Journal of Clinical Neuroscience 59 (2019) 6–11

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Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Review article

Influence of microglia and astrocyte activation in the neuroinflammatory

pathogenesis of Alzheimer’s disease: Rational insights for the
therapeutic approaches
Mir Hilal Ahmad, Mahino Fatima, Amal Chandra Mondal ⇑
Cellular and Molecular Neurobiology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India

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

Article history: Alzheimer’s disease (AD), the most common progressive neurodegenerative disorder is characterized by
Received 23 May 2018 the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). Increasing
Accepted 5 October 2018 evidences suggest a link between neuroinflammation and neuronal dysfunction in AD, orchestrated by
the progressive activation of microglial cells and astrocytes with the consequent overproduction of proin-
flammatory molecules. The concomitant release of anti-inflammatory mediators antagonizes the inflam-
Keywords: matory processes and leading to the severity of the AD pathology. The simultaneous detection of these
Alzheimer’s disease
inflammatory molecules in the pre-symptomatic stage may help in the early diagnosis of the AD. We have
Neuroinflammation
Cytokines
discussed the impact of microglia and astrocytic cells, the principal agents in the neuroinflammation pro-
Microglia cess, in relation to the progression of the AD. Modulation of the risk factors and targeting of these
Astrocytes immune mechanisms could lead to better therapeutic or preventive strategies for the AD. Further studies
need to determine, how the inhibition of inflammatory factors could be used for the AD alternative
therapies.
Ó 2018 Elsevier Ltd. All rights reserved.

1. Introduction Neuroinflammation in the AD is considered as a double-edged

AD, the most common chronic neurodegenerative dementia
[1–3] is characterized by the presence of intra and extracellular
protein aggregates [2]. Extracellular protein aggregates correspond
to the amyloid plaques, mainly composed of a 39 to 42 amino acids
peptide called b-amyloid (Ab), generated by abnormal proteolytic
cleavage of the amyloid precursor protein (APP) by beta and
gamma secretases [4]. These amyloid plaques accumulate around
neurons which cause abnormalities in synaptic functioning, dis-
rupt the mitochondrial functioning and decreased levels one of
the key neurotransmitters such as acetylcholine [5]. Intracellular
protein aggregates correspond to the NFTs produced by the accu-
mulation of paired helical filaments (PHF), generated by the aber-
rantly phosphorylated tau proteins [6–8]. Deposition of NFTs leads
to the neuronal cell death, destabilization of microtubules and
membrane degeneration [7–9]. Alongside the amyloid plaques,
NFTs and atrophy of the brain, the neuroinflammation triggered
by the central nervous system (CNS) as innate the immune
response, plays a significant role in the pathogenesis of AD [2,4].
The activity in the inflammatory cascades can be a response to
AD neuropathology [10].
⇑ Corresponding author.
E-mail address: acmondal@mail.jnu.ac.in (A.C. Mondal).
sword where the immune cells of the brain have beneficial effects
by degrading Ab accumulation as well as the adverse effects by
producing cytotoxic substances that exacerbate Ab deposition
resulting in the neuronal dysfunctions [6,11]. High expression of
inflammatory mediators has been reported around the Ab plaques
and NFTs exemplifying the relationship between neuroinflamma-
tion and AD pathology [2]. In the early stages of the AD, neuropro-
tective pathways, such as amyloid plaque clearance and
antioxidant mechanisms against reactive oxygen species (ROS)
generation, are very effective [12]. But with the progression of
AD, the elevated degree of oxidative stress up-regulates cellular
mediators of the immune system, resulting in the overproduction
of pro-inflammatory molecules, and inflammation in the brain
[13]. Cells in the CNS such as microglia, astrocytes and neurons
constitute the basis for neuroinflammation [14]. Microglial activa-
tion is one of the early events in the AD pathology which results in
the increased pro-inflammatory effects and leading cause of neuro-
toxicity [15–17].
Activated microglia can results in the AD progression through a
sequence of overactivation and up-regulation of proinflammatory
factors, oxidative stress and ultimately neuroinflammation
[18–20]. The induction of microglia-induced inflammatory
response results in the release of neurotoxic cytokines [21]. The
persistent microglia activation and the subsequent release of

https://doi.org/10.1016/j.jocn.2018.10.034
0967-5868/Ó 2018 Elsevier Ltd. All rights reserved.
 M.H. Ahmad et al. / Journal of Clinical Neuroscience 59 (2019) 6–11
pro-inflammatory cytokines induce a cascade of neurotoxic
changes leading to the AD onset/progression [22]. Astrocytes are
also suggested to play a key role in the AD progression. Ab plaques
also activate astrocytes which results in the overexpression of
cytokines (e.g., IL-1b or IL-6) and a higher degree of oxidative stress
[13]. The dysfunctions between the astrocytes and the surrounding
neurons disrupt the synaptic connections and initiate a cascade of
neuronal injury [23–24].
Astrocytes engulf the oligomer forms of the Ab, however, they
get accumulated resulting in the extracellular annular protofibrils
which cause elevated oxidative stress and loss of neurons
[25–26]. Neurons are also suggested to be involved in neuroinflam-
mation, by increasing the expression and production of the
inflammatory molecules [27–28]. Neurons produce an inflamma-
tory response by exacerbating local inflammatory reactions
resulting in their own destruction [29]. In this review, we have
addressed on how neuroinflammatory processes are directly
related to AD progression. Moreover, we have discussed the
implications of the involvement of microglia and astrocytes in both
the inflammatory and neuro-immunomodulatory processes during
the AD progression
2. Microglial activation in the AD progression
Microglia are the brain’s resident immune cells which are found
throughout the brain, spinal cord, retina and optic nerves but
mainly in the hippocampus and substantia nigra [2,15]. Functions
of the microglial cells in the CNS appear to be complex as they
exhibit both neuroprotective and neurotoxic effects. It is precisely
this delicate balance between the neurotoxic and neuroprotective
and between proinflammatory and anti-inflammatory which
determines the role of microglia in AD onset/progression. In their
resting form, they perform neurogenesis, neuroprotection and
synaptic pruning, which is complement dependent [30–31], but
their persistent over activation results in the ineffective Ab deposi-
tion clearance by microglia resulting in a proinflammatory state
[32–34]. Activated microglia produce and secrete several proin-
flammatory mediators, [18–20,35] including tumor necrosis
Fig. 1. Possible role of microglia/astrocytes in the onset/progression of the AD pathology through cytokines mediated neuro-inflammation.
7
factor-a (TNF-a), interleukin (IL)-6, and nitric oxide (NO, which
confer the AD onset/progression [21].
In the past decades, many studies have focused on the under-
standing of mechanisms of microglial activation in response to
neuropathological conditions in vivo and in vitro. During AD pro-
gression, the microglia respond to various stimuli, including amy-
loid beta peptides and NFTs [36]. The persistent classical form of
microglial activation occurs by many receptors, including scav-
enger receptor class A type 1, MARCO, scavenger receptor class B
member 1, CD36, and the receptor for advanced glycation end pro-
duct [37–38]. G protein-coupled receptors formyl peptide receptor
2 and chemokine-like receptor 1, TLR2 [39–40] toll-like receptors
(TLRs) [41] TLR4, and the CD14 co-receptor, and a6b1 integrin [42].
The association between Ab deposits and these receptors results
in the production of inflammatory mediators such as cytokines
(interleukin [IL]-1a, IL-1b, IL-6, IL-8, IL-12, IL-18, and IL-23, inter-
feron (IFN)-c, TNF-a, and granulocyte-macrophage colony-
stimulating-factor (GMCSF) [43–44], chemokines (monocyte
chemotactic protein 1 (MCP1), MCP-113, fractalkine) [45–46],
CD36 receptors [47], and NOD-like receptors (NLRs). The TNF-a
level is found proximal to amyloid plaques in an elevated level in
the AD patients which reflecting of disease severity and contribut-
ing to the inflammatory milieu [48]. IL-1b levels elevated during
the progression of AD especially in response to the tau protein
over-expression [49]. Exposure of cultured human brain endothe-
lial cells to Ab1–40 elicited expression of inflammatory molecules
IL-1b and IL-6 during AD progression [50]. The levels of IL-18
increased significantly in different regions of AD brains, where it
co-localized with Ab-plaques, IL-8 also increases expression of
glycogen synthase kinase-3b (GSK-3b) and cyclin-dependent
kinase 5 (cdk5), involved in hyperphosphorylation of tau-protein
[51]. Additionally, IL-12 and IL-23, which are known to be pro-
duced by leucocytes, are produced by microglia in the mouse mod-
els of AD [52] and inhibition of these cytokines reduces AD
pathology [53]. This classical activation of microglia leads to the
adaptive immune response by expressing major histocompatibility
class II (MHC-II) molecules and interaction with the T-cells [54].
Besides the proinflammatory molecules, activated microglia also
8 M.H. Ahmad et al. / Journal of Clinical Neuroscience 59 (2019) 6–11
Fig. 2. Possible influence of the pro-inflammatory cytokines released by activated microglia/astrocytes in the neuroinflammation, neuronal death and neurodegeneration
during the AD pathology.
release cytotoxic factors such as superoxide radicals (O
2 ), NO and
ROS [55–56], therefore activated microglia play a crucial role in the
innate immunity and are the main source of proinflammatory
molecules leading to the neuroinflammation during the AD pathol-
ogy. The possible mechanism of activated microglia in the neuroin-
flammation during the AD pathology is given in Figs. 1, 2, and
Table 1.
3. Astroglial activation in the AD onset/progression
Astrocytes located in the CNS support the endothelial cells of
the blood-brain barrier (BBB), maintain ion balance, and provide
nutrients to the neurons [2]. In AD brains, there are clear signs of
astrogliosis (increased number of astrocytes) around Ab deposits
[57–58]. Like microglia, astrocytes release cytokines, ILs, NO,
and other potentially cytotoxic molecules after exposure to Ab,
thereby exacerbating the neuroinflammatory response. Pathological
astrocytes observed in the brains of patients with dementia were
initially analyzed by Dr. Alois Alzheimer, which found abundant
glial cells in the neuritic plaques [2]. A more detailed analysis of
astrogliosis in the brains obtained from elderly patients (with
and without AD confirmed) has shown a correlation between the
degree of astrogliosis and cognitive impairment.
Ab deposits can activate the astrocytes, leads to the over-
expression of cytokines (e.g., IL-1b or IL-6) resulting in oxidative
stress. Astrocytes damage and dysfunctions between astrocytes
and the surrounding neurons can destroy the synaptic homeostasis
and initiate the cascade for neuronal injury [23–24]. These mech-
anisms could result in enhanced ROS production and loss of astro-
cytes and eventually the death of neurons [59–60].
During AD pathology, astrocytes start to express BACE 1, thus
acquiring Ab producing ability [61]. Brains at the later stages of
the AD, astrogliosis was observed in both the human tissues and
in the brains isolated from AD animal models [57,62]. Large
 M.H. Ahmad et al. / Journal of Clinical Neuroscience 59 (2019) 6–11
Table 1
The impact of microglia and astrocytes in the AD pathogenesis mediated by pro-inflammatory cytokines.
CNS origin Pro-inflammatory cytokines
Microglia TNF-a
Astrocyte
Microglia IL-1b
Astrocytes
Microglia IL-6, IL-8
Astrocytes
Microglia IL-18, IL-23
Astrocytes
numbers of astrocytes associated with Ab deposits in AD brain
regions suggesting that these lesions can generate chemotactic
molecules that induce recruitment of astrocytes. It has been found
that astrocytes throughout the entorhinal cortex of AD patients
gradually accumulate Ab1–42 positive material and the amount of
this material is positively correlated with the extent of local AD
pathology. Ab1–42 within these astrocytes appears to be of neuronal
origin, possibly accumulated by phagocytosis of locally degener-
ated dendrites and synapses, especially in the cortical molecular
layer [63]. In support of this finding, recent evidences suggest that
astroglial cells are able to phagocytize Ab peptides, a process which
may depend on their ApoE status, suggesting that ApoE polymor-
phisms may influence the risk to develop AD by affecting astroglial
Ab phagocytosis [64]. With the established fact that Ab deposition
is a potent glial activator, therefore astrocytes and microglial acti-
vation could be an early event in the disease process, occurring
even in the absence of focal Ab deposition [65]. AD is associated
with specific damage to astroglia, which may occur at the early
stages of the disease and contribute to cognitive abnormalities
[57]. Additionally, synchronous hyperactivity and intercellular
Ca2+ waves have been observed in astrocytes in response to AD,
both in vivo and in vitro [66–67]. A possible mechanism of astro-
cytes in inflammation in AD pathogenesis is given in Figs. 1, 2,
and Table 1.
4. Therapeutic strategies for targeting neuroinflammation in AD
pathology
The Ab accumulation and tau kinase activity can be decreased
by using IL-1b or TNF-a/TNF-a, receptor peroxisome proliferator-
activated receptor gamma (PPARc) agonists, cannabinoids,
minocycline or nicergoline and tyrosine kinase inhibitors.
[4,43,68–71]. For example, galantamine, an acetylcholinesterase
inhibitor engages the nicotinic acetylcholine receptor a7 and can
thereby increase the microglial uptake of Ab [72]. Likewise, PPARc
represents another factor that can be targeted by existing drugs,
like thiazolidinedione class of antidiabetics [73]. The treatment of
APP/PS1 mice with PPAR-c agonists rapidly removes Ab by micro-
glia and, presumably astrocytes [74]. The possible mechanisms for
this may be the direct up-regulation of microglial CD36 expression
[75] and lipidation of apolipoprotein E dependent on transcription
factors of the LXR family [74]. Similarly, minocycline has been
demonstrated to prevent the buildup of Ab deposition, reducing
caspase-3 activation and BACE1 levels in mice model of AD [76].
Various epidemiological studies demonstrated that the use of
non-steroidal anti-inflammatory drugs (NSAIDs) showed the pro-
tective effect in AD patients [7,77]. Both in vitro and in vivo studies
9
Effect on AD progression References
"tau hyperphosphorylation [85–86]
" nitric oxide
"Ab synthesis; ;Ab clearance
" tau phosphorylation [32,68,87–89]
; tau pathology
" APP transcription and transduction in neurons
"Ab synthesis
;Ab related pathology
"tau hyperphosphorylation [90–92]
"production of APP
"Ab production
"tau hyperphosphorylation [51,93–94]
" GSK-3b expression
"Cdk5 expression
"production of APP
"Ab production
have shown that pharmacological inhibition of (cyclooxigenase-2)
COX-2 and inducible NO synthase have shown promising results
[78–82]. Ibuprofen reduced amyloid beta deposition and tau hyper
phosphorylation in the hippocampus in transgenic (Tg) mouse
models [82]. Likewise, a clinical trial with naproxen reduced the
tau phosphorylation and Ab levels in cerebrospinal fluid and
plasma [83]. NSAIDs may decrease the AD progression reducing
the inflammatory processes in the brain, by inhibiting the inflam-
matory response of microglial and/or astrocytes, reducing cell
death due to excitotoxicity mediated by glutamate [2]. Lastly,
modulating the GSK-3b activity can be potential alternative thera-
peutic target to consider [84].
5. Conclusions and future research directions
The production of neuro-inflammation which appears to be an
early biomarker significantly contributes to the progression of
the AD. The concomitant release of anti-inflammatory mediators
sometimes antagonizes the inflammatory processes and leading
to the severity of the disease. Strategies, such as the interruption
of defective inflammatory pathways or microglial stimulation,
which may increase the Ab clearance, could be successful. Several
cytokines and other inflammatory molecules have been described
as possible target candidates for AD therapies, but additional stud-
ies are needed to clarify, how they could contribute to alternative
therapies of different neurodegenerative diseases. Blocking gene
expression of targeted cytokines, their receptors, or better regulat-
ing the functioning of cells implicated in the neuroinflammation
are strategies still in exploration. Some therapeutic strategies or
dietary recommendations can be implemented as a preventive
measure which successfully targets the ongoing inflammation.
Another crucial factor is the comprehension of the role of each cel-
lular component in the inflammatory process, for example, the
identification of cell-specific biomarkers. Indeed, specifically clari-
fying changes in both immune system and inflammatory machin-
ery would make available different pathways for pharmacological
manipulations aimed at delaying the onset and/or the progression
of the AD. Finally, it is important to recognize each phase to AD
progression and to clarify which processes are protective and
which ones are detrimental. This will help to achieve more focused
and functional therapeutic strategies against AD progression.
Acknowledgements
ACM gratefully acknowledges the financial support from JNU
UPE-II (Project Id-247), DST-PURSE-II, DBT (BT/PR16164/
NER/95/88/2015), Ministry of Science and Technology (Govt. of
10 M.H. Ahmad et al. / Journal of Clinical Neuroscience 59 (2019) 6–11

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