Astrocytes and neuroinflammation in Alzheimer’s disease
Emma C Phillips1, Cara Croft1, Ksenia Kurbatskaya1, Michael J O’Neill2, Michael L Hutton2,
Diane P Hanger1, Claire J Garwood3*, Wendy Noble1*a
King’s College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny
Park, London, UK.
1
2
Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, UK.
Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University
of Sheffield, Sheffield, UK.
3
*These authors contributed equally to this work.
a
Corresponding author:
Dr Wendy Noble, Department of Neuroscience, King’s College London, Institute of
Psychiatry, De Crespigny Park, London, UK. Tel: 020 7848 0578. Email:
wendy.noble@kcl.ac.uk.
Keywords: Alzheimer’s disease, tauopathy, astrocyte, glia, inflammation
Abstract
Increased production of β-amyloid (Aβ) and altered processing of tau in Alzheimer’s disease
are associated with synaptic dysfunction, neuronal death, cognitive and behavioural deficits.
Neuroinflammation is also a prominent feature of Alzheimer brain and considerable evidence
indicates that inflammatory events play a significant role in modulating the progression of
AD. The role of microglia in AD inflammation has long been acknowledged. Substantial
evidence now demonstrates that astrocyte-mediated inflammatory responses also influence
pathology development, synapse health and neurodegeneration in AD. Several antiinflammatory therapies targeting astrocytes show significant benefit in models of disease,
particularly with respect to tau-associated neurodegeneration. However, the effectiveness of
these approaches is complex since modulating inflammatory pathways often has opposing
effects on the development of tau and amyloid pathology, and is dependent on the precise
phenotype and activities of astrocytes in different cellular environments. Increased
understanding of interactions between astrocytes and neurons under different conditions is
required for the development of safe and effective astrocyte-based therapies for AD and
related neurodegenerative diseases.
Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common
form of dementia. Clinical symptoms of AD include memory loss, confusion and behavioural
changes. AD is characterised neuropathologically by the development of ß-amyloid (Aß)
containing extracellular plaques, intracellular neurofibrillary tangles, comprised mainly of
abnormally phosphorylated and aggregated tau protein, and widespread synaptic
degeneration and neuronal loss [1].
It seems likely that several interconnected events lead to synaptic dysfunction and neuronal
death in AD. A complex relationship between Aβ and tau is believed to play a key role in
these processes [1], with tau deficiency protecting from Aβ-induced neurodegeneration and
cognitive decline [2]. Neuroinflammation is another prominent feature of AD brain that plays
a significant role in modulating disease progression [3].
Neuroinflammation in Alzheimer’s disease
Rather than being simply a “bystander” pathology, experimental evidence demonstrates that
neuroinflammation plays an active role in the development and progression of AD [3, 4]. In
support of this view, recent genome-wide association studies have shown that variants of
several immune genes, including complement receptor 1 (CR1) and triggering receptor
expressed on myeloid cells 2 (TREM2), increase the risk of developing AD [5]. Aß-containing
plaques in AD brain are surrounded by a halo of activated glial cells [6], and Aß is known to
lead to the activation of astrocytes and microglia, along with induction of inflammatory
signalling cascades [7, 8].
Both microglia and astrocytes release a myriad of pro- and anti- inflammatory cytokines
under different conditions. Changes in the cellular environment elicit a range of responses
that are not well defined or predictable, and that likely account for reports of both protective
and neurotoxic effects of glial stimulation in models of disease [8-10].
Cytokines can be classified into several sub-families, including the interferons (IFNs),
interleukins (IL)-1, -2, -10, and -17, tumour necrosis factors (TNFs), and chemokines,
including monocyte chemoattractant proteins (MCPs) and macrophage inflammatory
proteins (MIPs). There is usually some redundancy in these secreted factors, with several
different cytokines having similar actions. Cytokines signal via a number of pathways that
have been implicated in AD. For example, binding of MCP-1, IL-1, IL-6, TNFα and
interferons to their neuronal receptors leads to activation of protein kinase C, caspase-1 and
caspase-3, p38 and JNK mitogen-activated protein kinases (MAPKs), and phosphoinositide
3-kinase pathways [11]. In affected regions of AD brain, increased amounts of several
classes of cytokines, including IL-1β, IL-6, IL-8, IL-18, MIP-1β, S100β, MCP-1, TNF-α and
transforming growth factor beta (TGFβ), have been detected in association with plaques and
tangles [12-15]. In accordance with this, the amounts of several pro-inflammatory mediators
in peripheral fluids have been suggested as sensitive and specific biomarkers of AD [16].
The majority of transgenic rodent models of AD also exhibit prominent neuroinflammatory
responses, with the severity of inflammatory cell infiltration correlating strongly with
pathology development [17-18], cognitive decline [19], synaptic degeneration and neuronal
death [17,20]. In addition, lipopolysaccharide-induced glial activation results in inflammatory
responses that accelerate disease progression in transgenic models of AD [21]. These
results suggest that, rather than simply occurring as a response to neurotoxic stimuli,
inflammation directly affects pathways that lead to neurodegeneration.
Much research has focussed on elucidating the role of microglia in the development of AD.
There appears to be a spectrum of microglial changes that can have either a protective
influence or be detrimental to neuron health [9]. For example, phagocytosis of Aβ by
microglia is believed to be a protective mechanism [22], at least in younger animals [23].
However, increased pro-inflammatory cytokine production by microglia also results in
neuronal loss in models of AD [23]. There is also evidence that microglial responses can
have opposing influences on the development of amyloid and tau pathology. The NOD-like
receptor family, pyrin domain containing 3 (NLRP3) inflammasome plays an important role in
microglial inflammatory reactions. When NLRP3-deficient mice are crossed with a mouse
model of AD that over-expresses mutant human amyloid precursor protein together with
mutant presenilin (APP/PS1), the offspring show rescue of spatial memory, reduced
caspase-1 activation and increased Aß clearance [24], suggesting that microglial activation
exacerbates AD-like pathology. Conversely, fractalkine receptor (CX3CR1) is microglial
specific, and its chemokine ligand (CX3CL1) is highly expressed in neurons. Crossing
fractalkine receptor-deficient mice with mice that overexpress the entire wild-type human tau
gene in the absence of mouse tau (htau mice), results in offspring with enhanced microglial
activation and increased tau phosphorylation and aggregation [25]. Thus, microglial
fractalkine may play a neuroprotective and anti-inflammatory role in animals that model tauassociated neurodegeneration.
Astrocytes in healthy and Alzheimer’s disease brain
It is estimated that astrocytes represent between 30%-50% of human neural cells [26], and
they have long been acknowledged to provide crucial trophic and metabolic support for
neurons. They have multiple roles, including secretion of important neurotrophic factors,
such as TGFβ, brain-derived neurotrophic factor (BDNF) and nerve growth factor, they
transport the vast majority of extracellular glutamate, and they convert glucose to lactic acid,
which is taken up by neurons and converted to pyruvate for energy metabolism [27].
Astrocytes are also essential components of tripartite synapses [28], which are responsible
for bidirectional communication between pre- and post-synaptic neurons and integrated glial
cells. As such, astrocytes are critical for basal synaptic transmission, long-term potentiation
(LTP), and cortical circuit function [29].
In AD brain, there are alterations in astrocyte morphology, gene expression, protein
composition and activity, that are linked to changes in astrocyte function [30].
Altered
astrocyte morphology in aging and diseased brain is complex and region-specific [31],
however, the accumulation of activated astrocytes, often in clusters around amyloid plaques
[6], correlates strongly with Braak staging in AD [32]. Importantly, astrocyte activation,
together with the presence of phosphorylated tau in synapses, is one of the best biological
correlates of cognitive decline in AD [33]. Accumulations of activated astrocytes in affected
brain regions are also observed in many transgenic mouse models of AD, often prior to the
appearance of plaque and/or tangle pathology [34], suggesting that astrocyte activation is
involved in disease pathogenesis.
Astrogliosis is associated with a series of cellular events including the release of nitric oxide
(NO), reactive oxygen species, pro-inflammatory cytokines (such as TNFα, IL-1β and IL-6),
and prostaglandin, all of which can have deleterious effects on neuronal function and health.
In addition, many activated astrocytes in AD brain and in transgenic models of AD, express
high levels of calcineurin, a protein phosphatase that mediates inflammatory responses.
Recent studies have shown that astrocytes are activated by A, resulting in the release of
inflammatory factors that reduce synaptic and neuronal health in cell models of AD [7, 8, 35].
Importantly, astrocytes are required to mediate the effects of Aβ on tau phosphorylation and
cleavage, and this is linked with increased release of inflammatory mediators including IL-1,
TNF and IL-6 [8]. Astrocyte activation and increased amounts of these inflammatory factors
are also associated with the development of tauopathy in htau mice [18]. Taken together,
this suggests that astrocytes play a part in disease progression in AD, likely due to their
activation resulting in increased secretion of inflammatory mediators.
The
therapeutic potential
of
targeting astrocytes
and
disrupting
astrocytic
inflammatory signalling
In many AD patients there is a relatively late onset of symptomatic impairment which creates
an opportunity for effective therapeutic intervention. However, currently prescribed drugs
only reduce the symptoms of disease, and have little or no effect on disease progression. A
variety of therapies, primarily designed to prevent excess Aβ production, tangle formation,
and/or the spread of disease pathologies, are currently under investigation. Another active
area of interest is reduction of inflammatory signalling, since this may result in reduced
neuronal vulnerability to degenerative mechanisms.
Some of the best evidence that targeting inflammatory responses in astrocytes could be an
effective therapeutic strategy in AD was provided by Furman et al. [35]. In response to Aβ
and inflammatory mediators, astrocytic calcineurin is activated, leading to dephosphorylation
of nuclear factor of activated T-cells (NFAT) transcription factors, and induction of astrocyte
activation and inflammatory cytokine production. Furman et al. [35] showed that modulating
astrocytic inflammatory signalling in APP/PS1 mice by targeted expression of VIVIT, a
peptide that interferes with calcineurin/NFAT signalling, prevents astrocyte activation, lowers
Aβ levels and improves synaptic function and measures of learning and memory.
Pharmacological approaches also demonstrate the benefits of reducing astrocyte activation
in transgenic mouse models of AD. Treatment of htau transgenic mice with minocycline, a
tetracycline antibiotic derivative with potent anti-inflammatory effects, significantly reduced
numbers of activated astrocytes and inflammatory mediators [18], and decreased
pathological phosphorylated, cleaved and aggregated tau species [36]. Follow up studies in
primary neural cell cultures demonstrated that minocycline diminishes the release of
inflammatory factors from astrocytes, thereby preventing Aß-induced increases in tau
phosphorylation, tau cleavage, and neurotoxicity. Comparison of the effects of minocycline in
pure neuronal cultures with mixed neuronal and astrocytic cultures, showed that the
protective effects of minocycline were mediated by astrocytes, and that neurons were
relatively resistant to Aß in the absence of astrocytes [8].
Neutral sphingomyelinase (N-SMase) inhibitors have also shown benefit in models of AD by
reducing astrocytic inflammatory pathways. N-SMase degrades sphingomyelin to produce
ceramide, a lipid second messenger molecule that can trigger cell death in neurons and
astrocytes [37]. Aß and IL-1 activate N-SMase and induce production of ceramide in human
primary neurons [7]. Inhibiting N-SMase, either by knock down or by pharmacological
inhibition, reduces astrocyte activation and amounts of pro-inflammatory cytokines, thereby
protecting neurons from Aß-induced cell death [7]. Taken together, this evidence suggests
that targeting astrocytic inflammatory pathways may be a means to slow the development of
tau and amyloid pathologies, synaptic dysfunction and neuron death in AD.
There is also evidence that astrocytes may be protective in animal models of AD. For
example, genetic ablation of glial fibrillary acidic protein and vimentin in APP/PS1 mice,
prevents astrocyte activation and results in accelerated plaque deposition and increased
dystrophic neurites [38]. The apparent discrepancies in the influence of astrocytes in these
disease models may reflect differences in the mechanisms by which astrocytes are
associated with tau- and Aβ- mediated degeneration, as discussed above for microglia.
However, protective effects of astrocytes in tau models of dementia have also been
reported. Transgenic mice over-expressing mutant (P301S) tau display age-dependent
development of tau pathology, neuroinflammation, cognitive decline and loss of specific
cortical neurons [39]. Hampton et al. [10] set out to determine if transplantation of neural
precursor cells was able to prevent the disease phenotype in these animals. Unexpectedly,
they found that the transplanted neural stem cells differentiated into astrocytes and that this
conferred neuroprotection. A similar approach was taken in 3xTg-AD mice, which express
mutant forms of human tau (P301L), APP (K670N-M671L), and PS1 (M146V). When neural
stem cells were transplanted into the brains of these mice, the majority of the cells
differentiated into astrocytes, and recovery of hippocampal synaptic degeneration, spatial
learning and memory deficits were observed [40]. The beneficial effects observed in this
mouse model were ascribed to production of BDNF from the transplanted cells [40]. These
studies further indicate that the phenotype of astrocytes under different conditions can have
widely divergent effects, depending on their environment. In the studies described here,
these differences likely reflect the protective/neurotrophic influence of naïve new-born
astrocytes, and the toxic influence of astrocytes that have changed their phenotype as a
result of aging and/or their sustained presence in a diseased (and possibly pro-inflammatory)
environment.
Targetting specific inflammatory signalling pathways
Targeting specific pro-inflammatory cytokines could represent an alternative approach for
treating AD. IL-1ß is a pro-inflammatory cytokine synthesised and released by both activated
microglia and astrocytes. Single nucleotide polymorphisms in IL-1ß increase the risk of
developing AD, and IL-1ß expression is elevated in AD relative to age-matched control brain
[41]. In primary mixed neuronal and glial cultures, IL-1ß elevates tau phosphorylation via p38
MAPK and decreases the amount of the pre-synaptic marker, synaptophysin [42], changes
that are blocked by IL-1 receptor antagonists. Similarly, increased levels of phosphorylated
tau closely correlate with IL-1β amounts in the cortex of htau mice, and treatment of these
mice with minocycline reduces both IL-1β and phosphorylated tau [18]. Finally, transgenic
over-expression of IL-1ß in 3xTg-AD mice causes substantial increases in tau
phosphorylation that is associated with activation of p38 MAPK and GSK-3 [43]. However,
marked reductions in the burden of Aβ in the brains of these animals were also observed,
again highlighting a possible dissociation between the effects of inflammatory mediators on
tau and Aβ pathologies.
IL-18 is another pro-inflammatory cytokine released by activated astrocytes. IL-18 can
regulate N-methyl-D-aspartate (NMDA) receptor function, and may impair LTP [44]. NMDA
receptor activity can influence tau structure and function in multiple ways. For example,
NMDA receptor-mediated signalling influences the cleavage of tau by calpains and also tau
phosphorylation by kinases such as extracellular signal-related kinase [45]. Furthermore,
stimulating NMDA receptor activity elevates neuronal tau release in vivo [46]. The transsynaptic spread of tau pathology in AD is thought to underlie the progression of disease
through anatomically connected brain regions [47], and thus it is possible that inflammatory
mediators such as IL-18 may influence tau transmission via an effect on NMDA receptor
function.
Conclusions
Neuroinflammation is a prominent feature of AD brain that has a significant influence on
disease progression [3]. Microglia, the primary immune cells in the brain, play a major role in
mediating inflammatory responses in AD brain, however, recent evidence has suggested
that astrocytes also play a key role in disease pathogenesis. Activation of astrocytes leads
to increased release of inflammatory mediators, including IL-1ß and IL-18. These proinflammatory cytokines can signal to neurons and initiate signalling pathways that affect Aβ
production, tau processing and function. Genetic and pharmacological modulation of
astrocytic inflammatory signalling results can be beneficial in cell and animal models of AD,
particularly with respect to tau-associated degeneration. Astrocytes are critical for many
fundamental CNS functions that are known to be dysregulated in AD, including regulation of
cellular calcium, basal synaptic transmission, LTP, cortical circuit maintenance, and synaptic
pruning [29, 48]. Many of these processes are known to be influenced by inflammatory
mediators, particularly IL-1 [49-50], and thus modulating the astrocytic inflammatory
signalling could have substantial benefit in AD. However, the effectiveness of astrocytetargetted anti-inflammatory treatments is significantly confounded by the complex interplay
between tau and amyloid pathologies, and the phenotype and function of activated
astrocytes in different cellular environments. A greater understanding of these events is
required for the development of safe and effective astrocyte-based therapies for AD.
Acknowledgements
Work in the authors’ laboratories is supported by the Biotechnology and Biological Sciences
Research Council, National Council for the Replacement, Refinement and Reduction of
Animals in Research, Alzheimer’s Research UK, and Eli Lilly and Co. Ltd.
List of abbreviations
Aß: ß-amyloid
AD: Alzheimer’s disease
APP: amyloid precursor protein
GSK-3: Glycogen synthase kinase 3
IFN: interferon
IL: Interleukin
LTP : long-term potentiation
MAPK : mitogen activated protein kinase
MIP : macrophage inflammatory protein
MCP : monocyte chemoattractant protein
NFAT: nuclear factor of activated T-cells
NMDA: N-methyl-ᴅ-aspartate
N-SMase: Neutral sphingomyelinase
PS: presenilin
TNF: Tumour necrosis factor
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