebellar granule neu- Flow Metab 2011;32:643–53.
rons. Cell Mol Life Sci 2001;58:1950–60. [272] Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A,
[258] Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, la Monte et al. Obesity in Aging Exacerbates Blood-Brain Barrier Disruption,
de SM. Intracerebral streptozotocin model of type 3 diabetes: Rele- Neuroinflammation, and Oxidative Stress in the Mouse Hippocam-
vance to sporadic Alzheimer’s disease. J Alzheimer’s Dis 2006; pus: Effects on Expression of Genes Involved in Beta-Amyloid Gen-
9:13–33. eration and Alzheimer’s Disease. J Gerontol Ser A Biol Sci Med Sci
[259] De Felice FG, Vieira MNN, Bomfim TR, Decker H, Velasco PT, 2014;69:1212–26.
Lambert MP, et al. Protection of synapses against Alzheimer’s-linked [273] Perry VH, Holmes C. Microglial priming in neurodegenerative dis-
toxins: insulin signaling prevents the pathogenic binding of Abeta ease. Nat Publishing Group 2014;10:217–24.
oligomers. Proc Natl Acad Sci U S A 2009;106:1971–6. [274] Kim D-G, Krenz A, Toussaint LE, Maurer KJ, Robinson S-A,
[260] Li W, Risacher SL, Gao S, Boehm SL II, Elmendorf JS, Saykin AJ, Yan A, et al. Non-alcoholic fatty liver disease induces signs of
et al. Type 2 diabetes mellitus and cerebrospinal fluid Alzheimer’s Alzheimer’s disease (AD) in wild-type mice and accelerates path-
disease biomarker Ab1-42 in Alzheimer’s Disease Neuroimaging ological signs of AD in an AD model. J Neuroinflammation
Initiative participants. Alzheimer’s & Dementia: Diagnosis, Assess- 2016;13:1.
ment & Disease Monitoring 2017;10:94–8. [275] Ledo JH, Azevedo EP, Beckman D, Ribeiro FC, Santos LE,
[261] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression Razolli DS, et al. Cross talk between brain innate immunity and
of tumor necrosis factor-alpha: direct role in obesity-linked insulin serotonin signaling underlies depressive-like behavior induced by
resistance. Science (New York, N.Y.) 1993;259:87–91. Alzheimer’s amyloid- oligomers in mice. J Neurosci 2016;
[262] Roytblat L, Rachinsky M, Fisher A, Greemberg L, Shapira Y, 36:12106–16.
Douvdevani A, et al. Raised interleukin-6 levels in obese patients. [276] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer
Obes Res 2000;8:673–5. disease: risk, mechanisms and therapy. Nat Rev Neurol 2013;
[263] Koenig W, Khuseyinova N, Baumert J, Thorand B, Loewel H, 9:106–18.
Chambless L, et al. Increased concentrations of C-reactive protein [277] Dorey E, Chang N, Liu QY, Yang Z, Zhang W. Apolipoprotein E,
and IL-6 but not IL-18 are independently associated with incident amyloid-beta, and neuroinflammation in Alzheimer’s disease. Neuro-
coronary events in middle-aged men and women: results from the sci Bull 2014;30:317–30.
MONICA/KORA Augsburg case-cohort study, 1984-2002. Arterios- [278] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA,
cler Thromb Vasc Biol 2006;26:2745–51. Mayeux R, et al. Effects of age, sex, and ethnicity on the association
[264] Nieto-Vazquez I, Fernandez-Veledo S, Kr€amer DK, Vila-Bedmar R, between apolipoprotein E genotype and Alzheimer disease. A meta-
Garcia-Guerra L, Lorenzo M. Insulin resistance associated to obesity: analysis. APOE and Alzheimer Disease Meta Analysis Consortium.
the link TNF-alpha. Arch Physiol Biochem 2008;114:183–94. JAMA 1997;278:1349–56.
[265] Bermejo P, Martın-Aragon S, Benedı J, Susın C, Felici E, Gil P, et al. [279] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El
Differences of peripheral inflammatory markers between mild cogni- Fatimy R, et al. The TREM2-APOE pathway drives the transcrip-
tive impairment and Alzheimer’s disease. Immunol Lett 2008; tional phenotype of dysfunctional microglia in neurodegenerative
117:198–202. diseases. Immunity 2017;47:566–581.e9.
[266] van Himbergen TM. Biomarkers for Insulin Resistance and Inflam- [280] Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role
mation and the Risk for All-Cause Dementia and Alzheimer Disease. of APOE ε4 in modulating effects of other risk factors for cognitive
Arch Neurol 2012;69:594–617. decline in elderly persons. JAMA 1999;282:40–6.