Hormonal Regulation of TNF in Alzheimer's Disease

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ASSOCIATE EDITOR: DAVID R. SIBLEY
Tumor Necrosis Factor-Induced Cerebral Insulin
Resistance in Alzheimer’s Disease Links Numerous
Treatment Rationales
Ian Clark, Craig Atwood, Richard Bowen, Gilberto Paz-Filho, and Bryce Vissel
Research School of Biology, Australian National University, Canberra, Australia (I.C.); Department of Medicine, University of Wisconsin-
Madison School of Medicine and Public Health, Madison, Wisconsin (C.A.); School of Exercise, Biomedical and Health Sciences, Edith
Cowan University, Joondalup, Australia (C.A.); OTB Research, Charleston, South Carolina (R.B.); John Curtin School of Medical
Research, Australian National University, Canberra, Australia (G.P.-F.); and the Neurodegeneration Research Group, Garvan Institute of
Medical Research, Sydney, Australia (B.V.)
Abstract............................................................................... B
I. Introduction ........................................................................... B
II. Gonadotropins, sex steroids, tumor necrosis factor, and Alzheimer’s disease.................. B
III. Tumor necrosis factor and Alzheimer’s disease ............................................ C
IV. Tumor necrosis factor, amyloid
␤
, and
␶
.................................................. D
V. Insulin................................................................................ E
A. Insulin in basic biology and the brain................................................. E
B. Insulin resistance and Alzheimer’s disease ............................................ E
C. Tumor necrosis factor and insulin resistance .......................................... F
D. Functional links of glucagon-like peptide-1 to insulin resistance ......................... G
VI. Tumor necrosis factor and glycogen synthase kinase-3 ..................................... G
VII. Tumor necrosis factor and mitochondrial dysfunction ...................................... H
VIII. Tumor necrosis factor and progenitor cells................................................ H
A. Progenitor cells, tumor necrosis factor, and insulin resistance ........................... H
B. Clock genes, controlled by tumor necrosis factor, govern progenitor activity............... I
IX. Streptozotocin ......................................................................... J
A. Streptozotocin model for diabetes and Alzheimer’s disease .............................. J
B. Streptozotocin induces tumor necrosis factor........................................... J
X. The broader picture—stroke, traumatic brain injury, and infectious disease.................. K
XI. Therapeutic implications................................................................ K
A. Specific inhibition of tumor necrosis factor ............................................ K
B. Nonspecific inhibition of tumor necrosis factor ......................................... L
1. Thalidomide and curcumin........................................................ L
2. Minocycline ..................................................................... L
3. Erythropoietin ................................................................... L
C. Administering leptin as a counter to insulin resistance ................................. M
D. Administering insulin as a counter to insulin resistance ................................ N
E. Glucagon-like peptide-1 mimetics and dipeptidyl peptidase-4 inhibitors as counters to
insulin resistance ................................................................... N
F. Glycogen synthase kinase-3 antagonists............................................... N
H. Apolipoprotein E mimetics and bexarotene ............................................ O
XII. Conclusions ........................................................................... P
References ............................................................................ P
Address correspondence to: Prof. Ian Clark, Division of Medical Science and Biochemistry, Research School of Biology, Australian National
University, Canberra ACT 0200, Australia. E-mail: ian.clark@anu.edu.au
This article is available online at http://pharmrev.aspetjournals.org.
http://dx.doi.org/10.1124/pr.112.005850.
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PHARMACOLOGICAL REVIEWS Vol. 64, No. 4
Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 5850/3792099
Pharmacol Rev 64:A–W, 2012
A
Pharmrev Fast Forward. Published on September 10, 2012 as DOI:10.1124/pr.112.005850
Copyright 2012 by the American Society for Pharmacology and Experimental Therapeutics.

Abstract——The evident limitations of the amyloid
theory of the pathogenesis of Alzheimer’s disease are
increasingly putting alternatives in the spotlight. We
argue here that a number of independently developing
approaches to therapy—including specific and non-
specific anti-tumor necrosis factor (TNF) agents, apo-
lipoprotein E mimetics, leptin, intranasal insulin, the
glucagon-like peptide-1 mimetics and glycogen syn-
thase kinase-3 (GSK-3) antagonists—are all part of an
interlocking chain of events. All these approaches in-
form us that inflammation and thence cerebral insulin
resistance constitute the pathway on which to focus
for a successful clinical outcome in treating this dis-
ease. The key link in this chain presently absent is a
recognition by Alzheimer’s research community of the
long-neglected history of TNF induction of insulin re-
sistance. When this is incorporated into the bigger
picture, it becomes evident that the interventions we
discuss are not competing alternatives but equally
valid approaches to correcting different parts of the
same pathway to Alzheimer’s disease. These treat-
ments can be expected to be at least additive, and
conceivably synergistic, in effect. Thus the inflamma-
tion, insulin resistance, GSK-3, and mitochondrial dys-
function hypotheses are not opposing ideas but stages
of the same fundamental, overarching, pathway of Alz-
heimer’s disease pathogenesis. The insight this pro-
vides into progenitor cells, including those involved in
adult neurogenesis, is a key part of this approach. This
pathway also has therapeutic implications for other
circumstances in which brain TNF is pathologically
increased, such as stroke, traumatic brain injury, and
the infectious disease encephalopathies.
I. Introduction
Despite its increasingly high incidence, harmful ef-
fects on people and society, and the considerable funding
directed toward understanding its mechanism, differing
ideas on the driving force of Alzheimer’s disease (AD
1
)
remain unresolved. For decades, the bulk of the research
effort has been focused by the wealth of logic in the idea
that amyloid
␤
(A
␤
), the major neurohistological hall-
mark of this condition, triggers the onset of disease. This
approach was very encouraging in mouse studies
(Huang et al., 1999; Hung et al., 2008), but the negative
outcome of recent human trials, including when amyloid
was confirmed to have been reduced (Holmes et al.,
2008; Green et al., 2009; Salloway et al., 2009; Extance,
2010), has led to much reassessment and repositioning
that has led to lucid arguments for nonfailure of the
amyloid model itself (Karran et al., 2011; Sperling et al.,
2011). These negative human trials may have also led to
wider acceptance of AD research that has thrown the net
wider, taking into account the pathophysiology this dis-
ease shares with a range of conditions, both infectious
and noninfectious. This has allowed ideas such as the
cerebral insulin resistance model (de la Monte and
Wands, 2008) to gain warranted prominence (Correia et
al., 2011; McNay and Recknagel, 2011).
As discussed below, two therapeutic approaches al-
ready realized to be consistent with the model we are
proposing are intranasal insulin and parenteral gluca-
gon-like peptide-1 (GLP-1) mimetics. A major purpose of
this review is to summarize the large volume of pub-
lished evidence that, taking into account TNF and func-
tionally similar cytokines, dramatically reinforces the
likelihood that cerebral insulin resistance is indeed cen-
tral, albeit somewhat downstream, in the etiology of this
disease. The AD literature on leptin is also consistent
with this. Here we present the case that a number of
proposed treatments for AD are functionally linked, ei-
ther by their capacity to lower insulin resistance or to
deal with the consequences of this event (Fig. 1). These
treatments include leuprolide acetate, various ways to
reduce TNF levels (specific anti-TNF biological agents,
and nonspecific down-regulators of TNF production
(thalidomide, curcumin, and their derivatives; minocy-
cline; erythropoietin variants; and sex steroids), the
GLP-1 mimetics and dipeptidyl peptidase-4 (DPP-4) in-
hibitors, leptin, insulin itself, as well as glycogen syn-
thase kinase-3
␤
(GSK-3
␤
) inhibitors. All are under ac-
tive investigation by researchers presently coming from
different perspectives.
As we also discuss, not only are extensive links be-
tween TNF and AD now reported, but also between TNF
and gonadotropins as well as TNF and cell division,
insulin resistance, type 2 diabetes (T2DM), mitochon-
drial dysfunction, and the pathologic condition caused
by intracerebroventricular streptozotocin. These well
documented aspects of the repertoire of TNF activity,
which we suggest should become common currency in
AD research, are expanded upon in this review.
II. Gonadotropins, Sex Steroids, Tumor Necrosis
Factor, and Alzheimer’s Disease
Considerable evidence exists that elevated levels of
the gonadotropins luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) are associated with neuro-
degenerative disease. For examples, total brain levels of
A
␤
, a traditional histological marker for AD, are in-
creased by high LH levels [such as after ovariectomy
(Frye et al., 2007)], and decreased by the gonadotropin
superagonist leuprolide acetate (Bowen and Atwood,
2004; Casadesus et al., 2006; Berry et al., 2008). Cogni-
1
Abbreviations: A
␤
, amyloid
␤
;A
␤
PP, amyloid
␤
precursor protein;
ACT,
␣
1-antichymotrypsin; AD, Alzheimer’s disease; Akt, protein ki-
nase B; apoE, apolipoprotein E; BBB, blood-brain barrier; CD14, cluster
determinant 14; CNS, central nervous system; CRP, C-reactive protein;
CSF, cerebrospinal fluid; DPP-4, dipeptidyl peptidase-4; EPO, erythro-
poietin; FSH, follicle-stimulating hormone; GLP-1, glucagon-like pep-
tide-1; GSK, glycogen synthase kinase; IFN, interferon; IL, interleukin;
LH, luteinizing hormone; NP12, 4-benzyl-2-methyl-1,2,4-thiadiazoli-
dine-3,5-dione; SB216763, 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-
3-yl)-1H-pyrrole-2,5-dione; SZT, streptozotocin; T2DM, type 2 diabetes;
TBI, traumatic brain injury; TNF, tumor necrosis factor.
BCLARK ET AL.

tive function follows the same pattern, with low LH
levels improving memory and cognition and high levels
making them worse, provided LH receptors are present
(Casadesus et al., 2006, 2007; Bryan et al., 2010; Ziegler
and Thornton, 2010; McConnell et al., 2012). We have
discussed previously the developing field of physiological
sex hormone replacement therapy for AD treatment
(Clark and Atwood, 2011). This is rationalized, at least
in part, by the capacity of both estradiol and progester-
one to reduce TNF expression in astrocytes (Kipp et al.,
2007). These hormones have been reported to protect
against AD (Honjo et al., 1989; Asthana et al., 2001).
Gonadotropins can regulate production of TNF, which
was shown to alter cell cycle dynamics by the group that
first described it (Darzynkiewicz et al., 1984). In brief,
FSH has been reported to induce TNF in vitro (Iqbal et
al., 2006), and high LH and FSH levels have allowed the
rationalization, through their association with high TNF
and IL-1
␤
, of the onset or exacerbation of rheumatoid
arthritis in women at menopause (Kåss et al., 2010). As
we have noted (Clark and Atwood, 2011), the antigo-
nadotropic actions of leuprolide render it an anti-mitotic
and anti-inflammatory agent when used to treat endo-
metriosis. In this context, leuprolide has been reported
to reduce a number of inflammatory cytokines [e.g.,
IL-1
␤
(Meresman et al., 2003), IL-6 (Ferreira et al.,
2010; Ficicioglu et al., 2010), and monocyte chemotactic
protein-1 (Khan et al., 2010)], all of which are induced by
TNF (Shalaby et al., 1989; Charles et al., 1999; Mueller
et al., 2010) and reduced by anti-TNF treatment (Bren-
nan et al., 1989; Redl et al., 1996; Charles et al., 1999).
Insulin resistance, commonly a TNF-induced state, and
now regarded to be central to AD (see section V.B), is
routinely seen in late pregnancy (Ryan et al., 1985). Late
pregnancy is also a time of physiological low-grade in-
flammation (de Castro et al., 2011) that is plausibly
regulated by the interactions of gonadotropins and TNF.
Not enough is yet known about the integration of
these reproductive hormones into broader physiology
and disease. Nevertheless, they already give an encour-
aging lead into how TNF might become excessive very
early in AD (Clark and Atwood, 2011). As was TNF for
years, in most minds these widely published hormones
are still in a nomenclature straightjacket arising from
their first description. This generates popular assump-
tions and limits enquiry into their relevance across
wider biology. The potential for their involvement is
there, because LH receptors, for example, are present on
an astonishing array of cell types, ranging from thymo-
cytes and peripheral lymphocytes (Rao et al., 2003) and
macrophages (Sonoda et al., 2005) through endothelial
cells (Tsampalas et al., 2010) to neurons and various
microglial cells (Rao et al., 2003), as well as where one
would expect them to be from the gonadotropin function
of LH.
III. Tumor Necrosis Factor and
Alzheimer’s Disease
The literature often gives the impression that TNF is
the only inflammatory cytokine, and most of this review,
for the sake of brevity, is no exception. TNF is at present
widely regarded, mainly from experience in the field of
rheumatology (Brennan et al., 1989; Charles et al.,
1999), as the master cytokine that starts the inflamma-
tory cascade. Nevertheless, mediators such as the inter-
FIG. 1. The overarching inflammatory pathway to Alzheimer’s disease that becomes evident once it is appreciated that TNF induces insulin
resistance (red arrow). Treatment concepts now in development (in blue) all address this pathway.
TNF CAUSES INSULIN RESISTANCE:IMPLICATIONS FOR AD C

leukin-1s (of which IL-1
␤
is the form released into ex-
tracellular fluids) are also inflammatory and may well
develop their own literature parallel to that described
here for TNF. IL-1 is the most advanced in this regard
(Griffin et al., 1989; Kitazawa et al., 2011). A mutual
dependence of these two cytokines is evident in the
brain, with reports of anti-TNF agents limiting the re-
lease of IL-1 (Terrando et al., 2010) and TNF levels
being reduced when IL-1 signaling is blocked (Kitazawa
et al., 2011). A number of higher numbered interleukins,
such as IL-12, IL-17, and IL-22, have become function-
ally linked with TNF but are, so far, little studied in the
brain. It also warrants noting, for clarity, that the term
TNF (Carswell et al., 1975) is identical to TNF-
␣
, the
commonly seen suffix being a now-meaningless relic
from when lymphotoxin was, for a limited period some
years ago, referred to as TNF-
␤
.
Although some still regard inflammation in AD as
solely a secondary downstream consequence of A
␤
gen-
eration (as reviewed by Zotova et al., 2010), evidence
continues to accumulate (for review, see Clark et al.,
2010) for excess cerebral TNF, and therefore the cascade
of cytokines it initiates, to be viewed as an essential
preillness step in its pathogenesis. Some time ago,
higher cerebrospinal fluid (CSF) levels of TNF from 56
subjects with mild cognitive impairment, but not 25
age-matched controls subjects, were reported to predict
which patients would develop frank AD (Tarkowski et
al., 2003). Other researchers, taking advantage of the
increased sensitivity of assaying for soluble TNF recep-
tors rather than TNF itself, found that their levels in
serum and CSF predicted, over a 4- to 6-year period,
conversion to clinical AD (Buchhave et al., 2010). Some
groups studied plasma levels of C-reactive protein (CRP)
and
␣
1-antichymotrypsin (ACT) (Engelhart et al., 2004)
(two acute-phase proteins up-regulated by TNF or IL-1)
or of CRP alone (Laurin et al., 2009; Schuitemaker et al.,
2009) and found that these markers of inflammation
were present in serum and CSF before any indications of
increased A
␤
.
These studies on the primary role of inflammatory
mediators have now been extended by a report that
plasma levels of another acute-phase protein, clusterin
(apolipoprotein J), are intimately associated with onset,
progression, and severity of AD (Thambisetty et al.,
2010). A novel proteomic neuroimaging paradigm was
employed. Unfortunately, the authors offered only an
A
␤
-based rationale for these findings and did not note
that clusterin is an acute-phase protein (Hardardo´ttir et
al., 1994). Therefore, it is a marker, as surely as are CRP
and ACT, of increased pro-inflammatory cytokines such
as TNF and IL-1. One of their more telling findings was
that clusterin is raised 10 years earlier in the course of
the disease than is fibrillar A
␤
deposition. Moreover, a
metastudy has determined that CLU, the clusterin gene,
is the second highest of a list of the 15 top-rated genes
linked to AD on the Alzgene web-based collection (Ol-
giati et al., 2011). Taken together, these arguments are
consistent with the key nature of inflammation in AD
onset. The induction of insulin resistance, accepted for
years by the wider literature to be mediated by TNF (see
section V.D), is, like TNF, also a very early event in AD,
even preceding the onset of minimal cognitive impair-
ment (Baker et al., 2011). Indeed, insulin resistance has
been reported to be associated with reduced executive
function in older people lacking any evidence of T2DM or
dementia. The concept of age-related cytokine increase
driving this insulin resistance was one of the possibili-
ties the authors considered (Abbatecola et al., 2004).
IV. Tumor Necrosis Factor, Amyloid
␤
, and
␶
With more than 30 years of dominance of the AD
literature by amyloid
␤
precursor protein (A
␤
PP) and its
cleavage product, A
␤
, it is not surprising that most
pathologic conditions associated wth AD, including in-
sulin resistance, have been seen as consequences of A
␤
deposition (Balaraman et al., 2006; Perry et al., 2007;
Townsend et al., 2007; Li et al., 2010; Lei et al., 2011).
However, current clinical trial outcomes are consistent
with A
␤
being little more than a marker for more rele-
vant events (Holmes et al., 2008; Green et al., 2009;
Salloway et al., 2009; Extance, 2010).
Unfortunately, the direction of AD research has a
momentum that has not yet, on the whole, taken into
account that A
␤
is a highly TNF-dependent protein. For
instance, A
␤
PP, the centerpiece of the amyloid theory of
AD pathogenesis, is induced by inflammatory cytokines,
including TNF and IL-1. This is a widespread phenom-
enon. In addition to the fact that the promotor region of
the A
␤
PP gene is controlled by these cytokines (Ge and
Lahiri, 2002), its induction by these inflammatory cyto-
kines is reported in endothelial cells (Goldgaber et al.,
1989), skeletal muscle (Schmidt et al., 2008), and 3T3 L1
adipocytes (Sommer et al., 2009) as well as brain (Brugg
et al., 1995; Buxbaum et al., 1998). Its presence in brain
is not confined to noninfectious diseases, being described
in AIDS dementia (Stanley et al., 1994) and cerebral
malaria (Medana et al., 2002). Regarding A
␤
PP cleav-
age, in 2004 it was reported that IFN-
␥
, IL-1
␤
, and TNF
specifically stimulate
␣
-secretase activity, with an ac-
companying increased production of A
␤
(Liao et al.,
2004). IFN-
␥
and TNF were subsequently shown to en-
hance A
␤
production from A
␤
PP-expressing astrocytes
and cortical neurons, and the numbers of astrocytes
expressing IFN-
␥
were shown to have increased
(Yamamoto et al., 2007). This group also showed that 1)
TNF directly stimulates
␤
-site A
␤
PP-cleaving enzyme
(or
␤
-secretase) expression and thus enhances
␤
-site pro-
cessing of A
␤
PP in astrocytes and 2) that TNFR1 deple-
tion reduced
␤
-site A
␤
PP-cleaving enzyme activity, as
well as learning and memory deficits (Yamamoto et al.,
2007). Taken together, these data imply that anti-TNF
agents should be effective A
␤
PP cleavage inhibitors.
DCLARK ET AL.

Data from a mouse AD model after long-term inhibition
of TNF are functionally consistent with this (McAlpine
et al., 2009).
In contrast, it now seems reasonably appreciated that
inflammatory cytokines such as TNF mediate events
downstream of A
␤
. Nearly a decade ago TNF was re-
ported to alter synaptic transmission in hippocampal
slices (Tancredi et al., 1992). Several years later (Wang
et al., 2005b; Rowan et al., 2007), it was shown that this
earlier observation explained the ability of A
␤
, through
TNF, to do the same. Other researchers expanded the
roles of TNF in this context (Pickering et al., 2005;
Stellwagen et al., 2005). The capacity of A
␤
to act as a
ligand for CD14 and toll-like receptor-2 (Fassbender et
al., 2004; Jana et al., 2008; Tu¨kel et al., 2009) indicates
that these findings with A
␤
(Wang et al., 2005b; Rowan
et al., 2007) are consistent with basic immunology, be-
cause occupancy of CD14 and toll-like receptors is how
the usual bacterial- and protozoal-origin inducers of
TNF operate (Beutler and Poltorak, 2001). Key support
for this concept has been provided by the recent demon-
stration that the release of proinflammatory cytokines
from astrocytes is necessary for either A
␤
to be neuro-
toxic or
␶
phosphorylation to be initiated (Garwood et al.,
2011). Much research on A
␤
’s causing the pathological
features of AD (Hardy and Selkoe, 2002; Games et al.,
2006; Marwarha et al., 2010) appears yet to take this
body of literature into consideration. In short, it should
by now be clear that many experimental observations
attributed to added A
␤
might well actually be caused by
the inflammatory cytokines, including TNF. This addi-
tional TNF may have added to the total load (Fig. 1), but
if it were a significant contributor to the clinical out-
come, we would expect the human trials of antiamy-
loid therapies discussed earlier to have given positive
results.
Likewise, hyperphosphorylated
␶
, another histological
sign of high cytokine activity (Medana et al., 2005, 2007;
Gorlovoy et al., 2009) can be regarded as one of the
obvious markers of GSK-3 (see section VI) activation
subsequent to cytokine-induced insulin resistance,
rather than as an essential early step in the pathogen-
esis of the disease. Hyperphosphorylated
␶
has been
advocated for many years as a primary mechanism of
loss of cerebral function and cell loss (Goedert, 2004;
Go¨tz et al., 2012), and mice expressing mutant human
␶
are reported to exhibit many of the features of AD
(Takeuchi et al., 2011). However, claims for a direct
harmful effect on neurons need to be reconciled with
evidence of a large reversible increase in hyperphospho-
rylated
␶
, leaving function and structure able to return
unscathed once experimentally induced mammalian hi-
bernation is reversed (Ha¨rtig et al., 2007). Conceivably
this particular phosphorylation, although spectacular
down a microscope, may well be the least important of
the myriad of other, unseen, phosphorylations caused by
GSK-3 activation. In summary, we argue that the now-
known complexities of the current literature on the cy-
tokines, insulin resistance, and GSK-3 reduce the need
for incorporating the traditional AD hallmark proteins,
however histologically intriguing, into our model to un-
derstand the origins and mechanism of this disease.
V. Insulin
A. Insulin in Basic Biology and the Brain
Over the decades, the literature of soluble mediators
referred to as cytokines or hormones (conceivably inter-
changeable terms) have taken unexpected turns, typi-
cally through the discovery of functions quite unrelated
to those for which they first came to notice. For instance,
given its original function of tumor killing (Carswell et
al., 1975), it was difficult to get acceptance of any role for
TNF in innate immunity or disease pathogenesis (Clark
et al., 1981). Insulin receptors had already been noted to
be widely distributed in the central nervous system of
the rat (Havrankova et al., 1978). This unexpected in-
formation was soon followed by reports of conventional
insulin and insulin receptors in flies, earthworms, and
bacteria (LeRoith et al., 1981a,b). The central relevance
of insulin to brain physiology was a ground-breaking
revelation (for review, see Adamo et al., 1989). Clearly,
these and similar developments indicate that insulin
has a central importance in biological signaling.
As has recently been reviewed (Correia et al., 2011),
once bound to the extracellular domain of a specific
tyrosine kinase receptor, insulin causes autophosphory-
lation of its intracellular component, triggering a chain
of tyrosine kinase activity. As these authors discuss,
subsequent phosphorylation activates cascades that in-
clude phosphoinositide 3-kinase/protein kinase B (Akt).
This pathway (one of those inhibited by excess TNF) in
turn phosphorylates and thereby inhibits (Cross et al.,
1995) the
␣
and
␤
cytosolic forms of GSK-, which is a
serine/threonine protein kinase with profound impor-
tance in many biological systems, including neurotrans-
mission at the synaptic level (Smillie and Cousin, 2011).
Other pathways, such as c-Jun N-terminal kinase/mito-
gen activated protein kinase, omitted here for brevity,
are also involved. The phosphoinositide 3-kinase/Akt
cascade also triggers translocation of the insulin-sensi-
tive glucose transporter 4 to the cell surface, enhancing
glucose uptake (Bryant et al., 2002). This is clearly cen-
tral to mitochondrial function and therefore ATP pro-
duction in AD. Nevertheless, there is ample evidence
that insulin has the capacity to control memory indepen-
dently of its effects on glucose uptake (Craft et al., 1996,
1999).
B. Insulin Resistance and Alzheimer’s Disease
Insulin resistance can be regarded as 1) a decreased
response in the presence of normal insulin levels or as
2) the need for more insulin for a normal response (i.e.,
the uptake of glucose, amino acids and fatty acid by
TNF CAUSES INSULIN RESISTANCE:IMPLICATIONS FOR AD E

peripheral tissues). As far as we are aware, the first
suggestions that insulin function was suppressed in AD
were made more than a decade ago in the context of
energy metabolism (Hoyer et al., 1994, 2000). Given the
many essential roles of insulin documented in neuro-
physiology, the consequences of alterations in cerebral
insulin resistance are inevitably widespread. This re-
view focuses on more recent studies on the control of
insulin resistance, and its implications, in a number of
diseases, including AD, where it is attracting much cur-
rent attention from prominent groups coming from quite
different directions (Correia et al., 2011; Liu et al., 2011;
McNay and Recknagel, 2011).
C. Tumor Necrosis Factor and Insulin Resistance
The basic literature that spans both immunity and
metabolism accepts that pro-inflammatory cytokines
cause insulin resistance, and anti-inflammatory cyto-
kines promote insulin sensitivity (Chawla et al., 2011).
Nevertheless, the implications of this link have not yet
reached the AD literature, even though it dwells consid-
erably on both inflammation and insulin resistance, two
of the most recognized processes associated with the
disease. Likewise, an awareness of this connection adds
an important additional dimension to the literature on
the pathogenesis of fetal alcohol syndrome disorder. As
with AD, research on this disorder contains two fields,
presently discrete, that it would be useful to conceptu-
ally merge: 1) ethanol induction of TNF in vivo (Qin et
al., 2008) and in vitro (Boyadjieva and Sarkar, 2010),
thus harming neurons (Boyadjieva and Sarkar, 2010;
Hicks and Miller, 2011), and 2) ethanol-induced insulin
resistance (de la Monte et al., 2005, 2011; de la Monte
and Wands, 2010). As Fig. 1 illustrates, this would open
up a wider awareness of treatment possibilities for both
conditions.
The causative link between TNF and insulin resis-
tance has a long history. In 1967, insulin resistance was
observed in a patient with tularemia (Shambaugh and
Beisel, 1967), a condition caused by Francisella tularen-
sis, a Gram-negative tick-borne coccobacillus that much
later proved to be a strong inducer of TNF and its down-
stream cytokines (Golovliov et al., 1996). By 1974, insu-
lin resistance had been reported in septic and trauma-
tized patients (Gump et al., 1974) and was generated in
vivo by injecting bacterial endotoxin (Chaudry et al.,
1974). This same agent was shown, in 1975, to be the
prototype inducer of TNF (Carswell et al., 1975). That
year also saw burn injury, recognized decades later to
increase TNF to a functionally important degree (Gi-
roir et al., 1994; Boehm et al., 2010), being reported to
cause insulin resistance in rats (Frayn, 1975). The
endotoxin concept of insulin resistance in sepsis was
extended to skeletal (Raymond, 1984) and cardiac
(Raymond et al., 1988) muscle, although with no men-
tion of TNF or other cytokines as intermediaries. Im-
portantly, these authors proposed that a post-insulin
receptor site was responsible.
In the early 1980s, after acceptance that harmful ef-
fects of bacterial endotoxin and other functionally simi-
lar agents were caused through host-origin soluble pro-
teins (eventually termed cytokines) that were elicited
from patients’ cells, these proteins were linked with
induction of insulin resistance. Initially, a semipurified
protein that bacterial endotoxin released from macro-
phages was demonstrated to cause insulin resistance in
adipocytes (Pekala et al., 1983). This undefined protein,
in a class then termed monokines, did not affect insulin
binding or stimulation of glucose uptake. Two years
later it was sequenced (Beutler et al., 1985) and found,
unexpectedly, to be identical to a previously sequenced
molecule, TNF (Aggarwal et al., 1985). In 1989, a group
who explored this area by infecting rats with Esche-
richia coli (Lang and Dobrescu, 1989) also predicted a
defect in insulin signaling distal to receptor binding but
again did not mention the link, by then well established,
between endotoxin from this bacterium and TNF induc-
tion (Carswell et al., 1975).
A milestone article, also in 1989 (Fraker et al., 1989),
demonstrated that injecting insulin and recombinant
TNF concurrently into rats prevented or significantly
reduced a range of metabolic and pathological changes
seen in acute TNF toxicity. Various interpretations were
proposed, but none proved satisfactory. With hindsight,
it seems plausible that sufficient insulin had been in-
jected to overcome much of the insulin resistance caused
by the coadministered TNF. If so, the breadth of meta-
bolic and histological observation in this text gives an
intriguing insight into the wide influence of signal mod-
ification driven by cytokine-induced insulin resistance,
much still unexplored. Weiner et al. (1991) found insulin
and recombinant TNF to produce potent and opposing
physiological signals in adipocytes. This paved the way
for groups interested in various non-AD diseases, includ-
ing examples caused by infectious agents known to in-
duce TNF, to demonstrate that this cytokine was a po-
tent cause of insulin resistance (Lang et al., 1992;
McCall et al., 1992; Davis et al., 1993; Feinstein et al.,
1993; Hotamisligil et al., 1993, 1996; Li et al., 2007; Qin
et al., 2007; Lorenzo et al., 2008). Feinstein et al. (1993)
seem to have been the first to argue that TNF exerts a
major part of its antiinsulin effect by interrupting insu-
lin-stimulated tyrosine phosphorylation, a key observa-
tion that was confirmed in cells from knockout mice by
Nieto-Vazquez et al. (2007). Much of this work was done
in the context of T2DM. Newer reports from within the
T2DM and AD interface discuss, as one entity, the cere-
bral and peripheral TNF and insulin relationship (Liu et
al., 2011; Bomfim et al., 2012).
Inhibiting TNF can prevent or reverse insulin resis-
tance. Uysal et al. (1997) showed that insulin resistance
did not develop in obese mice lacking TNF function.
Seven years later a series of patient studies began to
FCLARK ET AL.

appear in which commercial anti-TNF biological agents
reduced insulin resistance in T2DM (Yazdani-Biuki et
al., 2004), rheumatoid arthritis [in some (Kiortsis et al.,
2005; Gonzalez-Gay et al., 2006, 2010, 2012) but not all
(Ferraz-Amaro et al., 2011) reports], and ankylosing
spondylitis (Kiortsis et al., 2005). In addition, inflix-
imab, one of these commercial anti-TNF biological
agents, was tested in obese diabetic mice, and it im-
proved insulin signal transduction in muscle, liver, and
hypothalamus. In doing so, it completely restored the
activity of insulin-induced insulin receptor, insulin re-
ceptor substrate-1, and receptor substrate-2 tyrosine
phosphorylation and Akt and forkhead box protein O1
serine phosphorylation (Arau´jo et al., 2007). In the same
vein, others have reported that insulin signaling in en-
dothelial progenitor cells, measured by the phosphory-
lated to total Akt ratio, was reduced by 56% on exposure
to TNF (Desouza et al., 2011). Even more recently, inf-
liximab has been employed to demonstrate that the in
vitro insulin resistance induced by A
␤
is inhibited by
neutralizing TNF (Bomfim et al., 2012).
Because treatment of AD with large anti-TNF biolog-
ical agents is focused on delivering them into the CSF
(section XI.B), the most AD-relevant in vivo demonstra-
tion to date of altering insulin resistance in this way has
been done by Arruda et al. (2011), who showed that
intracerebroventricular infliximab improved insulin sig-
nal transduction through insulin receptor substrate 1.
This was accompanied by a whole-body reduction in
insulin resistance.
D. Functional Links of Glucagon-Like Peptide-1 to
Insulin Resistance
Certain gut peptides, the most prominent being
GLP-1, have emerged as central to understanding
both brain function (During et al., 2003) and insulin
physiology. As has been reviewed in the context of
neurodegenerative disease (Greig et al., 2004b;
Ho¨lscher and Li, 2010; Holst et al., 2011), GLP-1, an
endogenous insulinotropic peptide, reduces insulin re-
sistance (Cabou et al., 2008; Knauf et al., 2008). It was
originally believed to arise only from L cells in the
distal ileum and colon but is now intensively studied
as a peptide of brain origin, with key brain functions.
GLP-1 and its mimetics provide a set of signals that
are the reverse of those (e.g., regarding Akt and c-Jun
N-terminal kinase) generated by excess TNF (Li et al.,
2005; Ferdaoussi et al., 2008; Natalicchio et al., 2010).
Consequently, GLP-1 mimetics have the capacity to
reduce insulin resistance in ways shared by exogenous
anti-TNF agents. Because GLP-1 is rapidly degraded
in vivo, degradation-resistant analogs have been de-
veloped and are in therapeutic use for T2DM. As dis-
cussed in section XI.F, these agents also show promise
in AD models.
VI. Tumor Necrosis Factor and Glycogen
Synthase Kinase-3
In the literature, GSK-3
␤
predominates over the very
similar GSK-3
␣
form and, for simplicity, is referred to
exclusively in this text. As with a number of other mol-
ecules with very high profiles, the fame of GSK-3
␤
not
rests not on its first description [arising from the capac-
ity to phosphorylate and thence inactivate glycogen syn-
thase (Embi et al., 1980)] but on the gradual realization
of its very great number of substrates, more than 50 of
them documented by 2003 (Doble and Woodgett, 2003).
Fifteen years earlier, TNF had caused a similar stir
when, as a cytokine still traditionally linked in most
minds only to tumor necrosis, it was noted to possess a
remarkably high number of physiological as well as
pathological functions (Nathan, 1989). We have previ-
ously discussed this in the CNS context (Clark et al.,
2010). In hindsight, this information contained the po-
tential to have opened minds to the possibility of a
functional link between these two strikingly pleiotropic
molecules associated with normal physiology, innate im-
munity, and inflammation.
As with TNF, many groups are interested in the roles
of GSK-3
␤
in brain function. Over the years, those ar-
guing for a primary role for hyperphosphorylated
␶
in
AD pathogenesis have, as expected, focused on GSK-3
␤
as the phosphorylating kinase that generates this form
of
␶
(Mandelkow et al., 1992; Lovestone et al., 1994;
Lovestone and Reynolds, 1997). Other have examined
its effects on the brain itself and produced much com-
pelling data suggesting that GSK-3
␤
, in its inhibited
state, is essential for normal brain function, and its
activated state leads to the array of functional loss seen
in AD (Jope and Johnson, 2004; Balaraman et al., 2006;
Engel et al., 2006; Hooper et al., 2007; Kimura et al.,
2008; Salcedo-Tello et al., 2011; Smillie and Cousin,
2011). As noted in section VI, the argument that when-
ever GSK-3
␤
activation is high, the hyperphosphory-
lated
␶
generated initiates disease (Goedert, 2004) has
yet to explain the reported harmlessness of this protein
in induced mammalian hibernation (Ha¨rtig et al., 2007).
Certainly, the position of hyperphosphorylated
␶
in Fig.
1 is reinforced by the evidence that it is reduced when
the tap is turned off at the top of the cascade by LH
ablation (Lin et al., 2010), anti-TNF (Shi et al., 2011),
IL-1 signaling blockade (Kitazawa et al., 2011), minocy-
cline (Garwood et al., 2010), sex steroids (Carroll et al.,
2007), or additional insulin (Hong and Lee, 1997).
TNF and GSK-3
␤
have proved to be functionally
linked, both in physiology and disease pathogenesis.
Insulin resistance, a phenomenon readily caused by
TNF (see section V.C), has long been known to influence
GSK-3
␤
activity (for review, see Jope 2004; Jope and
Johnson, 2004). As noted above (Fraker et al., 1989),
insulin also reduces the harmful effects of excess TNF
production, as do sex steroids (e.g., (Jiang et al., 2009).
TNF CAUSES INSULIN RESISTANCE:IMPLICATIONS FOR AD G

In addition, the reduction of endotoxin and peptidogly-
can-induced pathologic conditions in rats by insulin, in-
dependent of blood glucose changes, has been demon-
strated to involve GSK-3 inhibition (Dugo et al., 2006).
Others reported that the insulin resistance and associ-
ated increase in GSK-3
␤
activity in brains of a mouse
model of T2DM, as well as what the authors noted were
learning difficulties parallel to those seen in AD, were
corrected by administering insulin (Jolivalt et al., 2008).
Moreover, the specific GSK-3
␤
inhibitor 3-(2,4-dichloro-
phenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione
(SB216763) altered the cytokines released from endotoxin-
stimulated human monocytes to a strongly anti-inflamma-
tory profile (Martin et al., 2005). Nevertheless, the separa-
tion of the two in the minds of most researchers has led to
the existence of both inflammatory and GSK-3 models of
AD. Rarely are they discussed together, and then only in
terms of post-A
␤
secondary inflammation, not as two sub-
units of an essential component of disease initiation
(Hooper et al., 2008).
VII. Tumor Necrosis Factor and
Mitochondrial Dysfunction
As we have reviewed previously (Clark et al., 2010),
the concept of dysfunctional mitochondria, and thus poor
oxygen utilization and energy production, is important
in understanding disease pathogenesis. This seems to
have been first suggested, on the basis of organelle elec-
tron microscopy, in malaria (Maegraith, 1954). Nearly
20 years later, it appeared in the sepsis literature (Mela
et al., 1972). A further 2 decades later, TNF, by then well
established as a key mediator in infectious disease, was
first demonstrated to suppress mitochondrial respira-
tion (Stadler et al., 1992). By the end of that decade,
extensive functional studies in this context were begun
(Fink, 1997, 2000, 2001), and the general reasoning was
extended to HIV dementia (Kruman et al., 1999) and
influenza encephalopathy (Yokota, 2003). More recent
research on TNF’s ability to induce mitochondrial dys-
function (Chen et al., 2010) again noted that direct treat-
ment with TNF led to reduced intracellular ATP and
more generation of reactive oxygen species. More signif-
icantly, the anti-TNF biological agent etanercept has
been shown to ameliorate cardiac mitochondrial dys-
function in vivo (Moe et al., 2004). Systemic mitochon-
drial dysfunction, as part of cytokine-induced inflamma-
tion, is still very topical in the pathophysiology of sepsis
(Garrabou et al., 2012).
Mitochondrial dysfunction has an early onset in AD
(Hauptmann et al., 2009) and is widely regarded as
important in its pathogenesis (Castellani et al., 2002).
Although the first group to propose mitochondrial func-
tional defects as a mechanism for AD was primarily
interested in oxidative stress as a mechanism (Blass and
Gibson, 1991), it did not take long for researchers of A
␤
,
by then dominating AD disease pathogenesis, to incor-
porate the mechanism of mitochondrial dysfunction into
their reasoning (Kaneko et al., 1995). This view persists
to the present day (Borger et al., 2011) and has remained
largely unquestioned despite the implications of the
prevalence of TNF in AD brains (section III) and the
widely published capacity of this cytokine to induce both
A
␤
PP and A
␤
(section IV) and to directly cause mito-
chondrial dysfunction (see above). Young-Collier et al.
(2012) found that the reduced expression of mRNA of
genes responsible for mitochondrial function in human
AD neurons could not be duplicated with 3 days of cul-
ture with A
␤
1–42
(instead, expression rose); this might
now encourage investigation into other possible mecha-
nisms for the finding.
Does mitochondrial dysfunction precede or follow in-
sulin resistance? Both viewpoints appear in the litera-
ture, with discussion of excessive fat intake being com-
mon to several articles arguing that mitochondrial
dysfunction occurs first (Anderson et al., 2009; Rector et
al., 2010). In contrast, a study designed to investigate
the mitochondrial dysfunction during fasting concluded
it was a consequence rather than a cause of insulin
resistance (Hoeks et al., 2010). Indeed, when associated
with cell death or apoptosis, mitochondrial dysfunction
is reported to occur after GSK-3
␤
activation (Petit-Paitel
et al., 2009; Wang et al., 2011), placing it after insulin
resistance (Fig. 1). Its position here is consistent with
experiments in which the mitochondrial dysfunction in-
duced by SZT, an agent that mimics T2DM or AD (sec-
tion IX.A), was corrected by administering insulin
(Chowdhury et al., 2010). Clearly, this implies that im-
proved cerebral mitochondrial function is a plausible
consequence of treating AD with intranasal insulin (sec-
tion XI.E; Fig. 1).
VIII. Tumor Necrosis Factor and
Progenitor Cells
A. Progenitor Cells, Tumor Necrosis Factor, and
Insulin Resistance
Adult neurogenesis, which is low or absent in the
shrunken brains of patients with AD, is essential for
normal memory formation (Clark et al., 2010). Such
progenitor activity, requiring activin A (Abdipranoto-
Cowley et al., 2009), is part of a normal organism-wide
pattern in which such cells are controlled by a sex hor-
mone-TNF pathway to maintain cellular homeostasis.
The dynamic regulation of neurogenesis by hypothalamic-
pituitary-gonadal axis hormones, including activins, go-
nadotropins, and sex hormones, particularly progesto-
gens, is well established (Vadakkadath Meethal and
Atwood, 2005). However, the sequence of events through
which sex hormones seem to modulate TNF during con-
trol of progenitor cells is not yet known. Despite this
incomplete picture, the literature to date is consistent
with the idea that increased TNF induces insulin resis-
tance, and thus GSK-3
␤
activation (Verhees et al.,
HCLARK ET AL.

2011), and constitutes the major pathway in progenitor
cell homeostasis.
T2DM is a good example of a disease combining
chronic systemic inflammation, insulin resistance, and
widespread defects in progenitor cell function. It is tell-
ing that it should both predispose to AD (Arvanitakis et
al., 2004) and share cerebral insulin resistance with this
condition (Liu et al., 2011). The details of the signaling
deficits are also the same (Liu et al., 2011). In neurogen-
esis (and, as far as has been examined, a general rule in
other progenitors), physiological levels of TNF and its
downstream cytokines enhance proliferation, whereas
supraphysiological levels inhibit proliferation (Ber-
nardino et al., 2008). This phenomenon has been dem-
onstrated in thymocytes (Ranges et al., 1988; Herna´n-
dez-Caselles and Stutman, 1993), hepatocytes (Bour et
al., 1996; Diehl and Rai, 1996), hematopoiesis (Clark
and Chaudhri, 1988; Rebel et al., 1999) and, of plausible
relevance to data from AD brains (Sheng et al., 2012),
impaired mitochondria biogenesis (Valerio et al., 2006).
The relevance of TNF-induced insulin resistance to the
pathogenesis of the widespread degenerative change
that characterizes chronic inflammatory diseases can be
gleaned from the literature on endothelial cell progeni-
tors (Cubbon et al., 2009; Abbas et al., 2011; Desouza et
al., 2011) and thus nephropathy; muscle progenitors
(Pajak et al., 2008) and thus cachexia; fibroblast progen-
itors (Frankel et al., 2006; Goren et al., 2006; Siqueira et
al., 2010) and thus poor wound healing; cartilage pro-
genitors (Alblowi et al., 2009; Kayal et al., 2009) and
thus poor fracture repair; and erythroblasts (Tsinka-
lovsky et al., 2007) and thus the anemia of chronic dis-
ease. Whether the recorded protective effect of sex hor-
mones in some of these circumstances is an independent
property parallel to their ability to reduce production of
TNF (He et al., 2004; Kipp et al., 2007) is a yet to be
tested. We note, however, that estrogen has been re-
ported to promote cutaneous wound healing (Campbell
2010) by means other than its anti-inflammatory mech-
anism. Nevertheless, the poor wound healing in rheu-
matoid arthritis, a condition exhibiting insulin resis-
tance reversible by anti-TNF agents (Kiortsis et al.,
2005; Gonzalez-Gay et al., 2006), has been reported to be
countered by anti-TNF treatment (Shanmugam et al.,
2011). Although on a small scale, this study is intrigu-
ing, because conventional wisdom, predicated on the
idea that such anti-TNF treatment has the potential to
suppress immunity against certain pathogens that could
infect wounds, would have us expect the opposite out-
come. As might be expected, elevated levels of sex ste-
roids, such as during pregnancy or after hormonal re-
placement therapy, and known to suppress TNF, leads
to diminished disease activity in rheumatoid arthritis
(Ostensen et al., 1983; Kanik and Wilder, 2000; Islander
et al., 2011). In contrast, the disease is often aggravated
after parturition (Ostensen et al., 1983).
B. Clock Genes, Controlled by Tumor Necrosis Factor,
Govern Progenitor Activity
The control of progenitor cells homeostasis by TNF is
but a small part of the broader control that tissue clocks
exert in all tissues through circadian, or clock, genes.
Indeed, cell division in general is under their control
(Matsuo et al., 2003). Likewise, the normal diurnal cy-
cles in food intake, sleep, insulin requirements, and
mitochondrial function, kept in their normal circadian
patterns when these genes remain under physiological
diurnal fluctuations of sex hormones, TNF and down-
stream cytokines (Kohsaka and Bass, 2007), run amok
in well documented ways during illness (Hart, 1988;
Bluthe et al., 1994; Dantzer and Kelley, 2007). For as
long as TNF and IL-1
␤
are in pathological disease-in-
duced excess, clock genes undergo a longer-term sup-
pression (Cavadini et al., 2007). Hence mechanisms gov-
erned by clock genes, including cell cycling (Matsuo et
al., 2003), can be expected to undergo pathological
change. Several years ago we proposed that such sup-
pression can explain the pattern of pathology that char-
acterizes severe bacterial, protozoal, viral and post-
trauma disease (Clark et al., 2008).
Among the clock genes suppressed by excess TNF and
IL-1
␤
are the period genes, Per1,Per2 and Per3 and the
central, interconnecting, response element clock gene,
rev-erb
␣
(Cavadini et al., 2007). The existence of an
essentially parallel literature on reproductive hormones
and clock genes (Nakamura et al., 2008; Nakamura et
al., 2010; Karatsoreos et al., 2011) again demonstrate
the present minimal awareness of the functionally im-
portant adjacent positions of sex hormones and TNF in
the same regulatory pathway. Certain clock genes have
been demonstrated to undergo insulin-dependent regu-
lation (Tahara et al., 2011), and to control adult neuro-
genesis, including in the hippocampus (Moriya et al.,
2007; Borgs et al., 2009; Kimiwada et al., 2009), as well
as endothelial cell (Wang et al., 2008) and cartilage
(Mengatto et al., 2011) progenitors. Of particular rele-
vance here are the data from experiments published in
2004 (Kuriyama et al., 2004) in which the normal circa-
dian clock oscillation, present in all tissues, was exam-
ined in heart and liver of mice in which diabetes was
generated with SZT. Per2 was diurnally inhibited, but
this could be corrected by injecting insulin, i.e., by over-
coming insulin resistance. This is consistent with gluca-
gon-like peptide-1 (GLP-1) mimetics, clinically useful
against T2DM because of their ability to correct insulin
resistance (see next Section), promoting neurogenesis in
AD models (Hamilton et al., 2011; Holst et al., 2011).
Predictably (Jope and Johnson, 2004), the degree of ac-
tivation of GSK-3
␤
proves to be what ultimately controls
the clock genes, and thus proliferation (Hirota et al.,
2008; Ko et al., 2010; Kozikowski et al., 2011). Again as
expected, phosphorylation of GSK-3
␤
itself normally un-
TNF CAUSES INSULIN RESISTANCE:IMPLICATIONS FOR AD I

dergoes robust circadian oscillation, and it readily phos-
phorylates Per 2 (Iitaka et al., 2005).
Taken together, the wider progenitor cell literature is
therefore consistent with inhibition of neurogenesis in
AD by excess brain TNF through a pathway that in-
volves inhibition of clock genes by insulin resistance,
thus damping down or switching off progenitor cells.
Evidence also incriminates chronic inflammation in re-
duced recruitment of new neurons into the hippocampal
networks that underlie memory consolidation (Belarbi
et al., 2012a). Inhibited neurogenesis and distorted cell
cycling (Yang and Herrup, 2007) in AD are but two
consequences of this widely applicable principle in dis-
ease pathogenesis. Logically speaking, AD is therefore
susceptible to treatment with any of the approaches
discussed herein that rectify insulin resistance. More-
over, the main stages of this pathway are recognized
general principles as much at home in physiology [e.g.,
in the metabolic shutdown of hibernation (Stieler et al.,
2011) and dauer, or suspended animation, forms of the
nematode Caenorhabditis elegans (Tissenbaum and Ru-
vkun, 1998; Forsythe et al., 2006)] as in other human
diseases beyond AD and T2DM, including stroke (Val-
erio et al., 2011) and depression (Li and Jope, 2010)
(Fig. 2). These last two conditions have an emerging
literature on therapy with anti-TNF biological agents
(Uguz et al., 2009; Tobinick, 2011).
IX. Streptozotocin
A. Streptozotocin Model for Diabetes and
Alzheimer’s Disease
SZT, originally isolated from Streptomyces achromo-
genes for use as an antibiotic (Vavra et al., 1959), was
later realized to be a potent diabetogenic agent (Junod et
al., 1967); since then, it has had an important role in
diabetes research. In 1983, awareness developed that
SZT, besides leading to pancreatic
␤
-cell destruction,
also inhibits metabolic responsiveness to insulin rather
than its binding to its receptor (Hansen et al., 1983). A
decade later it was appreciated that intracerebroventric-
ular injection of SZT produces changes in glucose me-
tabolism that parallel those seen in AD (Plaschke and
Hoyer, 1993); subsequently, its ability to bring about a
wide range of the rest of the changes seen in AS began to
be uncovered. For example, rats receiving intracerebro-
ventricular injections of SZT, which does not alter sys-
temic glucose metabolism, develop insulin receptor de-
fects and thus insulin resistance (Hoyer et al., 2000).
They also exhibit brain atrophy, neurodegeneration, gli-
osis, and increased immunoreactivity for activated
GSK-3
␤
and hyperphosphorylated
␶
, as observed in AD
(Lester-Coll et al., 2006). This model is seen as increas-
ingly important because, in contrast to genetically gen-
erated mouse strains that dominate the experimental
literature, it closely resembles the most common human
condition, termed sporadic AD. There is now a consider-
able literature on the use of SZT to establish models of
insulin resistance (Blondel and Portha, 1989; Koopmans
et al., 2006; Cheng et al., 2010; Thackeray et al., 2011).
As reviewed previously (de la Monte and Wands, 2008),
these SZT-induced changes could be reduced or pre-
vented by early treatment with peroxisome proliferator-
activated receptor agonists in doses smaller than rou-
tinely used to treat diabetes type 2. TNF down-regulates
certain peroxisome proliferator-activated receptor re-
ceptors (Beier et al., 1997).
B. Streptozotocin Induces Tumor Necrosis Factor
The capacity for SZT to induce TNF has been docu-
mented since the mid-1990s (Sagara et al., 1994; Herold
et al., 1996). Cai et al. (2011) reported that it increases
TNF and IL-1
␤
in rat hippocampus. This activity of SZT
to induce TNF has been exploited to help understand the
consequent pathologic features of diabetes (Sagara et
al., 1994; Holstad and Sandler, 2001; Zauli et al., 2010;
Devaraj et al., 2011). Specific examples include diabetic
cardiomyopathy (Westermann et al., 2007) and diabetic
nephropathy (Mensah-Brown et al., 2005; Navarro et al.,
2005). In the latter, successful experimental treatments
include combined insulin (overcoming insulin resis-
tance) and curcumin [reducing the inflammatory re-
sponse (Sharma et al., 2007)] as well as curcumin alone
(Soetikno et al., 2011). A commercial anti-TNF biological
agent has also been used, to good effect, for this purpose
(Yamakawa et al., 2011). As far as we are aware, Isik et
al. (2009) are the only researchers to use an anti-inflam-
matory approach (curcumin) to rationalize post-SZT in-
sulin resistance. As might be expected from the inter-
play between reproductive hormones and TNF, sex
steroids are well recognized to reverse post-SZT insulin
resistance and protect from insulin resistance in rats
exhibiting SZT-induced diabetes (Coleman et al., 1982;
Ordonez et al., 2008). Surprisingly, the consensus from
FIG. 2. The TNF-induced pathway leading to inhibition of progenitor
cells. The first two cell types listed are relevant to conditions such as
Alzheimer’s disease, where excess TNF production is largely restricted to
the brain, and all the cell types listed can be expected to be relevant to
T2DM and severe systemic disease. As discussed and shown, these prin-
ciples are manifest in the physiology of mammalian hibernation and the
dauer forms of C. elegans.
JCLARK ET AL.

this literature (i.e., that neutralizing excess TNF is a
logical step in alleviating pathologic features of diabe-
tes) has yet to translate across to research that uses SZT
to duplicate AD. This should prove to be an excellent
model in which to develop a close laboratory-based un-
derstanding of the effects of anti-TNF agents and sex
hormones in this disease.
X. The Broader Picture—Stroke, Traumatic
Brain Injury, and Infectious Disease
This review focuses on the pathogenesis of AD, with
some reference to T2DM, but the gist of the pathway we
have constructed (Fig. 1) evidently extends to under-
standing other encephalopathies in which cerebral TNF
is increased by routes with current explanations other
than LH/FSH (Section II). Stroke, traumatic brain in-
jury (TBI), and brain involvement in malaria, a systemic
infectious disease, are examples (Fig. 3). As summarized
by Simpkins et al. (2009), AD, stroke and TBI tend to
become one syndrome with the passage of time since
onset. Moreover, TBI is often seen and postcerebral ma-
laria syndrome is usually seen (Boivin et al., 2007; Ki-
hara et al., 2009; Idro et al., 2010) in the young, before
reproduction or menopause.
Induction of TNF in the penumbra of brain ischemia,
the area surrounding the region worst affected by the
vascular obstruction, involves glutamate and nuclear
factor-
␬
B (Kaushal and Schlichter, 2008) and is inhib-
ited by regulatory T cells (Liesz et al., 2009). Cerebral
ischemia has also been reported (Wen et al., 2004a) to
induce aberrant neuronal cell cycle re-entry that can be
reduced by 17
␤
-estradiol, an inhibitor of TNF (Hsu et
al., 2000), a cytokine with a long history of interfering
with mitosis (Darzynkiewicz et al., 1984) and more re-
cently demonstrated to cause aneuploidy (Wu et al.,
2011), the phenomenon that sets the scene for aberrant
cell cycling and thus apoptosis. As recently reviewed by
Clark et al. (2010), trauma triggers release of inflamma-
tory cytokines through the action of mitochondrial DNA
set free from disrupted cells (Zhang et al., 2010). In
infectious diseases, much evidence exists for the direct
induction of TNF by products of the pathogen, beginning
with the example of bacterial lipopolysaccharide in the
original TNF article (Carswell et al., 1975). For instance,
ample evidence exists for the malaria toxin as a TNF
inducer (Bate et al., 1989; Tachado and Schofield, 1994).
As with AD and T2DM, insulin resistance is documented
in stroke (Calleja et al., 2011), TBI (Mowery et al., 2009;
Ley et al., 2011), and cerebral malaria (Eltahir et al.,
2010b). Likewise, A
␤
and hyperphosphorylated
␶
, the
proteins widely regarded as AD hallmarks and appreci-
ated to be indicators of chronically high TNF (section IV)
and GSK-3 hyperactivation induced by insulin resis-
tance (section VI), respectively, are also present in
stroke (Irving et al., 1996; Nihashi et al., 2001; Wen et
al., 2004b), TBI (Irving et al., 1996; Smith et al., 2003;
Tran et al., 2011), and cerebral malaria (Medana et al.,
2002, 2005).
Before expanding on the encephalopathies of system
infectious diseases, we recall the proposal that the A
␤
induced in AD (Bowen et al., 2004) and deposited in the
cerebrovasculature is a response, albeit sometimes an
insufficient one, to seal these vessels to minimize blood-
brain barrier (BBB) breakdown (Atwood et al., 2002;
Atwood, 2010). These arguments, developed in part to
explain the neuroinflammatory reaction frequently ob-
served during normal aging (Wilson et al., 2008), provide
a plausible novel amyloid-based degree of complexity to
the development of the BBB changes commonly seen in
the encephalopathies of infectious disease. For instance,
this reasoning plausibly applies to the A
␤
PP present in
cerebral malaria brains (Medana et al., 2002). In addi-
tion, the antimicrobial properties of its cleavage product,
A
␤
(Soscia et al., 2010), can be expected to minimize
secondary bacterial invasion (a common problem in ma-
laria because of immunosuppression) at this critical lo-
cation. The association of BBB lesions with TNF gener-
ated by infectious agents is already in place in the
encephalopathies associated with sepsis (Alexander et
al., 2008), trypanosomiasis (Quan et al., 1999; Kristens-
son et al., 2010), malaria (Adams et al., 2002) influenza
(Ichiyama et al., 1996), and AIDS (Mastroianni et al.,
1990; Nolting et al., 2009).
Research on cerebral insulin resistance and GSK-3
activation is sparse regarding the encephalopathies of
infectious disease, although some publications link sys-
temic insulin resistance with poor cognitive performance
in women infected with HIV (Valcour et al., 2012) and
fatal malaria with cerebral symptoms (Eltahir et al.,
2010a).
XI. Therapeutic Implications
A. Specific Inhibition of Tumor Necrosis Factor
The obvious way to capitalize on the relationship be-
tween inflammation and insulin resistance is to specifi-
FIG. 3. Examples of the range of different inducers, in different dis-
eases, that can lead to increased cerebral TNF and thence clinically
similar outcomes.
TNF CAUSES INSULIN RESISTANCE:IMPLICATIONS FOR AD K

cally neutralize excessive TNF, as is widely recognized
to be useful in a number of systemic, but not cerebral,
inflammatory diseases. Clearly, this limitation is im-
posed by the large molecular size of current therapeuti-
cally successful specific anti-TNF biological agents, such
as infliximab and etanercept, which precludes their pas-
sage through the blood-brain barrier when administered
subcutaneously or intravenously. Indeed, a negative re-
sult (a small 24-week double-blind trial) with subcuta-
neous etanercept against AD has been reported (Bohac
et al., 2002), as has a positive mouse intracerebroven-
tricular injection trial, albeit measuring only the indi-
rect indicator A
␤
(Shi et al., 2011). Because the intrace-
rebroventricular route is a precarious one, unsuited to
regular administration to the same patient, a number of
ways to circumvent this problem are being developed to
widen the use of these highly successful biological
agents to a new patient group. The earliest of these is a
novel approach termed the perispinal route (Tobinick et
al., 2006, 2010, 2012). Its logic depends on 1) a short
period of head-down tilting to gain a gravitational ad-
vantage, 2) an awareness of anatomy of Batson’s plexus
[a valveless venous system that surrounds the spinal
column in continuum with the choroid plexus (Nathoo et
al., 2011)], and 3) knowledge of the effect of acute hy-
pertension on choroid plexus permeability [a 30-fold in-
crease in albumin in CSF within 10 min of pharmaco-
logically induced acute local hypertension (Murphy and
Johanson, 1985)]. Not surprisingly, therefore, the grav-
itational effect on this valveless blood column of a 5-min
head-down tilt of head and trunk has been reported, in
anesthetized rabbits, to increase dramatically the pas-
sage of albumin and globulin, molecules of etanercept
size, from plasma to the cerebrospinal fluid (Wen et al.,
1994). The authors noted that this would be a useful way
to get large molecules into the CSF for therapeutic
purposes.
The apparent indifference of the makers of etanercept
to the claims of the perispinal anti-brain TNF approach
to treating AD (Tobinick et al., 2006; Tobinick and
Gross, 2008) has not deterred other investigators from
aspiring to the same outcome by several approaches.
One group is developing what it refers to as a molecular
Trojan horse decoy receptor system to get a similar
anti-TNF fusion molecule into the brain (Pardridge,
2010; Zhou et al., 2011). Others (http://www.neurokine.
com/index-3.html) employ encapsulation of etanercept in
liposomes, a well recognized technology (Paolino et al.,
2011), to get the same result. It is encouraging that this
web site notes Dr. Patrick McGeer, a long-time exponent
of earlier approaches to minimizing brain inflammation
(McGeer and McGeer, 1995), as a consultant. Another
approach under way is to devise anti-TNF nanoantibod-
ies small enough to pass the BBB (Harmsen and De
Haard, 2007; Vandenbroucke et al., 2010).
It warrants noting here that the dual activity of TNF
as a component of innate immunity and disease patho-
genesis has made it inevitable that certain infections,
particularly tuberculosis and those caused by certain
protozoa, have a tendency to be exacerbated during long-
term anti-TNF therapy. This has been comprehensively
reviewed (Clark et al., 2010). The very extensive use of
this treatment in a number of inflammatory diseases,
particularly rheumatoid arthritis, demonstrates that
this challenge can be managed successfully.
B. Nonspecific Inhibition of Tumor Necrosis Factor
1. Thalidomide and Curcumin. Brain TNF levels
can also be diminished therapeutically by thalidomide
(Alkam et al., 2008; Ryu and McLarnon, 2008) or its
derivatives (Greig et al., 2004a; Tweedie et al., 2007;
Belarbi et al., 2012b), and current research programs
are examining this in an AD context. Likewise, cur-
cumin, a long-appreciated inhibitor of TNF (Chan,
1995), is used for this purpose in its original form (Cole
et al., 2007) as well as more effective (i.e., in terms of
brain entry) derivative forms (Chiu et al., 2011; Tsai et
al., 2011). All of the authors whose work is cited in this
section might have unwittingly been improving insulin
signaling as well as achieving their stated aims, but this
remains unexplored. The exception appears to be IIsik et
al. (2009), who employed the anti-inflammatory activity
of curcumin to examine its effects on both insulin resis-
tance and memory in a rat model of SZT-induced AD.
Curcumin is also reported to protect testosterone-pro-
ducing Leydig cells and pancreatic cells from toxicity
(Giannessi et al., 2008).
2. Minocycline. Minocycline is a particularly broad-
spectrum oral tetracycline that was synthesized from a
naturally occurring antibiotic decades ago (Church et
al., 1971). Being the most lipid-soluble of this class of
drug, it enters the brain more readily than the rest.
Although not without side effects, it has been known for
15 years to be anti-inflammatory in vivo (Tilley et al.,
1995), and its avid brain penetration is responsible for
the attention it has received in the neuroinflammation
literature (Peng et al., 2006). It is often termed an in-
hibitor of microglial activation, and the list of inflamma-
tory cytokines it down-regulates, in brain and else-
where, includes TNF and IL-1
␤
(Ce´le´rier et al., 1996;
Lee et al., 2004; Suk, 2004; Wang et al., 2005a). Consis-
tent with the overarching pathway central to this re-
view, minocycline shows experimental promise as a
treatment, complementary to the others we discuss, for
the various manifestations of excess production of these
cytokines in the brain (Familian et al., 2006; Seabrook et
al., 2006; Choi et al., 2007; Fan et al., 2007; Noble et al.,
2009). A human AD trial with minocycline is under way
(http://clinicaltrials.gov/ct2/show/NCT01463384).
3. Erythropoietin. Another endogenous humoral fac-
tor, these days referred to as a cytokine but described
decades before this term was in use, is erythropoietin
(EPO). It was discovered as a hormone that drives eryth-
rogenesis and thus provides the means to deliver more
LCLARK ET AL.

oxygen to tissues. Apart from its large-scale clinical use
in treating chronic anemias, it gained notoriety as a
performance-enhancing drug, in due course an illegal
one, in sports. EPO warrants mention in this section
because it has proved to be extremely pleiotropic, in
retrospect probably because of its capacity to inhibit
nuclear factor
␬
B-inducible pathways (Nairz et al.,
2011). It has been reported for many years to have
protective roles in stroke and traumatic brain injury (for
review, see Sargin et al., 2010; Chateauvieux et al.,
2011; Nairz et al., 2012; Sølling, 2012), and it is referred
to as a multifunctional tissue-protective cytokine. EPO
is also on record as enhancing neurogenesis (Osredkar et
al., 2010), oligodendroglial progenitors (Kim and Jung,
2010), endothelial progenitors (Xu et al., 2011), and mi-
tochondrial biogenesis (Carraway et al., 2010). It has the
potential to inhibit cell-mediated immunity as well as
disease (Nairz et al., 2011), as can anti-TNF treatment
(Mayordomo et al., 2002). Hippocampal memory is also
reported to be enhanced in mice treated with EPO for 3
weeks (Adamcio et al., 2008).
All of these phenomena have TNF mirror images in
the literature, sometimes discussed in terms of the in-
sulin resistance TNF induces (Meistrell et al., 1997;
Valerio et al., 2006; Alkam et al., 2008; Bernardino et al.,
2008; Cubbon et al., 2009; Chio et al., 2010; Chen et al.,
2011). Thus, the concept of endogenous anti-TNF activ-
ity being one of the biological roles of EPO is very plau-
sible, as is harnessing this attribute for disease therapy.
Unfortunately, the long history of indifferent recombi-
nant EPO trials in disease has been clouded by a pro-
pensity for its erythropoietic properties to dominate,
with a sometimes fatal thrombosis a feature of its
chronic use (Patel et al., 2011a). Thus nonerythropoietic
variants of this molecule are being developed. They fall
into two main categories: carbamylated EPO (Ramirez
et al., 2009; Leconte et al., 2011) and nonerythropoietic
tissue-protective proteins that mimic the three-dimen-
sional structure of EPO, such as pyroglutamate helix
B-surface peptide (Patel et al., 2011b). Hand and Brines
(2011) and Sølling (2012) have reviewed this area. In-
formation such as toxicity and efficacy within the wide
range of activities of native EPO is still being gathered
for these variants.
The retarded neurogenesis seen in infection with
Japanese encephalitis virus has been reported to be
reversible by abrogating the inflammatory response of
microglia, including TNF production, with exposure to
minocycline (Das et al., 2011). Protection against sim-
ian cerebral pathologic conditions related to HIV by
minocycline has also recently been recorded (Ratai et
al., 2010; Campbell et al., 2011). Therefore, it war-
rants testing whether all of the above reasoning ap-
plies to possible treatments for the encephalopathies
of systemic infectious disease.
As noted above, malaria comes into the category of
systemic inflammatory diseases that may develop an
associated encephalopathy. This condition in children in
tropical Africa is also noteworthy for a well documented
AD-like syndrome that can follow acute cerebral symp-
toms, despite recovery from systemic disease. This syn-
drome correlates with CSF levels of TNF and exhibits
long-term cognitive impairment, including deficits in
memory, attention, visuospatial skills, language, and
executive function (Carter et al., 2005; Boivin et al.,
2007; John et al., 2008a,b; Kihara et al., 2009). This
condition is also noted for aggressive behavior (Idro et
al., 2010), as is AD (Ballard and Walker, 1999). We have
reviewed the literature linking TNF with aggression
(Clark et al., 2010). Researchers were alerted to the
possible implications of the tissue-protective aspects of
EPO in malaria through evidence that its recombinant
form lowered TNF levels and prevented cerebral compli-
cations and death in a mouse model of the disease (Kai-
ser et al., 2006). Raised serum levels of EPO have been
reported to be associated with a lower incidence of neu-
rological sequelae in Kenyan children infected with ma-
laria (Casals-Pascual et al., 2008), leading to the sugges-
tion of using this cytokine therapeutically to protect
against brain damage (Casals-Pascual et al., 2009). Al-
though a short-term open trial in Mali showed no in-
creased mortality (Picot et al., 2009), others (John et al.,
2010) have pointed out the limited opportunity to detect
thrombotic side effects, the chief concern in the wider
literature (Patel et al., 2011a), on using unaltered eryth-
ropoietin. Meanwhile, there appears to be a consensus
(Casals-Pascual et al., 2009; John et al., 2010) to await
the outcome of basic studies of the EPO variants dis-
cussed earlier (Hand and Brines, 2011; Leconte et al.,
2011; Patel et al., 2011b). Some of the potentially less
damaging approaches depicted in Fig. 1, such as oral
minocycline or inhaled insulin, could be considered in
the meantime. Nevertheless, we regard EPO variants as
exciting future prospects for therapeutically addressing
the overarching pathway developed in this review.
C. Administering Leptin As a Counter to
Insulin Resistance
Clark et al. (2011) summarized the literature on leptin
and TNF having mirror image effects on AD. As noted,
administering additional leptin and lowering TNF levels
are both on record as improving memory and learning,
reducing anxiety, lowering A
␤
and hyperphosphorylated
␶
, reducing
␤
-secretase activity, increasing dendritic
spine growth, activating GSK-3, and activating AMP
kinase-activated, pentylenetetrazole-induced seizures.
As we noted (Clark et al., 2011), this pattern had previ-
ously escaped recognition. A case for the centrality of
insulin resistance in AD is further strengthened by the
opposite effects on insulin resistance of leptin (German
et al., 2010; Koch et al., 2010) and TNF, leptin reducing
and TNF increasing it.
Leptin may also have additional direct effects on neu-
rons as an antiapoptotic, proneurogenic adipokine (Paz-
TNF CAUSES INSULIN RESISTANCE:IMPLICATIONS FOR AD M

Filho et al., 2010b), and its administration to leptin-
deficient humans has altered brain function and
increased gray matter (London et al., 2011). Leptin is
currently administered in other diseases, such as lipo-
dystrophy syndromes, hypothalamic amenorrhea, and
nonalcoholic steatohepatitis, but its CNS effects have
not yet been thoroughly evaluated. Its endogenous levels
have been negatively correlated with the risk of devel-
oping AD in lean (leptin sensitive) but not obese (leptin
insensitive) older people (Lieb et al., 2009), implying
that only lean people would be susceptible to treatment
with leptin (Paz-Filho et al., 2010a).
Neither leptin nor anti-TNF agents yet appear to have
been tested against the SZT model of AD, although
leptin reduces insulin resistance (Lin et al., 2002) and
leptin deficiency increases it (German et al., 2011), in
the SZT model of T2DM. Because normal insulin sensi-
tivity keeps GSK-3
␤
activity low, administering leptin
should also decrease its activation and
␶
hyperphospho-
rylation. This, too, has also been reported in neurons
(Greco et al., 2009). The ability of leptin to increase
insulin sensitivity has yet to be explored as an explana-
tion for the novel observation that intracerebroventric-
ular injection of leptin dramatically, albeit briefly, im-
proves a wide range of pathologic features in a mouse
model of type 1 diabetes (Fujikawa et al., 2010). The
systemic improvements recollect those achieved, as dis-
cussed earlier, with intracerebroventricular injections of
infliximab, a commercial anti-TNF biological agent (Ar-
ruda et al., 2011).
D. Administering Insulin As a Counter to
Insulin Resistance
Interest in this approach to treating AD appears to
have arisen when it was realized that the temporary
memory improvement in patient brain function after
systemic administration of insulin was independent of
the attendant serum glucose concentration (Craft et al.,
1996, 1999). Evidently, more subtle pathways are at
work. Others found that the effects of intranasal insulin
could alter basic central nervous system function in eu-
glycemic healthy volunteers (Kern et al., 1999) and a few
years later documented the changes in CSF levels of
insulin so caused, as well as the absence of systemic
changes in insulin or glucose (Born et al., 2002). By 2004
(Benedict et al., 2004), they had reported improvements,
in a similar group of healthy volunteers, in memory and
mood after 8 weeks of treatment. Soon after, another
group reported a pilot trial that exhibited memory im-
provement after this treatment in patients with AD
(Reger et al., 2006). They also reported, then and subse-
quently (Reger et al., 2008), that responses were absent,
under the conditions tested, in apolipoprotein E (apoE)4-
positive patients. Given that a major controller of insu-
lin resistance is the inflammatory cytokine TNF (see
section V.C), it is important, when considering possible
reasons for this difference, to take into account the in-
teractions between apoE4
⫹
and TNF. One study of pos-
sible relevance, as yet unexplored, concerns the inflam-
matory status of microglia (and thus effects on insulin
resistance, although this was not in their protocol) from
mice expressing different numbers and types of human
apoE genes (Vitek et al., 2009). This is discussed further
in section XI.H.
Ott et al. (2012) discussed the pitfalls and potential of
intranasal insulin administration on cognitive function
in general, and Ketterer et al. (2011) focused on possible
ways, through new insulin analogs, such as aspart and
detemir, to optimize reduction of cerebral insulin resis-
tance. Subsequently, Benedict et al. (2012) and Schio¨th
et al. (2012) documented an association between im-
paired insulin resistance with deficits in verbal fluency
and temporal lobe gray matter volume in the elderly and
evaluated the therapeutic potential of reversing this
resistance with intranasal insulin. The former of these
publications is reminiscent of the association observed
between insulin resistance and executive function (Ab-
batecola et al., 2004).
E. Glucagon-Like Peptide-1 Mimetics and Dipeptidyl
Peptidase-4 Inhibitors As Counters to
Insulin Resistance
Being rapidly degraded (minutes) in vivo by DPP-4
(see section V.E), native GLP-1 is impractical as a ther-
apy. Hence, degradation-resistant GLP-1 receptor ago-
nists, often termed GLP-1 mimetics, have been devel-
oped (Ahre´n, 2011a,b), and a number of these agents are
in therapeutic use subcutaneously in T2DM. Exenatide
is an example from a group of drugs based on exendin-4,
a GLP-1-like molecule isolated from a reptile. Another
approach, based on synthesizing GLP-1 analogs, has led
to other subcutaneous agents, such as liraglutide (Buse
et al., 2009). Both of these types of GLP-1 mimetics pass
through the blood-brain barrier and have proved to be
strikingly active against AD models (Perry et al., 2003;
Liu et al., 2009; Porter et al., 2010; Li et al., 2011;
McClean et al., 2011) as well as against a model of the
cognitive defects in T2DM (Gault et al., 2010). Recent
basic studies give impressively detailed reinforcement to
this approach (Bomfim et al., 2012; Talbot et al., 2012).
In addition, a number of agents have been developed,
such as sitagliptin, which inhibits the catalytic site of
DPP-4 (Ahre´n and Foley, 2008; Ahre´n, 2009) to extend
the life of endogenous GLP-1. They are marketed for
treating T2DM and have the practical advantage of be-
ing administered orally, although their testing in AD
models remains in its infancy (D’Amico et al., 2010).
F. Glycogen Synthase Kinase-3 Antagonists
SB216763, presumably tested for its effects on endotoxin-
treated human monocytes (Martin et al., 2005), showed a
degree of promise in a model of AD generated by injecting
an A
␤
oligomer into aged rats but made outcomes worse in
control rats (Hu et al., 2009). As this group suggested, less
NCLARK ET AL.

potent inhibitors that do not inhibit constitutional GSK-3
may be necessary. The study by Engel et al. (2006) is
consistent with this. In terms of lowering phosphorylated
␶
levels and decreasing spatial memory loss, others success-
fully tested a GSK-3 inhibitor, a thiadiazolidinone termed
4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (NP12),
in a transgenic mouse model of AD (Sereno´ et al., 2009).
However, the mice did not live longer. 2-Methyl-5-(3-{4-
[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-
oxadiazole, another novel GSK-3 inhibitor, has recently
been reported to produce a similar positive outcome in
vitro and in a mouse model (Onishi et al., 2011). Success-
fully targeting GSK-3, now a goal in many disease fields, is
evidently a complex undertaking. Engagingly, cardiac re-
searchers have referred to the challenge it presents as a
very sharp double-edged sword (Cheng et al., 2011). This
approach, as well as those discussed in the rest of this
section, is shown in Fig. 1. The major treatment concepts
and their intended or predictable consequences are col-
lected in Table 1.
H. Apolipoprotein E Mimetics and Bexarotene
As reviewed by Laskowitz et al. (2001), the protein
apoE was identified by its role in the transport and
metabolism of cholesterol and triglycerides. It is the
major apolipoprotein generated in the brain, where it
originates from glial cells. Human genetic variation ac-
commodates three isoforms: apoE2, apoE3 (the most
common), and apoE4. In brief, the more apoE4 gener-
ated, the less functional apoE protein is present (Riddell
et al., 2008). Almost as soon as it was appreciated that
the presence of the apoE4 allele was robustly associated
with an increased risk of developing most forms of AD
(Corder et al., 1993), two apparently unrelated threads
of research on apoE function developed. One was based
on connecting apoE, through its lipid-binding domain, to
the formation of the A
␤
and hyperphosphorylated
␶
, the
histologically discernible proteins historically associated
with AD (Strittmatter et al., 1993, 1994). The other
thread, not lipid-related, focusing on innate immunity
and inflammatory mediators rather than lipids, sought
to explain why the link between apoE4 and disease risk
was far wider than AD, encompassing traumatic brain
injury and stroke, and bacterial infections (Roselaar and
Daugherty, 1998; de Bont et al., 1999), which have all
been argued to be inflammatory conditions since the
early 1990s. Indeed, the apoE4 connection with disease
susceptibility goes as far as HIV dementia (Corder et al.,
1998) and cerebral malaria (Aucan et al., 2004).
This second line of enquiry led to seminal outcomes
such as suppression of glial cell secretion of TNF by
apoE (Laskowitz et al., 1997) and inhibition of glial cell
activation and the endogenous CNS inflammatory re-
sponse (Lynch et al., 2001) and the general type 1 in-
flammatory response (Ali et al., 2005), which is medi-
ated by cytokines such as TNF and IL-1
␤
.A
comprehensive review of these concepts appeared 3
years ago (Vitek et al., 2009). This approach has led to
the attainment of a clinically useful anti-inflammatory
milieu in many mouse models of inflammatory disease
by subcutaneous injection of segments of the apoE mol-
ecule (apoE mimetics) that are small enough to enter the
brain. This duplicates the anti-inflammatory action of
complete apoE (Laskowitz et al., 2001). Examples in-
clude traumatic brain injury (Lynch et al., 2005; Las-
kowitz et al., 2007; Hoane et al., 2009; Kaufman et al.,
2010), stroke (Tukhovskaya et al., 2009), and AD (Vitek
et al., 2012).
Cramer et al. (2012) describe removal of A
␤
plaque
and correction of functional deficits in a strain of mice
prone to AD-like changes after oral administration of
bexarotene, an anti-tumor drug in clinical use. This
agent is small enough to enter the brain, where it in-
creases endogenous apoE levels through its activity as a
retinoid X receptor agonist. In a functional sense, bex-
arotene therefore promises to be the equivalent of the
apoE mimetics. Surprisingly, A
␤
plaque removal was
the only mechanism considered by these authors, de-
spite the doubt cast on the utility of this endpoint by the
AD patient trial of AN1792 (A
␤
42; Elan Pharmaceuti-
cals, South San Francisco, CA) several years ago (Hol-
mes et al., 2008). It is useful to recall, when interpreting
TABLE 1
A reference guide for the treatment concepts embodied in this review, and their consequences, either intended by the authors or predictable from
the literature
Treatment Concepts Predictable Consequences in
the Brain Predictable Downstream Consequences in
the Brain Reference
apoE mimetics 2TNF 2Insulin resistance Laskowitz et al., 2001
Thalidomide derivatives 2TNF 2Insulin resistance Greig et al., 2004a
Anti-TNF biologicals 2TNF 2Insulin resistance Tobinick et al., 2006
Minocycline 2TNF 2Insulin resistance Seabrook et al.. 2006
Leuprolide 2TNF 2Insulin resistance Clark and Atwood, 2011
Curcumin derivatives 2TNF 2Insulin resistance Tsai et al., 2011
Erythropoietin 2TNF 2Insulin resistance Nairz et al., 2011a
Bexarotene 2TNF 2Insulin resistance Cramer et al. 2012
GLP-1 mimetics 2Insulin resistance 2GSK3 activation Perry et al., 2003
Intranasal insulin 2Insulin resistance 2GSK3 activation Benedict et al., 2004
Leptin 2Insulin resistance 2GSK3 activation Koch et al., 2010
DPP-4 inhibitors 2Insulin resistance 2GSK3 activation D’Amico et al., 2010
GSK-3 antagonists 2GSK3 activation 2Harmful enzyme phosphorylation Onishi et al., 2011
2, reduction.
TNF CAUSES INSULIN RESISTANCE:IMPLICATIONS FOR AD O

this bexarotene data, that anti-TNF treatment produces
a very similar outcome in the same mouse model (Shi et
al., 2011), and an apoE mimetic has since done so in a
related mouse strain (Vitek et al., 2012). Literature ex-
ists on the side effects of bexarotene, but whether these
arise from high apoE or other consequences of retinoid X
receptor activation has yet to be determined.
XII. Conclusions
It seems not yet to have been taken into account in AD
research that TNF and related inflammatory cytokines
induce insulin resistance or that SZT also induces TNF.
The introduction of these concepts into this field consol-
idates numerous non-A
␤
models of AD. Accordingly, nu-
merous proposed treatments for AD, presently under-
taken with different rationales, seem to be functionally
linked by events that lower TNF levels (and thus insulin
resistance), lower insulin resistance directly, or deal
with its consequences. These presently independent sets
of arguments for therapy reinforce the logic of chronic
cerebral insulin resistance and, therefore, the degree to
which GSK-3 activation, and thus mitochondrial dys-
function, is central to understanding this disease. We
have reasoned that these superficially unrelated ap-
proaches to treatment are all aimed at chronic inflam-
mation and its consequences. Thus, they are, in a sense,
one tool, which invites collaborative searches for thera-
peutic synergy.
When considering how rapidly the therapies discussed
in this review might have the opportunity to demon-
strate whether they can help patients, we note that
anti-TNF biological agents, minocycline, and GLP-1 mi-
metics already have a history of clinical use for other
conditions, the first two for much longer, and on a much
larger scale, than the third. Intranasal insulin has been
used in human trials, produced no side effects, and
seems innately harmless at such doses. Leptin, like in-
sulin an endogenous molecule, has been used long-term
in a small number of patients without apparent harm,
whereas EPO variants still require basic toxicity and
efficacy studies. ApoE mimetics and GSK-3 inhibitors
warrant extending beyond rodent models.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Clark, At-
wood, Bowen, Paz-Filho, and Vissel.
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