J Neuroimmune Pharmacol (2012) 7:42–59

DOI 10.1007/s11481-011-9287-2

INVITED REVIEW

Tumor Necrosis Factor-alpha and the Roles it Plays

in Homeostatic and Degenerative Processes
Within the Central Nervous System
Sara L. Montgomery & William J. Bowers

Received: 1 June 2011 / Accepted: 20 June 2011 / Published online: 5 July 2011
# Springer Science+Business Media, LLC 2011

Abstract Tumor Necrosis Factor-alpha (TNF-α) is a
prototypic pro-inflammatory cytokine involved in the
innate immune response. TNF-α ligation and downstream
signaling with one of its cognate receptors, TNF-RI or
TNF-RII, modulates fundamental processes in the brain
including synapse formation and regulation, neurogenesis,
regeneration, and general maintenance of the central
Sources of Support: This work was supported by NIH F31-AG038063
to SLM and NIH R01-AG023593 and NIH R01-AG026328 to WJB.
S. L. Montgomery
Department of Pathology and Laboratory Medicine,
University of Rochester Medical Center,
Rochester, NY 14642, USA
W. J. Bowers
Departments of Neurology,
University of Rochester Medical Center,
Rochester, NY 14642, USA
W. J. Bowers
Microbiology and Immunology,
University of Rochester Medical Center,
Rochester, NY 14642, USA
nervous system (CNS). During states of chronic neuro-
inflammation, extensive experimental evidence implicates
TNF-α as a key mediator in disease progression, gliosis,
demyelination, inflammation, blood–brain-barrier deterio-
ration, and cell death. This review explores the complex
roles of TNF-α in the CNS under normal physiologic
conditions and during neurodegeneration. We focus our
discussion on Multiple Sclerosis, Parkinson’s disease, and
Alzheimer’s disease, relaying the outcomes of preclinical
and clinical testing of TNF-α directed therapeutic strate-
gies, and arguing that despite the wealth of functions
attributed to this central cytokine, surprisingly little is
known about the cell type- and stage-specific roles of TNF-
α in these debilitating disorders.
Keywords Neuroinflammation . Cytokine . Development .
Alzheimer’s disease . Parkinson’s disease . Multiple
Sclerosis . Intracellular signaling
Introduction

W. J. Bowers Tumor necrosis factor-alpha (TNF-α) is a critical regulatory

Pharmacology and Physiology,
University of Rochester Medical Center,
Rochester, NY 14642, USA
S. L. Montgomery : W. J. Bowers
Center for Neural Development and Disease,
University of Rochester Medical Center,
Rochester, NY 14642, USA
W. J. Bowers (*)
Department of Neurology,
Center for Neural Development and Disease,
University of Rochester Medical Center,
601 Elmwood Ave., Box 645, Rochester, NY 14642, USA
e-mail: william_bowers@urmc.rochester.edu
cytokine exerting both homeostatic and pathophysiological
roles in the central nervous system (CNS). This potent
cytokine drives acute and chronic inflammatory responses,
the former of which are normally self-limiting and leads to
the removal of injurious stimuli and restoration of homeo-
stasis. However, sustained inflammation for protracted
periods of time may result in cellular dysfunction and
initiation of disease. Chronic inflammation, as evidenced by
the elaboration of proinflammatory marker expression,
elevated cytokine and chemokines levels, and the prolifer-
ation and/or clustering of glial cells within afflicted brain
regions, are characteristic hallmarks of a number of
J Neuroimmune Pharmacol (2012) 7:42–59
neurodegenerative diseases. Although 36 years have passed
since TNF-α was first discovered by Carswell and
colleagues (Carswell et al. 1975), current strategies for
TNF-α intervention in the human brain appear to lack the
robustness and specificity necessary to ameliorate disease.
This review will summarize the homeostatic and pathologic
consequences imparted by TNF-α expression within the
CNS and will discuss the current views on the potential
therapeutic promise of anti-TNF-α therapeutics in preventing
and/or combating neurodegenerative diseases.
TNF-α signaling
TNF-α belongs to the large TNF ligand superfamily and is
generally produced as a type II integral membrane protein
(Wajant et al. 2003). Synthesis of this highly multifunc-
tional cytokine occurs in a broad range of cell types,
including immune regulatory macrophages, T cells, mast
cells, granulocytes, natural killer cells and non-immune
endothelial cells, osteoblasts, smooth muscle cells, fibro-
blasts, and keratinocytes. Within the central nervous
system, microglia, astrocytes and neurons are major sources
of TNF-α (Lieberman et al. 1989; Liu et al. 1994;
Morganti-Kossman et al. 1997; Lau and Yu 2001; Hanisch
2002; Klintworth et al. 2009).
TNF-α synthesis is stringently regulated and can be
triggered by bacterial and viral pathogens, injury and
immunological stimuli including cytokines, complement
factors, and immune complexes. TNF-α is regulated at the
transcriptional, post-transcriptional, and translational level.
Transcriptionally, the TNF-α gene is controlled at its 5′
flanking region that contains three κβ- like enhancers (four
in mouse) and a MHC class II-like “Y box” (Fig. 1) (Drouet
et al. 1991). Several transcription factors are capable of
binding and activating the TNF-α promoter, including NF-
κβ, CCAAT/enhancer binding protein β (C/EBPβ), SP-1,
Erg-1, and c-Jun (Pope et al. 1994; Wedel et al. 1996; Yao et
al. 1997; Udalova et al. 1998). TNF-α mRNA translation
leads to the generation of a 26-kDa precursor
transmembrane-associated TNF-α (tmTNF) protein. This
pro-TNF-α is proteolytically processed by the TNF-α
converting enzyme (TACE), a matrix metalloproteinase, to
release a soluble 17-kDa TNF-α (sTNF) homotrimer. Both
1 2
5 3 UTR
5 UTR
Fig. 1 Schematic representation of the TNF-α gene structure located
on human chromosome 6. The TNF-α genomic locus is approximately
3 kb in length and contains 4 coding exons interrupted by 3 introns. Solid
squares represent exons and introns are depicted by the horizontal line.
Over 80% of exon 4 encodes for the secreted protein, while exons 1 and 2
43
sTNF and tmTNF are biologically active and exert their
distinct signaling functions through engagement of two
cognate single-pass transmembrane glycoprotein receptors:
TNF-receptor 1 (TNF-RI) and TNF-receptor 2 (TNF-RII).
At the post-translational level, adenine-uracil rich elements
(ARE’s) located within the 3′ untranslated region (Fig. 1)
target TNF-α mRNA for translational degradation, thereby
preventing excessive cytokine production in the absence of
an inflammatory trigger (Kontoyiannis et al. 1999). Inflam-
matory mediators, such as prostaglandins and corticoste-
roids, downregulate TNF-α transcription and/or translation
to limit the duration of active TNF-α signaling (Huang and
Eden 1993; Schottelius et al. 1999; Yamane et al. 2000;
Shinomiya et al. 2001).
The two cognate TNF-α receptors, TNF-RI and TNF-
RII, are differentially expressed and controlled. TNF-RI is
constitutively expressed on most cell types, with the
exception of erythrocytes. Conversely, TNF-RII expression
is induced upon inflammatory stimulation and is limited to
hematopoietic lineage cells, including microglia and endo-
thelial cells. Due to its relatively restricted expression, it has
been generally accepted that fewer TNF-α related signaling
processes are driven by TNF-RII (Grell 1995; McCoy and
Tansey 2008). TNF-RI and TNF-RII share limited sequence
homology (28%) overall, with much of this homology
being shared within a cysteine-rich ectodomain (Aggarwal
et al. 2000). TNF-RI and TNF-RII can bind either sTNF or
tmTNF, but particular ligand-receptor combinations are
preferred. Secreted sTNF binds with high affinity to TNF-
RI and TNF-RII, but dissociates from TNF-RII much more
readily, supporting the ligand-passing hypothesis in which
sTNF binds to TNF-RII then quickly dissociates and
transfers to TNF-RI. This mechanism leads to increased
local concentrations of TNF-α and rapid signal transmis-
sion via TNF-RI (Tartaglia et al. 1993a). Similarly, pairing
of TNF-RII with the tmTNF ligand is favorable for highly
robust TNF-RII signaling activities (Grell et al. 1995).
Ectodomain shedding of TNF-RI and TNF-RII through
proteolytic cleavage can also occur, whereby these receptor
fragments act as neutralizing agents that inhibit the ability
of TNF-α to efficiently engage with functional membrane-
bound receptors (Wallach et al. 1991).
Cell type specificity of TNF-α receptor expression,
ligand affinity, and cellular composition within a given
3 4
3
encode the signal peptide sequence (Nedwin et al. 1985). The 3′ UTR
harbors an AU-rich element (ARE), while the 5′ UTR comprises
regulatory transcriptional elements including κβ enhancers and a Y-box
similar to that of the MHC class II gene (Idriss and Naismith 2000)
44
tissue are factors that significantly influence the types of
cellular responses elicited by TNF-α. Historically, TNF-RI
engagement was believed to promote apoptosis and
cytotoxicity, while cell survival, proliferation and protective
cellular responses elicited by TNF-α were attributed
primarily to TNF-RII binding. The complexity and pleio-
tropic activities of TNF-α in vivo have become better
appreciated during the past decade. The signaling cascades
underlying TNF-α function include activation of the highly
characterized NFκβ, p38 MAP kinase, c-jun N-terminal
kinase (JNK), and sphingosine-based ceramide pathways
(Hsu et al. 1995; Rothe et al. 1995a; Natoli et al. 1997;
Kronke 1999). Prior to TNF-α binding, the extracellular
pre-ligand-binding assembly domain (PLAD) allows for the
trimerization of the TNF-receptors, and this event is critical
for TNF-α signaling and activation. Ligation of TNF-α
occurs within the ligand-binding pockets of cysteine-rich
domains 2 (CDR2) and 3 (CDR3) of the extracellular
segments of the TNF receptors, resulting in signal transduction
at the cell surface and ligand-receptor clustering (Banner et al.
1993; MacEwan 2002). Both TNF-RI and TNF-RII lack
enzymatic activity within their respective intracellular
domains, and therefore, signal via intracellular adaptor
molecule aggregation (Magnusson and Vaux 1999). The
existence of a cytoplasmic protein-protein interacting death
domain within TNF-RI mediates the induction of apoptosis
and NFκβ signaling (Tartaglia et al. 1993b). Adaptor proteins
bind following the dissociation of the silencer of death
domain (SODD), a negative regulator that associates with the
death domain. Removal of SODD leads to the aggregation
and recruitment of the TNF receptor-associated death domain
(TRADD) (Magnusson and Vaux 1999). TRADD serves as a
signaling platform and recruits downstream signaling mole-
cules, including the Fas-associated death domain (FADD),
TNF-receptor associated factor 2 (TRAF2) and receptor
interacting protein (RIP) to form the active TNF-RI signaling
complex. Recruitment of cellular inhibitors of apoptosis
(cIAP) 1 and 2 to the TNF-RI signaling complex potentiates
signal activation through NFκβ, p38, JNK, and ceramide/
sphingomyelinase pathways (Fig. 2) (Rothe et al. 1995a;
Winston et al. 1995; Wang et al. 1998; Lee et al. 2003).
These same pathways, including those leading to
apoptosis, can be induced through TNF-RII signaling.
While TNF-RI indirectly recruits TRAF2, TNF-RII directly
associates with this adaptor protein along with TRAF1 to
elicit intracellular crosstalk between the receptors (Rothe et
al. 1994; Rothe et al. 1995b). Notably, when TNF-RI and
TNF-RII are co-stimulated an additive effect of NFκβ
transduction is observed, where it is likely both TNF-
receptor pathways share similar signaling proteins. Inter-
estingly, cooperativity between the two receptor types has
been shown to significantly enhance TNF-RI-induced
cytotoxicity (Weiss et al. 1997). TNF-RII, which lacks a
J Neuroimmune Pharmacol (2012) 7:42–59
death domain, is able to directly trigger TNF-α exposure-
related cell death (Heller et al. 1992), and Haridas and
colleagues demonstrated TNF-RII overexpression leads to
the induction of TNF-α-dependent apoptosis (Haridas et al.
1998). More recently, it has been reported that TNF-RII can
activate apoptosis independently of TNF-RI in PVC60 cells
and cell death can be blocked via caspase 1 and 8 inhibition,
implicating the upstream FADD adaptor protein in TNF-
RII-mediated cell death mechanisms (Depuydt et al. 2005).
TNF-RII signaling has been shown to be protective in a
considerable number of disease processes, including heart
disease, neurodegenerative disorders, ulcerative colitis and
Crohn’s disease, type 1 diabetes, retinal ischemia, and
familial rheumatoid arthritis (Shen et al. 1997; Weiss et al.
1998; Barton et al. 2001; Dieude et al. 2002; Sashio et al.
2002; Marchetti et al. 2004; Pierik et al. 2004; Monden et
al. 2007). In retinal ischemia, loss of TNF-RI resulted in
reduced neurodegeneration, while depletion of TNF-RII
increased neuronal cell loss, suggesting possible opposing
roles for TNF-RI and TNF-RII in cytotoxicity and
protection, respectively (Fontaine et al. 2002). TNF-RII is
critical for maintaining the oligodendrocyte progenitor cell
pool in a cuprizone model of demyelination (Arnett et al.
2001) and hippocampal neurons are sensitive to TNF-α
toxicity in the absence of TNF-RII, but not TNF-RI (Yang
et al. 2002). These differential effects of TNF-RI and TNF-
RII are dependent upon cell type, environment, age and the
activation status of those cells.
tmTNF can trigger TNF-α signaling by acting as both a
ligand and as a receptor. Reverse signaling, where membrane-
integrated TNF-α can mitigate intracellular signaling and
function as a receptor, allows for bidirectional communication
between cells (Fig. 2). Receptor-mediated tmTNF binding
with TNF-α antagonists or TNF-receptor-expressing cells
can provoke NFκB activation or programmed cell death, as
well as down-regulate sTNF-α, IL-1, IL-6, and IL-10
cytokine secretion (Eissner et al. 2000; Harashima et al.
2001; Zhang et al. 2008). Reverse signaling leads to an
enhancement of intracellular calcium and activation of p38
mitogen protein kinase (Watts et al. 1999; Waetzig et al.
2002). The function of reverse signaling is important during
immune responses such as T cell activation, formation of
germinal centers, and production of specific immunoglobulin
isotypes that are important in pathogen elimination and
allergic reactions (van Essen et al. 1995; Boursalian and Fink
2003). The regulation of reverse signaling appears to be
mediated, at least in part, by post-translational modification
of tmTNF-α. Casein Kinase 1 (CK1) phosphorylates a
conserved sequence in the cytoplasmic tail of TNF-related
family members, including TNF-α (Pocsik et al. 1995), and
this phosphorylation event has been shown to alter tmTNF-
α-mediated reverse signaling activity in monocytes (Watts et
al. 1999; Eissner et al. 2004). Friedmann and colleagues
J Neuroimmune Pharmacol (2012) 7:42–59 45

Fig. 2 Soluble and TNF-producing cell

transmembrane TNF-α signaling
through TNF-RI and TNF-RII. Reverse Signaling
tmTNF-α forms a trimeric
structure and is proteolytically
cleaved by TACE to release the
soluble homotrimeric TNF-α
protein. Both tmTNF-α and
sTNF-α bind receptors of the tmTNF TACE sTNF
TNF-receptor superfamily, Trimer
TNF-RI and TNF-RII, although
sTNF is primarily restricted to
TNF-RI and tmTNF associates TNF-RII TNF-RI
more prominently with TNF-RII.
A cytoplasmic death domain of
TNF-RI allows for the binding of
TRADD and the recruitment of
FADD to induce apoptosis. The
sphinomyelinase/ceramide
pathway is triggered via binding T
R FAN
the TNF-RI adaptor protein, FAN. A TRAF2 cIAP
F T SMase/
TRAF2 of TNF-RI or TNF-RII 1 R
A Ceramide
leads to the downstream cIAP F TRADD
activation of NFκβ, JNK, and 2 FADD
p38 signaling pathways and
MEKK
elicits diverse TNF-mediated
biological responses
RIP Apoptosis

JNK MKK3 NEMO

p38

Iκβ
cJun/AP-1
ATFs NFκβ

TNF-responsive cell
Activation

reported that in activated dendritic cells two transmembrane
aspartyl signal peptide peptidases (SPPLs) promote proteo-
lytic cleavage of the intracellular domain of tmTNF leading
to the induction of the pro-inflammatory cytokine, IL-12
(Weihofen et al. 2002; Friedmann et al. 2006). The
identification and involvement of other kinases, phospha-
tases, or proteases that may act to modulate tmTNF reverse
signaling continues to be a work in progress (Watts et al.
1999; Eissner et al. 2004).
TNF-α in the CNS
Development
TNF-α plays important roles during the development of the
mammalian CNS. One important characteristic of CNS
development is the extensive apoptotic cell death that
occurs when neurons do not receive sufficient neurotrophic
support during the process of target innervation (Oppenheim
1996; Pettmann and Henderson 1998). TNF-α-mediated
apoptosis during this period was proposed by Zhao et al. In
their study, which employed septo-hippocampal neuron
cultures, TNF-α induced death of neurons by stimulating
caspase-3, and ultimately led to the activation of apoptotic
machinery (Zhao et al. 2001). Sympathetic and nociceptive
sensory neurons require specific neurotrophic signaling from
nerve growth factor (NGF) to prevent programmed cell
death. Barker and colleagues demonstrated that TNF-α
exacerbates neuronal apoptosis when neurons are deprived
of NGF. In the same study, cell death was blocked with the
treatment of anti-TNF-α or TNF-RI antibodies in cultures of
NGF-dependent embryonic neurons from the trigeminal
ganglia (Barker et al. 2001). Intrinsic and extrinsic factors
46
have been reported to mediate cell death of motoneurons. In
rat explants, there appears to be a critical period for
motoneuron commitment to cell death. Prior to this critical
period, between E12 and E13, motoneurons transiently
express TNF-RI, and when exposed to macrophage-
secreted TNF-α, motoneurons undergo programmed cell
death, suggesting that TNF-α acts to initiate apoptosis in this
setting (Sedel et al. 2004).
Cell-fate determination during the differentiation of
neural stem cells into specific neuronal and glial cell
lineages, as well as migration and proliferation, are highly
orchestrated processes that are central to normal develop-
ment. TNF-α is one of many soluble factors that influences
neuronal maturation, survival, and function, although the
specific mechanisms by which TNF-α mediates these
processes are somewhat unresolved due to conflicting
results in the published literature. Keohane et al. reported
embryonic neural progenitor cell (NPC) proliferation is
unaffected by TNF-α, while cell lineage fate differentiation
is anti-neurogenically skewed resulting in a loss of
embryonic neurons and an elevation of newly born
astrocytes (Fig. 3) (Keohane et al. 2010). The authors
posited that TNF-α differentially regulates cell proliferation
and differentiation and these differences may be due to
upregulated HES1 gene expression, an anti-neurogenic
factor, and increased TNF-receptor expression subsequent
to the addition of TNF-α on differentiating NPCs.
Similarly, Liu et al. reported TNF-α negatively affects cell
fate determination of embryonic rat NPCs into neurons (Liu
et al. 2005b). Furthermore, TNF-α knockout mice exhibit
Neural Stem
Cell (NSC)
Self-renewal
TNF-α
Progenitor Cells
Glial Progenitor Neuronal Progenitor
Committed Cells
TNF-α
Oligodendrocyte Astrocyte Neuron
Fig. 3 Neural progenitor cell differentiation and maturation is TNF-α
dependent. TNF-α has been shown to be anti-neurogenic during cell
lineage fate determination, resulting in an increased numbers of newly
born astrocytes and TNF-α is required for neuron maturation in
specific contexts
J Neuroimmune Pharmacol (2012) 7:42–59
altered hippocampal development whereby dentate gyrus
maturation is quicker and dendritic tree arborization of the
CA1 and CA3 sub-regions are significantly retarded, which
may be due to the ability of TNF-α to modulate growth
factors that influence pyramidal cell migration of the
hippocampus (Golan et al. 2004). Interestingly, astrocytes
may promote these morphological alterations given that
astrocytic GFAP-deficient mice harbor neurons comprised
of dense and elongated neurites, possibly speaking to a role
for TNF-α in astrocyte differentiation as mentioned
previously (Menet et al. 2000; Keohane et al. 2010).
Nevertheless, data also support TNF-α as a pro-
neurogenic cytokine. At low concentrations, TNF-α pro-
motes neurogenesis and axonogenesis of subventricular
zone (SVZ) cultures and this response appears to be
dependent upon TNF-RI engagement with its ligand
(Bernardino et al. 2008). Obregon and colleagues further
alluded to a pro-neurogenic effect of TNF-α such that when
TNF-α is neutralized with antibodies, immature neuronal
cells lines are incapable of differentiating into mature
neurons (Fig. 3) (Obregon et al. 1999). TNF-α has also
been shown to alter the cellular morphology of hippocam-
pal neurons by increasing cell body size and reducing
neurite outgrowth (Neumann et al. 2002). Taken together,
these data suggest that there is a subtle line between TNF-
α-induced pro- and anti-neurogenic function, which may be
contingent on local TNF-α concentrations, timing, receptor
expression, and cellular location and context.
Synaptic transmission
Synaptic plasticity augments activity-dependent modifica-
tions of neuronal networks by rapidly adjusting individual
synapses in response to synaptic activity, as measured via
alterations in long-term potentiation (LTP) and long-term
depression (LTD) reviewed by (Bear and Malenka 1994).
Another process regulating synaptic plasticity is a homeo-
static mechanism called “synaptic scaling”. Chronic or
prolonged activity can induce neurons to alter the strength
of all synapses thereby allowing for the maintenance of
stably functioning circuits (Turrigiano et al. 1998). Pub-
lished evidence supports a role for TNF-α in synaptic
plasticity. For instance, TNF-α increases α-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid (AMPA) glutamate re-
ceptor expression leading to enhanced synapse efficacy
and rapid synaptic transmission. AMPA receptor insertion
is dramatically increased when hippocampal neurons in
culture are treated with TNF-α, and abrogation of TNF-α
signaling downregulates AMPA receptors (Beattie et al.
2002). Furthermore, in response to a prolonged absence of
neural activity, TNF-α induces synaptic scaling and relies
on glial cell-secreted TNF-α (Stellwagen and Malenka
2006). Other reports suggest that TNF-α is imperative for
J Neuroimmune Pharmacol (2012) 7:42–59
the maintenance of synaptic plasticity, and if TNF-α
signaling is neutralized for more than 12 h, neuronal
synapses are refined, where scaffold proteins important for
the make-up of the postsynaptic density are re-organized
leading to suboptimal synaptic connectivity and a reduction in
sustained synaptic scaling (Steinmetz and Turrigiano 2010).
N-methyl-D-aspartate (NMDA) receptors are also regulated
by TNF-α. Wheeler et al. demonstrated that through
increased ceramide by spingomyelinase-2 regulation,
NMDA surface localization was enhanced (Wheeler et al.
2009). In addition to glutamate receptor expression, calcium
homeostasis is modulated by TNF-α, where type-1 inositol
1,4,5-trisphosphate receptors that are involved in calcium
homeostasis and long-term potentiation mechanisms are
influenced by TNF-α, particularly through JNK signaling
(Fujii et al. 2000; Park et al. 2008).
The synapse represents a vital neuronal structure and
progressive loss of the circuitry is a common theme in
neurodegenerative diseases. Moreover, reduction in synapse
density has been shown to represent the best correlate to
disease progression, especially in the case of AD and brain
injury (DeKosky and Scheff 1990; Scheff et al. 2006; Ding
et al. 2009). Hermann and colleagues determined that
during injury, TNF-α in cooperation with glutamate,
promotes neuronal excitotoxicity due to the excessive and
rapid surface expression of AMPA receptors leading to
increased intracellular calcium (Hermann et al. 2001). In
addition, Ca2+ permeable AMPA/kainite channels of hippo-
campal CA1 and CA3 neurons are upregulated when
exposed to TNF-α, possibly indicating that during injury
or disease TNF-α may exacerbate damage (Ogoshi et al.
2005). In aggregate, these studies suggest that TNF-α is
critical in the normal brain for proper synaptic strength, but
that alteration in the level of this molecule, such as during
neurodegeneration and traumatic brain injury, results in
acute neuronal disruption and potential chronic dysfunction
that may ultimately compromise the viability of neurons.
Adult neurogenesis
Neural stem cells (NSCs) are present in the adult human
brain, and new neurons are continuously generated
throughout an individual’s lifetime (Stemple and Anderson
1992; Temple 2001). Two highly neurogenic regions of the
adult brain include the subgranular zone (SGZ) of the
dentate gyrus that gives rise to intermediate hippocampal
progenitors and the subventricular zone (SVZ) encompass-
ing the lateral ventricles that give rise to olfactory bulb
neurons (Lie et al. 2004; Deng et al. 2010). Chemokines
and cytokines exert critical functions in modulating NSCs
whereby some of these factors may induce, while others
impair, neurogenesis. In general, inflammation can restrict
the generation of new neurons. Specifically, LPS-induced
47
inflammation has been reported to significantly reduce
neurogenesis, and administration of an anti-inflammatory
antibiotic can reverse these suppressive actions (Ekdahl et
al. 2003). Since human NSCs express both TNF-RI and
TNF-RII, these cells can be influenced by TNF-α through
autocrine and paracrine actions (Sheng et al. 2005). TNF-α
has an anti-neurogenic effect during adult neurogenesis
whereby in culture, microglia-secreted TNF-α is detrimen-
tal to hippocampal progenitor cells (HPC) by abruptly
halting cell division and leading to progenitor cell death
(Cacci et al. 2005). In contrast, others have shown striatal
and hippocampal neurogenesis is compromised when an
antibody to TNF-α is transiently infused into the lateral
ventricle of a rat stroke model. This indicates that
subsequent to stroke, TNF-α can encourage the survival
of neural progenitor cells and the authors propose a
possible role for TNF-RII due to the reported neuro-
protective roles for TNFα engagement to this receptor
(Marchetti et al. 2004; Heldmann et al. 2005). Iosif et al.
demonstrated that TNF-RI negatively regulates adult neuro-
genesis of the hippocampus where TNF-RI or RI/RII
knockout mice exhibit an increased number of adult
hippocampal neurons following status epilepticus (Iosif et
al. 2006). In addition, during ischemic stroke, binding of
TNF-α to TNF-RI suppresses SVZ progenitor proliferation
(Iosif et al. 2008). These data demonstrate TNF-α has
positive and negative effects during adult neurogenesis,
which are dependent upon induction context and receptor
sub-type engagement.
TNF-α in neurodegenerative disease
Multiple sclerosis
Multiple sclerosis (MS) is an inflammatory autoimmune
disease of the CNS with the clinical manifestation of focal
demyelinating plaques, progressive axonal loss, and gliosis
(Trapp et al. 1998; Lassmann et al. 2007). Formation of
white matter lesions trigger infiltration of systemic lym-
phocytes, such as Th1 and Th17 cells, macrophages and
brain-resident microglia resulting in a T cell mediated
autoimmune attack against myelin peptide that eventually
leads to widespread demyelination. Pathological hallmarks
of MS are stage-dependent, where approximately 80% of
MS patients are diagnosed with relapsing/remitting MS and
65% of these patients follow a progressive phase called
“secondary progressive”. Relapsing MS is accompanied by
an inflammatory reaction and the formation of new
demyelinating lesions. In contrast, progressive MS includes
gray and white matter atrophy with limited genesis of new
inflammatory lesions (Sanfilipo et al. 2006; Lassmann et al.
2007). Inflammatory responses are the primary mechanism
48
leading to myelin destruction and olidgodendrocyte cell
death. Pro-inflammatory TNF-α is detected upon post-
mortem examination of MS brain lesions, is abnormally
elevated in the CSF of patients, and the levels of this
cytokine correlate with disease severity and progression
(Beck et al. 1988; Sharief and Hentges 1991) (Hofman et
al. 1989). In MS, TNF-α is implicated in myelin and
oligodendrocyte deterioration, lymphocyte infiltration, as-
trocyte activation, and the upregulation of major histocom-
patibility complex (MHC) I and II molecules on CNS-
resident cells, thereby triggering T cell responses (reviewed
in Constantinescu 2010).
Several animal model studies of MS suggest TNF-α
signaling leads to demyelination, increased inflammatory
status, and compromised oligodendrocyte health. In fact,
when TNF-α is overexpressed in the mouse brain, chronic
inflammation including reactive gliosis, T cell infiltration,
and demyelination occurs leading to premature death.
Remarkably, this phenotype is rescued with a TNF-α
neutralizing antibody and illustrates the deleterious effect
of TNF-α on myelin and oligodendrocyte integrity (Probert
et al. 1995). Furthermore, in experimental autoimmune
encephalomyelitis (EAE), a mouse model for brain inflam-
mation and MS, anti-TNF or sTNF receptor antibodies
ameliorate disease (Selmaj et al. 1991; Baker et al. 1994).
Studies have demonstrated that TNF-α is necessary for the
early initiation of EAE, where mice deficient in TNF-α
display delayed onset of disease compared to wild-type
counterparts. However in later phases of disease, TNF-
deficient mice still develop severe EAE with extensive
inflammation and primary demyelination, indicating that
TNF-α may be more important for initial leukocyte homing
rather than progression of later stage disease (Korner et al.
1997). The immunosuppressive roles of TNF-α may be one
possible explanation for disease progression in TNF-
deficient mice. TNF-α is partially involved in deactivating
myelin basic protein or (MBP)-reactive autoimmune T cells
and TNF-deficient mice harbor a prolonged T cell response
against myelin, but these reactive T cells accumulate and
subsequently contribute to chronic EAE (Kassiotis and
Kollias 2001). Failure to reverse these reactive T cell
responses appears to be TNF-RII-mediated, since TNF-RI
KO mice harbor reduced inflammatory cell infiltrates and
demyelination, while severe disease persists in TNF-RII
KO mice (Suvannavejh et al. 2000). These data suggest that
not only can TNF-α play a protective role in EAE by
suppressing potential MBP-reactive T cells, but at elevated
levels can accelerate disease progression and onset of white
matter lesions.
Therapeutic anti-TNF-α inhibition for MS patients has
had limited success, despite a wealth of preclinical research
findings indicating the beneficial effects of TNF-α sup-
pression. During an open-label phase I trial, a monoclonal
J Neuroimmune Pharmacol (2012) 7:42–59
TNF-α antibody was infused into two human patients
exhibiting rapidly progressing disease. As a result of
transient pan-TNF-α inhibition, magnetic resonance imag-
ing (MRI) revealed increased gadolinium-enhancing lesions
and lymphocyte numbers indicating exacerbation of disease
(van Oosten et al. 1996). Subsequently, in a double-blinded,
placebo controlled, multicentered phase II study, 168
relapse-remitting MS patients were administered lenercept,
a sTNF-RI fusion protein that neutralizes TNF-α. Com-
pared to placebo control patients, lenercept-treated individ-
uals experienced higher occurrence of relapse and increased
neurological deficit (1999). Moreover, anti-TNF-α agents
used to treat other inflammatory diseases such as psoriatic
arthritis, ankylosing spondylitis, and rheumatoid arthritis
have also been associated with demyelination that closely
resembles that observed in multiple sclerosis (Mohan et al.
2001; Titelbaum et al. 2005; Winkelmann et al. 2008). The
ineffectiveness of anti-TNF-α therapy in MS may be a
consequence of divergent roles for the TNF receptors,
considering that blocking TNF-RI in mouse models damp-
ens disease severity, while suppressing TNF-RII, the
receptor that induces remyelination and harbors immuno-
suppressive properties, results in exacerbated disease
(Arnett et al. 2001; Kassiotis and Kollias 2001).
Recently, pharmacological agents selectively targeting
TNF-RI have been investigated. Using phage display
technology, a TNF-RI antagonist was developed, and
upon evaluation in EAE mice it was found that adminis-
tration of this selective antagonist improved clinical
scores, lessened cerebral demyelination, and suppressed
the number of infiltrating inflammatory cells, as well as
Th1 and Th17 immune responses (Nomura et al. 2011).
Although these experiments were performed in mice, and
have yet to be tested in humans, investigators are actively
pursuing these more selective strategies to modulate TNF-α
signaling in MS.
Parkinson’s disease
Parkinson’s disease (PD) is the second most common age-
related neurodegenerative disorder causing progressive and
chronic mobility debilitation. Afflicted individuals develop
resting tremor, bradykinesia, muscle rigidity, and postural
irregularity. Hallmark pathologies include gradual loss of
dopaminergic neurons in the substantia nigra (SN) pars
compacta and intraneuronal proteinaceous inclusions called
Lewy bodies, which contain aggregates of fibrillar α-
synuclein and ubiquitinated proteins (Spillantini et al.
1997; Chung et al. 2001). Neuronal loss and degeneration
is most severe in the SN; however, non-motor, PD-
associated deficits in cognition and autonomic nervous
system function may be attributed to cholinergic, adrener-
gic, and serotoninergic cell death (Chaudhuri et al. 2006).
J Neuroimmune Pharmacol (2012) 7:42–59
Currently, there are no disease-modifying therapies for PD,
although symptomatic treatment is effective during earlier
stages of disease. Over time, with increasing disease
severity, these drugs are no longer effective (Schapira
2009). While the etiology of PD remains to be fully
elucidated, a majority of idiopathic PD cases appear to arise
from a complex interaction between genetic susceptibility
and environmental factors (Gorell et al. 2004). Increased
risk for PD has been shown with rural residency, pesticide
exposure, drinking well water and occupations including
mining, welding, and farming (Priyadarshi et al. 2001;
Firestone et al. 2005; Jankovic 2005). Beside environmen-
tal stimuli, 15 distinct chromosomal loci have been linked
to increased susceptibility to PD, and specific genes with
some of these loci have been identified and implicated in
pathogenesis (Lesage and Brice 2009).
Neuroinflammatory processes appear to play key roles in
DA neuron dysfunction and death in PD. Activated micro-
glia and T-lymphocytes are present in the SN of postmortem
PD brain and positron emission tomography (PET) studies
using [11 C](R)-PK11195, a marker for activated microglia,
show that more activated microglia selectively cluster in
regions of the brain damaged by PD, including the basal
ganglia, striatum, the pons, and frontal and temporal cortex
(McGeer et al. 1988; Banati et al. 1998; Imamura et al.
2003; Gerhard et al. 2006). In fact, large numbers of TNF-α
immunoreactive glial cells are found in the SN of PD
patients compared to healthy controls and most DA neurons
are TNF receptor-positive (Boka et al. 1994). TNF-α is
elevated in the striatum and cerebral spinal fluid (CSF) of
PD patients, while sTNF-RI levels are also increased in the
CSF (Mogi et al. 1994; Mogi et al. 1995; Dobbs et al. 1999;
Mogi et al. 2000). Single-nucleotide polymorphisms local-
ized to the TNF-α promoter region that positively correlate
with increased risk for developing sporadic PD have been
reported (Nishimura et al. 2001). Moreover, variance in
TNF-α promoter methylation patterns may favor selective
vulnerability to certain populations of neurons, particularly
to SN-resident neurons. In both healthy and PD patients
post-translational methylation is reduced in the SN com-
pared to the cortex. However, PD patients harbor a
significant increase in unmethylated cytosine CpG dinucle-
otide residues within the TNF-α promoter of SN neurons
that may modulate AP-2 and Sp1 transcription factor
binding, since promoter transcription factor binding is a
methylation-dependent process (Pieper et al. 2008). These
data may have implications in the role of TNF-α gene
transcriptional regulation and susceptibility of SN-resident
neurons to PD-related degeneration.
TNF-α levels have been shown to correlate with the
extent of DA neuronal death in PD-afflicted brain regions,
suggesting that either the death of DA neurons induces
local cytokine production or that increased TNF-α concen-
49
trations contribute to DA neuron demise in PD. In a 6-
hydroxydopamine (6-OHDA)-based animal model that
exhibits slowly progressing degeneration that is more
reminiscent of human PD, TNF-α protein levels are
significantly enhanced within the striatum and SN (Mogi
et al. 1999). When low levels of TNF-α (17–19 pg/mg) are
expressed in the SN for a period of 2 weeks, DA
neurodegeneration progressively ensues and leads to motor
impairments, infiltration of leukocytes, astrogliosis, and
microglial activation via COX-2 and/or NOS activity,
suggesting that TNF-α is both necessary and sufficient to
exacerbate DA neuron demise (De Lella Ezcurra et al.
2010). In another neurotoxicant PD model, intrastriatal
administration of a soluble TNF-α dominant-negative
inhibitor to neutralize endogenous TNF-α resulted in a
rescue of approximately 50% of the DA neurons that
typically succumb to oxidative neurotoxin 6-OHDA or
endotoxin-induced death (McCoy et al. 2006).
In contrast, several investigators have shown beneficial
effects for TNF-α in the context of PD. For example, mice
deficient for both TNF-RI and RII exposed to 1-methyl-4-
phenyl-1,2,3,4-tetrahydropyridine (MPTP), a DA neuronal
toxin, exhibit DA neuron loss and perform worse on the
rotarod motor test, as compared to mice lacking only one of
the TNF receptors or wild-type littermates (Rousselet et al.
2002). Similarly, wild-type, TNF-RI KO, and TNF-RII KO
mice treated with MPTP for 8 days displayed no differences
in striatal dopamine or dopamine transporter levels, arguing
against a role for TNF-α neurotoxicity (Leng et al. 2005).
In another study, mice lacking both high-affinity TNF
receptors exhibit decreased microglial activation within the
striatum following exposure to MPTP (Sriram et al. 2002).
Surprisingly, however, increased neuronal damage and
microtubule-associated protein-2 reactivity were found in
their hippocampi (Sriram et al. 2002, 2006), demonstrating
a clear region-specific difference in TNF-α signaling within
the same brain, where TNF-α is protective in the
hippocampus but drives neurodegeneration in the SN
following MPTP neurotoxicant exposure. Chertoff and
colleagues have also explored the concept of TNF-α
playing dual roles in PD pathophysiology. Young 2–
3 month-old mice subjected to 6-OHDA with constitutive,
low-level expression of TNF-α are spared in respect to
nigrostriatial degeneration, whereas overt neuronal loss and
inflammatory responses occurs in mice overexpressing
TNF-α, indicating that the level and timing of TNF-α
plays a pivotal role in the progression of disease (Chertoff
et al. 2011). Collectively, these data demonstrate that the
development of anti-TNF-α PD therapies requires a highly
tuned and selective strategy based upon assiduous exami-
nation of the dependence of disease stage, TNF-α levels,
cellular context, and individual receptor involvement in
multiple models of PD. It is clear with the latter that the
50
generation of predictive preclinical models of PD is of the
utmost importance if such complex signaling effects of
TNF-α during idiopathic PD are to ever be accurately
dissected.
Alzheimer’s disease
Alzheimer’s disease (AD) is the most prevalent age-related
disorder, which is associated with progressive development
of severe memory loss, cognitive deficits, personality and
behavior changes influencing mood, communication, judg-
ment, and reasoning. According to the Alzheimer’s Asso-
ciation, this neurodegenerative malady affects 5.4 million
Americans, and alarmingly, AD prevalence is ever increas-
ing. By 2050, it is projected that 11–16 million people in
the U.S. alone will be afflicted with AD (http://www.alz.
org/). Albeit the vast majority of AD cases are sporadic
with symptoms beginning after the age of 65, cases of
early-onset familial AD have been documented, which are
caused by inherited autosomal-dominant mutations in the
amyloid precursor protein (APP), presenilin-1 (PS1) and
presenilin-2 (PS2) genes. While the exact cause of sporadic
AD is not fully understood, age is the strongest predictor of
disease. Nevertheless, due to the complexity and multifac-
torial nature of AD, the development of effective disease-
modifying therapies has been especially challenging.
Classic neuropathological correlates of AD include
extracellular amyloid plaques primarily composed of
accumulated Aβ peptides and intraneuronal filamentous
inclusions called neurofibrillary tangles caused by hyper-
phosphorylation of the tau cytoskeletal protein (Merz et al.
1983; Braak and Braak 1988). In addition, brain region-
specific synapse loss, inflammation and neuronal death are
other major pathophysiological markers of AD. The
amyloid cascade hypothesis is a predominate theory in the
field stating that overproduction of Aβ, or a failure to
efficiently clear the peptide is the earliest initiating event in
AD. Aβ is fibrillogenic in nature and can further aggregate
into oligomeric structures, which are highly neurotoxic and
synaptotoxic, and eventually these Aβ aggegates form
higher order structures and deposit as plaques within the
brain parenchyma (Hardy and Higgins 1992; Pimplikar
2009). Amyloidogenic plaques are characterized by the
presence of intimately associated activated microglia and
reactive astrocytes. These cells, as stated above, are major
sources of pro-inflammatory molecules such as chemo-
kines, complement factors, cytokines, and reactive oxygen
species (Ruan et al. 2009). Therefore, it is not surprising
that the master regulating cytokine, TNF-α, has been
intensely studied and debated regarding its purported role
in AD pathogenesis. Examination of post-mortem AD
brains reveals that increased TNF-α co-localizes with Aβ
plaques, is upregulated in both CSF and serum, and its
J Neuroimmune Pharmacol (2012) 7:42–59
levels correlate with disease severity (Fillit et al. 1991;
Dickson 1997; Paganelli et al. 2002). More recently, MCI
patients who subsequently developed AD were found to
harbor increased levels of sTNF-RI and sTNF-RII that
correlate with β-site APP-cleaving enzyme 1 (BACE1)
cleavage activity, which is a key enzyme involved in
pathological Aβ metabolism (Buchhave et al. 2010). In
addition, genome-wide screens have attributed microsatel-
lite TNF-α and gene promoter polymorphisms to increased
production of TNF-α and increased risk for developing AD
(Culpan et al. 2003; Ma et al. 2004; Collins et al. 2000;
Laws et al. 2005).
Transgenic mouse models have been instrumental in
deciphering the role of TNF-α in AD, but like in the PD
research field, the accuracy of presently available models in
faithfully mimicking the human disease and their utility in
assessing potential efficacy of new therapeutic interventions
is up for debate. Given these caveats, TNF-α is upregu-
lated, co-localized with amyloid plaques, and neurotoxic in
mouse models that recapitulate specific human AD-related
pathologies. For instance, the triple transgenic mouse model
of AD (3xTg-AD) that harbors three familial-linked AD
mutations (APPswe, PS1M146V , and TauP301L) and progres-
sively develops amyloid and tau pathologies exhibits
increased TNF-α and monocyte chemoattractant protein-1
(MCP-1) transcript levels, as well as increased numbers of
activated microglia, in the entorhinal cortex at an age
preceding appearance of plaque and tangle pathologies
(Janelsins et al. 2005). The amyloidogenic Tg2576 mouse
model develops Aβ plaques, increased TNF-α immuno-
reactivity, and glial cell clustering adjacent to fibrillar
plaques (Mehlhorn et al. 2000). Similarly, in an APPswe/
PS1dE9 mouse model, TNF-α expression increases in a
disease stage-specific manner, and TNF-α immunoreactive
cells co-localize with ThioflavineS-positive Aβ plaques
(Ruan et al. 2009).
Significant experimental evidence exists that identify
relationships between Aβ and TNF-α signaling. Both
cognate TNF-α receptors have been shown to physically
bind soluble Aβ40 (Li et al. 2004), and overexpression of
TNF-RI in neurons exposed to Aβ40 in vitro induces
neuronal death (Li et al. 2004). TNF-α exposure triggers
APP cleavage to generate disease-related Aβ peptides by
regulating processing enzyme activity (Kuo et al. 2008;
Chen et al. 2011; Yamamoto et al. 2007). Elaboration of
Aβ42, the more hydrophobic plaque-associated form of Aβ,
is sequentially cleaved from APP by orchestrated β-
(BACE1) and γ-secretase processing enzyme activities.
TNF-RI-mediated TNF-α signaling upregulates BACE1
activity via NFκB activation and APP mice lacking TNF-RI
harbor reduced Aβ peptide concentrations and amyloid
plaque load (He et al. 2007). Competition for APP occurs
between BACE1 and TACE, the TNF-α converting
J Neuroimmune Pharmacol (2012) 7:42–59
enzyme (also referred to as α-secretase), which cleaves
both precursor TNF-α and the ectodomain of APP leading
to decreased Aβ generation (Skovronsky et al. 2000). Since
TNF-α is highly expressed in AD, TACE may be in high
demand for TNF-α maturation, and as a result, BACE1
may be more available to initiate amyloidogenic cleavage
of APP, thereby releasing more Aβ peptide. APP metabo-
lism by γ-secretase is also modulated by TNF-α and
depends upon JNK mitogen-activated protein (MAP) kinase
signaling (Liao et al. 2004).
Experimental manipulation of TNF-α levels in vivo has
provided valuable insight into the role of TNF-α during AD
pathogenesis and therapeutic potential of anti-TNF
approaches to prevent and/or treat AD. Employing a
selective soluble TNF-α dominant-negative inhibitor, which
has a predilection for TNF-RI engagement, transiently in
conjunction with LPS-induced inflammation, reduces intra-
neuronal Aβ accumulation and APP C-terminal fragment
generation in the hippocampus, cortex, and amygdala of
3xTg-AD mice (McAlpine et al. 2009). APP/PS1 transgen-
ic mice intracerebroventricularly injected with the mono-
clonal anti-TNF antibody, infliximab, for 3–14 days
exhibited reduced amyloid plaque deposition and tau
hyperphosphorylation. Interestingly, CD11c-positive
dendritic-like cells clustered in close proximity with
amyloid plaques specifically in mice receiving infliximab
(Shi et al. 2011), suggesting that these cells participated in
clearing Aβ peptide in treated mice (Butovsky et al. 2007).
Furthermore, by pharmacologically blocking TNF-α or
through use of TNF-RI knockout mice intrahippocampally
injected with Aβ1-40, learning and memory deficits typical-
ly evoked by the synergistic effects of TNF-α and Aβ were
rescued (Medeiros et al. 2007). While these studies have
been very informative in understanding the effects of TNF-
α on AD progression and support the use of anti-TNF-α
therapy for human treatment, a few critical unknowns
remain. The abovementioned studies were performed over a
relatively short period of time in rodent models, whereas
human patients would require longer-term administration of
anti-TNF-α inhibitors. Hence, what is the effect of long-
term suppression of TNF-α signaling and are there
distinct disease stage-specific positive roles that TNF-α
plays that would be inhibited by anti-TNF-α therapeu-
tics? In addition, the above studies do not take into
account cell type-specific mechanisms of TNF-α within
the CNS, where TNF-α signaling may need to be
maintained in one or several cell types for “normal”
physiologic processes. Pan-inhibition of TNF-α activity
in the setting of AD could undermine such processes and
lead to increased dysfunction.
Recently, Giuliani and colleagues demonstrated the
effect of chronic TNF-α ablation in the PDAPP mouse
model, which displays amyloid plaque pathology, neuro-
51
degeneration, and reactive gliosis (Giuliani et al. 2009). In
the absence of TNF-α, spatial memory as assessed by the
Morris Water Maze revealed no improvements in spatial
learning and memory at 6 and 15 months of age compared
to control mice, and amyloid burden was greatly enhanced
at 20 months of age (Giuliani et al. 2009). Furthermore,
long-term abrogation of TNF-α receptor expression leads to
elevated extracellular amyloid plaque deposition and
accelerated paired helical filament formation of 15 month-
old 3xTg-AD mice. The enhancement of amyloid pathol-
ogy is, in part, due to impaired phagocytosis activity by
microglia derived from 3xTg-AD mice lacking TNF-RI and
TNF-RII, suggesting that long-term pan TNF-α inhibition
worsens pathology and suppresses glial activation that may
be required for Aβ clearance (Montgomery et al., under
review). In further support for a possible protective role of
TNF-α in AD, mouse TNF-α was stereotaxically injected
into the hippocampus of TgCNRD8 mice using recombi-
nant adeno-associated virus 1/2 and amyloid plaque
pathology was dramatically decreased and a strong micro-
glia cell activation was induced (Chakrabarty et al. 2011).
Although this study overexpressed TNF-α transiently, it
ascertains potential beneficial roles for TNF-α in activating
microglia to mediate Aβ clearance and may address the
importance for cell-specific restriction and/or facilitation of
TNF-signaling during particular stages of AD.
Activated microglia are capable of Aβ peptide clearance
by internalizing both soluble Aβ and fibrillar Aβ con-
formations. Specifically, microglia-mediated internalization
of soluble Aβ transpires through fluidic macropinocytosis
that is distinct from phagocytosis and receptor mediated
endocytosis. In addition, soluble Aβ uptake, of which
localizes diffusely throughout the entire cell, seems to be
independent of clathrin-coated vesicle assembly and mem-
brane cholesterol, whereas internalization of fibrillary Aβ is
trafficked to primarily large cytoplasmic phagocytic
vesicles (Mandrekar et al. 2009). Phagocytosis of fibrillary
Aβ depends on cell surface marker expression, including
toll-like receptors, CD36, CD14, α6β1, CD47, and SIRP-
β1, and a subset of these proteins are regulated by TNF-α
(Koenigsknecht and Landreth 2004; Liu et al. 2005a;
Gaikwad et al. 2009; Reed-Geaghan et al. 2009). For
example, CD14 expression positively correlates with TNF-
α levels, whereas CD36 negatively correlates with TNF-α
(Liu et al. 2005a; Hickman et al. 2008). Moreover, TNF-α
is a strong inducer of microglial activation and appears to
be an important factor in regulating Aβ internalization.
Thus, intact microglial TNF-α signaling may facilitate
reduced Aβ plaque deposition via enhancement of Aβ
peptide clearance (Fig. 4). Further studies are needed to
fully understand and elucidate when microglial TNF-α
signaling is required, since during later stages of disease,
microglial phagocytosis or internalization of Aβ peptide
52
No TNF-α Modulation Pan TNF-α Modulation
TNF-α Production TNF-α Production
Microglial Neuronal Microglial
Signaling Signaling Signaling
Aβ Clearance Aβ Production Aβ Clearance
Transient
Suppression
Disease
Progression or Progression
Chronic
Suppression
Fig. 4 Potential anti-TNF-α therapeutic strategies for AD. Intact
microglial TNF-α signaling potentiates Aβ uptake and subsequent
clearance of the peptide. Neuronal TNF-α signaling may lead to
increased Aβ generation and eventually result in the death of this cell
type. Without any therapeutic TNF-α modulation, disease progression
ensues with heightened Aβ production and limited microglial-
pools become compromised resulting in the profound
production of highly toxic pro-inflammatory molecules that
contributes significantly to the chronic inflammatory milieu
and coincident neurotoxicity.
While microglial TNF-α signaling at certain stages of
AD may repress AD-associated pathology, other brain-
resident cells likely respond differently. Neurons have been
well studied in the AD field because these cells are the
primary sources of Aβ peptides and are the sites of
dysfunction. Existing data suggest TNF-α signaling in
neurons is neurotoxic, and considering the direct role TNF-
α plays in APP generation, it is plausible that inhibiting
neuronal TNF-α signaling would be protective. During AD,
neurons produce appreciable levels of TNF-α, and when
TNF-α is chronically overexpressed specifically by neurons
in the 3xTg-AD model, amyloid and phospho-tau pathol-
ogies are exacerbated compared to non-transgenic control
mice, eventually leading to neuronal cell death (Janelsins et
al. 2008). Similarly, primary neurons overexpressing TNF-
RI and treated with Aβ leads to neuronal cell death, while
neurons from TNF-RI knockout mice are spared in the
presence of Aβ (Li et al. 2004). These latter data suggest
that selectively preventing neuronal TNF-α signaling,
through targeted blocking of receptor expression, may
preserve neurons during the course of AD (Fig. 4).
Despite the ample data supporting detrimental effects for
intact neuronal TNF-α signaling, several reports have
alluded to neuroprotective roles for TNF-α. In the presence
of Aβ peptide, dissociated neuronal cultures pretreated with
TNF-α were saved from Aβ-induced neuronal death by
specifically protecting against iron and intracellular Ca2+
J Neuroimmune Pharmacol (2012) 7:42–59
Cell-selective TNF-α Modulation
TNF-α Production
Neuronal Microglial Neuronal
Signaling Signaling Signaling
Aβ Production Aβ Clearance Aβ Production
Disease Disease
? Progression
mediated Aβ clearance. Pan TNF-α inhibition may quell TNF-α
induced Aβ production by neurons, but also will suppress microglial
Aβ clearance. Selectively targeting neuronal TNF signaling and
allowing microglial signaling at certain disease stages may reduce
neuronal Aβ genesis but permit microglia-driven Aβ clearance
toxicity via NFκB-dependent signaling (Barger et al. 1995).
Furthermore, TNF-α is protective to neurons against
oxidative stress by stimulating antioxidant signaling and
superoxide accumulation through induced MnSOD activity
(Bruce et al. 1996; Bruce-Keller et al. 1999). Taken
together, more investigation is warranted to better discern
the cell-specific roles of TNF-α in the context of AD and
the cell-cell interactions amongst CNS-resident cell pop-
ulations in order to develop therapeutics that may be able to
selectively modulate TNF-α signaling in a cell type-
specific manner.
TNF-α ablation as a therapeutic strategy
Historical and epidemiological perspective for TNF-α
immune modulation in brain diseases
A naturally occurring TNF-α inhibitor was discovered in
human urine by Seckinger and colleagues in 1988, which
was identified as a soluble form of the TNF-receptor that
acted by neutralizing the cytokine (Seckinger et al. 1990).
Subsequently, two TNF-binding proteins were purified that
were capable of inhibiting the binding of TNF-α to cells
(Engelmann et al. 1990). The identification of soluble TNF-
receptors paved the way for the development of soluble
TNF-receptor antibodies currently used for the treatment of
several systemic inflammatory diseases, including rheuma-
toid arthritis (RA), juvenile polyarticular RA, inflammatory
bowel disease, psoriatic arthritis and ankylosing spondylitis
(Sfikakis 2010). There are three anti-TNF-α agents
J Neuroimmune Pharmacol (2012) 7:42–59
approved for clinical use: Etanercept (Enbrel®), infliximab
(Remicade®), and adalimumab (Humira®). The latter two
are full-length bivalent IgG monoclonal antibodies specific
for sTNF and tmTNF, whereas Etanercept is a genetically
engineered Fc fusion protein generated from the extracel-
lular domain of human TNF-RII and functions as a decoy
receptor to block sTNF, tmTNF, and distinct ligands of
lymphotoxin, a TNF-related protein (Tracey et al. 2008). A
detailed review of these TNF-α antagonists and their
mechanisms of action have been published elsewhere
(Tracey et al. 2008).
Epidemiological studies support the use of immunomo-
dulation strategies to suppress inflammatory processes in
neurodegenerative disease. Long-term use of non-steroidal
anti-inflammatory drugs (NSAIDs) that inhibit cyclooxy-
genase, an enzyme involved in prostaglandin synthesis, has
been shown in retrospective studies to be protective for
chronic brain diseases such as in PD and AD. In 1997,
Stewart et al. reported that prolonged use of NSAIDs for
2 years or more reduced AD onset in a longitudinal study of
1,686 subjects (Stewart et al. 1997). These results have
been confirmed by several other studies using population-
based cohort studies involving 6,989 participants, com-
bined data from nine different studies of 14,654 people, and
a large case–control study of 246,199 subjects (in t’ Veld et
al. 2001; Etminan et al. 2003; Vlad et al. 2008). In a pilot
study, while administration of a non-selective NSAID,
indomethacin, for 6 months appeared to slow cognitive
decline in mild to moderate impaired AD patients, a second
pilot study using diclofenac and misoprostal, a drug used to
protect the gastrointestine, reported no differences between
placebo and treated patients (Scharf et al. 1999). Large
multi-site trials were subsequently performed where people
with established AD were administered nimesulide, cele-
coxib, naproxen, or prednisone, which preferentially inhibit
cyclooxygenase 2 activity. No significant effects on
cognitive and behavioral function were observed (Aisen et
al. 2000; Aisen et al. 2002; Aisen et al. 2003). Possible
explanations for the failure of COX-2 inhibition could be
attributed to advanced disease stage of the patients, duration
of treatment, doses of drugs administered or targeting of the
wrong inflammatory pathway, since NSAIDs are broadly
acting, interact with many molecular targets, and are more
effective at inhibiting microglia-related inflammatory pro-
cesses (Mackenzie and Munoz 1998). In fact, Klegeris et al.
reported that NSAIDs reduced pro-inflammatory cytokine
production from microglia, increased microglial phagocy-
tosis activity, and prevented microglial-induced neuronal
cell killing (Klegeris and McGeer 2005). Besides targeting
cyclooxygenase activity, NSAIDs can activate the peroxi-
some proliferator-activated receptor gamma or PPARγ
(Jaradat et al. 2001). PPARγ is expressed by macrophages
and receptor engagement inhibits inflammatory processes
53
mediated by pro-inflammatory cytokines, including IL-1β,
IL-6, and pertinent to this discussion, TNF-α (Heneka and
O’Banion 2007). Cumulatively, these studies demonstrate
that inflammation is a critical mechanism in neurodegener-
ative disease progression and for a therapeutic benefit to be
realized, careful dissection of these processes in the setting
of disease-relevant models is crucial.
Clinical trials for selective TNF-α inhibition
Clinical trials examining the effects of TNF-α inhibition
have been conducted on patients with MS and AD. As
briefly discussed, strategies to inhibit TNF-α in MS seemed
promising in preclinical applications, but disappointingly,
have widely failed in human clinical trials due to the lack of
therapeutic selectivity. These studies employed either
infliximab or lenercept and broadly neutralized both
soluble and transmembrane TNF-α in all cell types
(1999; van Oosten et al. 1996). Infliximab was adminis-
tered to two patients with rapidly progressing disease
during an open-label phase I clinical trial, while in a
double-blinded and multicentered phase II study 168
relapse-remitting patients were given lenercept. In both
studies, disease status was intensified. TNF-α interven-
tion for AD has been evaluated in open-labeled phase I
clinical trials where perispinal extrathecal administration
of Etanercept was administered weekly to a small
number of patients ranging from mild to severe AD for
a short duration of 6 month that claimed substantial
cognitive and behavioral improvements, including verbal
fluency and aphasia (Tobinick et al. 2006; Tobinick and
Gross 2008). Currently, a phase II study is recruiting to
evaluate the safety and tolerability of Etanercept in AD
(www.clinicaltrials.gov). These results seem promising,
but conclusions regarding the promise of such a therapeu-
tic strategy should be reserved until after extensive
chronic suppression of TNF-α activity is performed in
preclinical models and double-blind human clinical trials
have been conducted and results critically reviewed by the
research community.
Conclusion and future considerations
There is no doubt inflammatory processes, especially those
mediated by the central pro-inflammatory cytokine, TNF-α,
play key roles in degenerative conditions afflicting the
CNS. The precise role(s) TNF-α plays, in particular, remain
highly controversial due to the complexity and pleiotropic
nature of this cytokine and the activities attributed to TNF-
α during critical developmental and homeostatic cellular
processes. Multiple factors determine whether TNF-α will
exert deleterious or beneficial effects for neuronal survival,
54
and some of these differential actions relate to its duration
of expression (chronic vs. transient), concentration, receptor
conformation, and the inflammatory milieu. However,
despite the elaborate and promising data collected thus far
to assign function to TNF-α in neurodegeneration, surpris-
ingly little is still known about the cellular and stage-
specific roles of this cytokine. Given the limited under-
standing of selective TNF-α signaling, caution is urged
when clinically inhibiting the activity of TNF-α, and it is
likely that prolonged global suppression of TNF-receptor
signaling may not be an effective approach to remedy
neurodegeneration and may even intensify the disease state.
Therefore, further in vivo dissection of TNF-α signaling
and its associated receptors in a cell and stage specific
context is justified for the successful development of
selective therapeutic interventions that are safe and effica-
ciously ameliorate the deleterious actions of TNF-α in
neurodegenerative disease.
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