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International Journal of Alzheimer’s Disease
Volume 2010, Article ID 587463, 7 pages
Bettina Linnartz,YinerWang,and HaraldNeumann
Neural Regeneration, Institute of Reconstructive Neurobiology, University Hospital Bonn, University Bonn, 53127 Bonn, Germany
Correspondence should be addressed to Harald Neumann, firstname.lastname@example.org
Received 24 February 2010; Accepted 13 May 2010
Academic Editor: Marcella Reale
Copyright © 2010 Bettina Linnartz et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Elimination of extracellular aggregates and apoptotic neural membranes without inflammation is crucial for brain tissue
homeostasis. In the mammalian central nervous system, essential molecules in this process are the Fc receptors and the DAP12-
associated receptors which both trigger the microglial immunoreceptor tyrosine-based activation motif- (ITAM-) Syk-signaling
cascade. Microglial triggering receptor expressed on myeloid cells-2 (TREM2), signal regulatory protein-β1, and complement
receptor-3 (CD11b/CD18) signal via the adaptor protein DAP12 and activate phagocytic activity of microglia. Microglial ITAM-
signaling receptors are counter-regulated by immunoreceptor tyrosine-based inhibition motif- (ITIM-) signaling molecules such
as sialic acid-binding immunoglobulin superfamily lectins (Siglecs). Siglecs can suppress the proinflammatory and phagocytic
on the neuronal glycocalyx. Thus, ITAM- and ITIM-signaling receptors modulate microglial phagocytosis and cytokine expression
during neuroinflammatory processes. Their dysfunction could lead to impaired phagocytic clearance and neurodegeneration
triggered by chronic inflammation.
1.Microgliaand Alzheimer’s Disease
Microglial cells originate from myeloid cells of the
hematopoietic lineage and are the resident immune cells
of the central nervous system (CNS). They are involved in
the active immune defense by their ability to phagocytose
invading bacteria and to release reactive oxygen species
acting as microbicides. In the healthy brain, microglia
are relative evenly distributed and predominantly found
in a so-called “resting” state, displaying a small cell body
with many highly branched processes, which are highly
motile and continuously monitor the brain parenchyma
[1–3]. Microglia are involved in tissue maintenance, exe-
cution of innate immunity, and participation in adaptive
searching for and reading biochemical signals of pathogenic
changes in the brain environment . In response to
injury, ischemia and inflammatory stimuli microglia change
from an immunologically silent state to an activated state
that is reflected in different morphological appearance—
amoeboid, rodlike, or phagocytic. They can migrate to the
site of disturbance, secrete a wide range of soluble factors
including cytokines as well as neurotrophic factors, and
phagocytose cellular debris. Thereby, microglia contribute
to tissue homeostasis and regeneration [2–5]. The effects
of activated microglia can be highly diverse. On the one
hand, they are neurotoxic by producing pro-inflammatory
mediators including cytokines and reactive oxygen species
such as interleukin-1β, tumor necrosis factor-α and nitric
oxide, which are potent inducers of neuronal damage and
cell death . On the other hand, they can also initiate anti-
inflammatory and immunosuppressive signaling that results
in repair, resolution of inflammation and turning back to
tissue homeostasis [3, 6, 7]. Furthermore, microglia act as
regulators of neuronal survival and development through
cytokines and chemokines such as interleukin-6 and CCL5
(RANTES). Activated, interleukin-6 producing microglia
have been shown to decrease in vitro the neurogenesis of
neural stem cells and increase the number of apoptotic cells
in differentiating cultures . Moreover, upon stimulation,
2 International Journal of Alzheimer’s Disease
RANTES is produced by microglia . Due to the observa-
tion that similar amounts of RANTES are produced by fetal
and adult microglia, Hu et al. suggest this chemokine to be
acquired early in brain development .
Increasing evidence indicates that microglia are involved
in almost all types of brain pathology. In the aging brain
and most chronic neurodegenerative diseases including
Parkinson’s disease and Alzheimer’s disease (AD), microglial
cells become activated and provoke ambivalent effects. They
can either be deleterious by enhancing neurodegeneration
through secreting cytokines and neurotoxins , or might
be beneficial by principally migrating to the amyloid-β (Aβ)
plaques and phagocytosing Aβ deposits. Recently, it was
models of AD that Aβ plaques could appear within 24 hours
and microglial cells are activated and recruited to the newly
formed plaques within one day . Additionally, within
one week after the onset of plaque formation dysmorphic
neurites were present . Interestingly, microglial cells
seem to contribute to AD progression. Although maintain-
ing their ability to produce pro-inflammatory cytokines,
microglia of aging APP/PS1-transgenic mice, a mouse model
of Aβ plaque formation associated with AD, become dys-
functional and display a reduced Aβ clearance capability
, suggesting that Aβ plaques might partially result from
impaired microglial removal. However, in APP-transgenic
mice that barely exhibit resident microglia, formation and
maintenance of Aβ plaques have been lately demonstrated
unchanged . Nevertheless, several lines of in vitro evi-
dence suggest the involvement of innate immune signaling
during recognition of Aβ. Different receptors expressed on
microglia such as CD14 and toll-like receptors (TLR) 2 and
4 are known to contribute to the clearance of Aβ plaques in
AD [14–16]. CD14 is involved in the uptake of the bacterial
component lipopolysaccharide (LPS) . To transduce
activation signals, CD14 interacts with TLR2 and TLR4
containing dimeric complexes [16, 17]. Additionally, CD14
has been shown to specifically mediate Aβ phagocytosis in
vitro. Cells expressing CD14 internalized significantly higher
amounts of Aβ compared to CD14-deficient cells while
the uptake of microbeads was unaffected . Moreover,
CD14 acts together with TLR2 and TLR4 to bind Aβ
and subsequently activate intracellular signaling leading
to phagocytosis in vitro. Cells deficient for either CD14,
TLR2 or TLR4 could not initiate the cascades inducing
phagocytosis . Recently, CD36, another coreceptor of
TLRs, has been described in vitro to facilitate the assembly
of a heteromeric complex of CD36, TLR4, and TLR6 upon
binding of Aβ . However, the exact receptors which
might scavenge Aβ and/or induce microglial phagocytic
responses and signaling pathways that impair microglial
phagocytosis in vivo are still unclear.
2. MicroglialITAM-ITIM Signaling
Latest publications indicate that immunoreceptor tyrosine-
based activation motif (ITAM) signaling plays an important
role in the phagocytic process. ITAM-containing signaling
ITAM signaling ITIM signaling
Figure 1: ITAM-/ITIM-signaling cascade. Left side: Upon ligand
binding, activatory receptors like TREM2, SIRPβ1, FcγRI or
FcγRIIIA associate with ITAM containing adaptor proteins such
as DAP12 or the common γ chains through interactions between
charged amino acids (−/+) within the transmembrane regions
of each protein. Subsequently, members of Src kinase family
(SKF) phosphorylate tyrosine residues of ITAMs. Phosphotyrosine
residues are docking sites for Syk protein kinases that upon
activation mediate cellular activation via a number of downstream
cascades. Right side: Upon ligand binding, inhibitory receptors like
most Siglecs recruit SHP1 and SHP2 which can in turn terminate
intracellular signals emanating from ITAM receptors.
adaptor proteins are associated with receptor subunits. After
the binding of ligand and receptor, the tyrosine residues
of the ITAMs become phosphorylated by members of the
Src kinase family (Figure 1, left side). These phosphotyro-
sine residues are docking sites for Src homology 2 (SH2)
domains of Syk protein kinases which upon activation
mediate cellular activation via a number of downstream
cascades [18–20]. The processes involved in phagocytosis
of apoptotic material are well conserved from worms to
mammals . Draper is a phagocytic receptor of the fruit
fly Drosophila with an ITAM in the intracellular domain.
Recently, it has been described that upon phosphorylation
of ITAM tyrosine residues, Draper can bind the nonreceptor
tyrosine kinase Shark which is similar to the mammalian
Syk. Moreover, not only the activity of Shark but also the
ITAM-phosphorylation of Draper is required for Draper-
mediated signaling events such as the attraction of glial
membranes to damaged axons and the glial phagocytic activ-
Drosophila and the DAP12-ITAM signaling of mammalian
immunoreceptors have a lot in common. The mammalian
DAP12 molecule is a transmembrane adaptor protein that
contains two ITAMs. It is expressed by microglia and
associates with cell membrane receptors such as triggering
regulatory protein-β1 (SIRPβ1) . Stimulation of SIRPβ1
International Journal of Alzheimer’s Disease3
or TREM2 occurs by yet unknown endogenous ligands.
For TREM2 it has been suggested that it binds to lipo-
oligosaccharides of Gram-positive and -negative bacteria.
carbohydrates led to the suggestion that a charge-dependent
ligand recognition takes place . Upon stimulation of
SIRPβ1 or TREM2, a phosphorylation of DAP12-ITAM is
induced and the phagocytic activity of microglial cells is
increased in vitro [22, 24, 25]. TREM2-DAP12 signaling
via ITAM also promotes phagocytosis of bacteria. It has
been demonstrated in vitro that TREM2 mediates binding
of bacteria and promotes their internalization dependent
on Src kinase mediated tyrosine phosphorylation .
ITAMs are counter-regulated by immunoreceptor tyrosine-
based inhibition motifs (ITIMs; Figure 1, right side). Upon
ligand binding, inhibitory receptors with ITIMs prevent the
activation signals that originate from receptors associated
with ITAMs through the recruitment of SH2 domain
containing tyrosine phosphatases (SHP1 and SHP2) which
in turn can modulate the function of various signaling
pathways [27, 28]. Most CD33-related sialic acid-binding
immunoglobulin superfamily lectins (Siglecs), a subgroup
of the immunoglobulin superfamily that recognizes sialic
acid residues of glycoproteins and glycolipids, have one or
more ITIMs in the cytoplasmic domain [27, 29]. Binding
of Siglecs to highly sialylated proteins and lipids such
as clusterin, apolipoprotein E and gangliosides that are
abundantly present in AD plaques could in turn mediate an
inhibitory signaling cascade. Thereby, microglial phagocyto-
sis is possibly suppressed and the AD plaques might be left
An important group of receptors on the surface of phago-
cytes, which signal via ITAM-Syk signaling and mediate
phagocytosis function, include the Fc receptors (FcR). FcR
interact with the Fc part of immunoglobulin (Ig) G bound
to antigen presented on microbial pathogens or autoantigens
[20, 30, 31]. Except for the human FcγRIIA (CD32a), which
itself possesses an ITAM located in the cytoplasmic region,
activating FcRs like FcγRI (CD64) and FcγRIIIA (CD16a)
of FcR that contain the required ITAMs. The common γ
chain of FcR is a homolog of the adaptor protein DAP12
and functionally close related to it. Subsequently, tyrosine
residues of the ITAM are phosphorylated by members of the
Src kinase family resulting in the establishment of docking
sites for Syk kinases (Figure 1, left side). Activated Syk
kinases in turn initiate a variety of downstream signals medi-
ated through calcium, protein kinase C, phospholipase A2,
kinase and GTPases of the Rho family leading to phago-
cytosis of IgG coated and opsonized particles and antigens
[31–33]. Accordingly, microglial cells express the activating
FcRs CD16, CD32 and CD64 and phagocytose antigens
via the corresponding IgG subtypes [34, 35]. Moreover, in
brain areas displaying neurodegeneration such as multiple
sclerosis lesions, the expression of those FcRs on microglia
is increased , suggesting a role of FcRs in protecting
the surrounding tissue from IgG-opsonized antigens .
Furthermore, there is an ongoing discussion whether FcRs
play a role in AD by contributing to microglial Aβ clearance
. In APP-transgenic mice it has been demonstrated that
antibodies directed against Aβ can enter the CNS . One
study described that immunization of APP-transgenic mice
with Aβ1-42, which induced Aβ1-42 specific antibodies,
reduced Aβ deposition regardless of whether the mice were
genetically deficient of the FcR domain FcRγ. The authors
suggest that FcR-mediated mechanisms are irrelevant for the
effectiveness of Aβ immunotherapy in vivo . However,
another study clearly demonstrated by using an ex vivo assay,
in which primary microglial cells were cultured with unfixed
cryostat sections of AD brains, that Aβ antibodies could
evoke FcR-mediated microglial phagocytosis of Aβ plaques
and subsequent Aβ degradation .
Several DAP12 associated receptors are known including
activating natural killer cell receptors, like KIR2DS and
NKG2D, and myeloid receptors, such as signal regulatory
protein-β1 (SIRPβ1), TREM1, -2, -3 , complement
receptors , and certain Siglecs, such as Siglec-16 .
This review will focus on some of them.
4.1. TREM2. The glycoprotein TREM2 is expressed on
microglia , and consists of one extracellular Ig-like
domain, a transmembrane region with a charged lysine
residue and a short cytoplasmic tail . As TREM2 lacks
an intracellular signaling tail, it is completely dependent on
the presence of the adaptor protein DAP12 [18, 42]. As
mentioned before, the mammalian adaptor molecule DAP12
is another protein besides the common γ chain of FcR
that activates an ITAM-Src kinase signaling pathway. Via
signaling through the adaptor protein DAP12, TREM2, a
phagocytic receptor with still unknown endogenous ligand,
leads to activation of microglial cells. Activated microglia
in turn can clear cellular apoptotic material, thereby con-
tributing to tissue repair [18, 24, 43]. Therefore, a non-
functional TREM2 might be involved in brain damage by
causing accumulation of toxic products. Interestingly, loss-
of-function mutations of DAP12 or TREM2 both lead to
a chronic neurodegenerative disease called Nasu-Hakola
or polycystic lipomembranous osteodysplasia with scleros-
ing leukoencephalopathy (PLOSL), an autosomal recessive
inherited disease . While this disease is characterized
by early onset presenile dementia followed by delayed
bone symptoms in patients carrying TREM2 mutations
, patients with mutations in DAP12 display an early
onset combination of presenile dementia and systemic
bone cysts [45, 46]. Moreover, it has been demonstrated
that TREM2 is down-regulated by inflammatory signals
. All these data indicate that TREM2 might be func-
tionally crucial for the prevention of neurodegenerative
4 International Journal of Alzheimer’s Disease
4.2. SIRPβ1. Recently, other new microglial receptors like
SIRPβ1 with a phagocytic ITAM signaling capacity have
been identified . Like TREM2, SIRPβ1 is expressed
on microglial cells. In APP-transgenic mice and a mouse
model for experimental autoimmune encephalomyelitis,
the expression levels of both proteins are increased .
Furthermore, TREM2 and SIRPβ1 are plaque-associated and
increase the phagocytic activity of microglia [24, 25, 42,
43]. Upon neurodegenerative signals, TREM2 expression is
induced leading to increased phagocytosis and decreased
pro-inflammatory responses of microglial cells . How-
ever, SIRPβ1 does not only specifically clear Aβ but also
neural debris and microsphere beads . A strong increase
of microglial SIRPβ1 gene transcript has been revealed in
the cerebral hemispheres and cerebellum of an animal model
of AD, while the gene transcript of DAP12 has only been
increased slightly. Thus, up-regulation of SIPRβ1 does not
simply reflect a higher number of microglia. Moreover, it is
not directly triggered by the amyloid plaques but by other
to influence the gene transcription of SIRPβ1 . So far,
concrete in vivo evidence for a direct pathophysiological
relevance of SIRPβ1 is missing. While SIRPβ1 could not
only be detected on microglial cells associated with plaques,
but also in those not directly associated with plaques, it is
4.3. Complement Receptor 3 (CD11b/CD18). Complement
receptor 3 (CD11b/CD18). Another potential microglial
DAP12-associated receptor is the complement receptor 3
(CR3), a major heterodimeric receptor consisting of the
integrins CD11b and CD18, which is involved in the com-
plement system. Complement 1q (C1q), the first component
of the classical pathway, mediates complement 3 (C3)
deposition on apoptotic cells. The phagocytic receptor CR3
plays an important role in the subsequent clearance of C3-
opsonized structures . Moreover, sequence similarities
to C1q-binding peptides in CD18 suggest direct binding of
CR3 (CD11b/CD18) to C1q . As for immunoreceptors,
signal transduction by CD18 could follow the ITAM-DAP12
signaling cascade although a direct binding of integrins with
ITAM-containing proteins has not been demonstrated so far.
But, it has been shown that CD18-mediated Syk activation
requires the ITAM-associated molecules DAP12 and FcRγ
. Furthermore, both DAP12 and CD11b are required
for targeted contact of microglia, like for the contact with
hippocampal neurons during development that induces cell
death . Switching on the complement system plays an
important role in initiating inflammatory reactions in the
CNS as observed in AD  by upregulation of phagocytosis
induced via activation and migration of immune cells .
Indeed, during formation of amyloid in APP-transgenic
mice increased mRNA and protein levels of components
of the complement system have been detected. Among
those there have been C1q and C3, at which the classical
and alternative pathway merge . Moreover, complement
activation has been described to occur in amyloid plaques
in AD brains [54, 55] and complement products like the
membrane attack complex (C5b-9) have been reported to
be associated with amyloid plaques . Additionally, C3
seems to be involved in the process of plaque clearance.
APP-transgenic mice either deficient in C3 or expressing
a C3 complement inhibitor display accelerated Aβ plaque
deposition and prominent neurodegeneration [51, 57] as
well as a changed activation state of the microglial cells
simultaneously . However, while evidences for the direct
induction of a phagocytic ITAM signaling by activation of
the complement signaling cascade are missing so far, these
data suggest an involvement of complement components in
microglia for an effective Aβ clearance.
Siglecs are members of a subgroup of the Ig superfamily
that recognize specific sugar residues on the periphery
of cell surface glycans, the sialic acids. Because of their
sequence similarity and evolutionary conservation, Siglecs
can be separated into two subsets . While CD33-related
16 evolve very rapidly by means of gene duplication or
conversion and exon shuffling or loss and show a similarity
of ∼50–99% in their protein sequences, other members
of the Siglec family such as sialoadhesin, CD22, myelin-
associated glycoprotein (MAG) and Siglec-15 are more
conserved and quite distantly related [27, 40, 59]. Humans
display ten CD33-related Siglecs and one Siglec-like protein;
mice however express only five CD33-related Siglecs, which
seem to have largely lost their CD33-related Siglec genes
[27, 40, 59–62]. Siglecs are type 1 transmembrane proteins
showing an amino-terminal Ig-like variable (V-set Ig-like)
domain that binds sialic acid and variable numbers of Ig-
like constant region type 2 (C2-set Ig-like) domains [27, 58,
62, 63]. Mostly, Siglecs function as inhibitory receptors via
one or more ITIMs in their cytoplasmic domain [27, 29].
ITAM receptors via the recruitment of tyrosine phosphatases
such as SHP1 and SHP2 which can lead to the termination
of intracellular signals (Figure 1, right side) [27, 59]. Most
CD33-related Siglecs, such as the human Siglec-11, are
predominantly expressed on mature cells of the immune
system such as monocytes and macrophages. Therefore,
CD33-related Siglecs are suggested to be important regu-
lators of the innate immunity [27, 59, 62–64]. Siglec-11
has been shown to interact with SHP1 and SHP2 upon
tyrosine phosphorylation . Interestingly, SHP1 seems
to be involved in antiinflammatory signaling of microglia.
Microglia deficient for SHP1 have been demonstrated to
produce higher amounts of neurotoxic substances upon
LPS stimulation . It has been shown that via inter-
action of microglial Siglecs with the neuronal glycocalyx
microglial neurotoxicity is alleviated. Furthermore, it has
been demonstrated that Siglec-11 expressing microglial cells
show a reduced phagocytic capacity of apoptotic material
in microglia-neuron coculture experiments , indicat-
ing that ITIM-signaling could be the opponent of the
phagocytosis-associated ITAM-Syk signaling pathway .
International Journal of Alzheimer’s Disease5
In addition to inhibiting cellular activation, CD33-related
Siglecs participate in the induction of apoptosis and the
release of pro-inflammatory cytokines [27, 67–69]. However,
few Siglecs have been demonstrated to associate with the
ITAM-containing adaptor protein DAP12, including the
recently discovered human Siglec-16. It contains a positively
charged lysine residue in its transmembrane domain but
lacks ITIM in its short cytoplasmic tail . Cao et al.
 have shown that Siglec-16 is expressed on macrophages
and on rare microglial-like cell populations in the normal
human brain. Phylogenetic analysis of the transmembrane
and cytoplasmic tail domain of human and mammalian
CD33-related Siglecs revealed that Siglec-16 and the before
mentioned Siglec-11 are found in humans, but no direct
proteins expressed on human myeloid cells could especially
be involved in diseases that are uniquely occurring with their
whole peculiarities only in humans such as AD. So far, it
is not known whether DAP12 associated Siglecs also have
a sialic acid binding specificity as observed for the ITIM
bearing Siglecs. This should be investigated in the future to
find out whether such Siglecs could counter-regulate each
other. However, the involvement of different Siglecs in all
processes including apoptosis and inflammation indicates
a modulatory role of Siglecs in neuroinflammatory and
The biological functions of ITAM-/ITIM-signaling in
microglia are not fully understood. Several publications
indicate the involvement of ITAM- and ITIM-signaling
receptors in CNS innate immune responses and neu-
roinflammation. It is now becoming evident that those
receptors also play a major role in modulating microglial
phagocytosis and cytokine expression. Thus, dysfunctional
ITAM-/ITIM-signaling receptors lead to chronic neurode-
generative diseases like Nasu-Hakola disease characterized
by presenile dementia. These new insights might have
important implications for the pathogenesis and treatment
of the neuroinflammatory component of neurodegenerative
The Neural Regeneration Group at the University Bonn LIFE
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Walter-und-Ilse-Rose-Foundation, German Research Coun-
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