European Journal of Pharmacology 626 (2010) 64–71

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European Journal of Pharmacology

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Review

Depression and Alzheimer's disease: Neurobiological links and common

pharmacological targets
Filippo Caraci a, Agata Copani a,b, Ferdinando Nicoletti c,d, Filippo Drago e,⁎
a
Department of Pharmaceutical Sciences, University of Catania, 95125, Catania, Italy
b
I.B.B., CNR-Catania, 95125, Catania, Italy
c
I.N.M. Neuromed, Località Camerelle, 86077, Pozzilli, Italy
d
Department of Human Physiology and Pharmacology, University of Rome La Sapienza, 00185 Rome, Italy
e
Department of Experimental and Clinical Pharmacology, University of Catania, 95125, Catania, Italy

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

Article history: Depression is one of the most prevalent and life-threatening forms of mental illnesses, whereas Alzheimer's
Accepted 9 October 2009 disease is a neurodegenerative disorder that affects more than 37 million people worldwide. Recent evidence
Available online 18 October 2009 suggests a strong relationship between depression and Alzheimer's disease. A lifetime history of major
depression has been considered as a risk factor for later development of Alzheimer's disease. The presence of
Keywords: depressive symptoms can affect the conversion of mild cognitive impairment into Alzheimer's disease.
Major depression
Neuritic plaques and neurofibrillary tangles, the two major hallmarks of Alzheimer's disease brain, are more
Alzheimer's disease
Chronic inflammation
pronounced in the brains of Alzheimer's disease patients with comorbid depression as compared with
β-amyloid Alzheimer's disease patients without depression. On the other hand, neurodegenerative phenomena have
Transforming-growth-factor-β1 been observed in different brain regions of patients with a history of depression. Recent evidence suggests
Brain-derived neurotrophic factor that molecular mechanisms and cascades that underlie the pathogenesis of major depression, such as chronic
Neuroprotection inflammation and hyperactivation of hypothalamic–pituitary–adrenal (HPA) axis, are also involved in the
pathogenesis of Alzheimer's disease. In particular, a specific impairment in the signaling of some
neurotrophins such as transforming-growth-factor β1 (TGF-β1) and brain-derived neurotrophic factor
(BDNF) has been observed both in depression and Alzheimer's disease. In the present review we will
examine the evidence on the common molecular pathways between depression and Alzheimer's disease and
we will discuss these pathways as new pharmacological targets for the treatment of both major depression
and Alzheimer's disease.
© 2009 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
2. The connection between depression and dementia: epidemiological evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3. The neurobiological links between depression and Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.1. Stress and dysfunction of the hypothalamic–pituitary–adrenal axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.2. Chronic inflammation in depression and Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.3. Impairment of neurotrophin signalling in depression and Alzheimer's disease: the role of BDNF and TGF-β1 . . . . . . . . . . . . . . 67
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

1. Introduction

Depression is one of the most prevalent and life-threatening forms

⁎ Corresponding author. Department of Experimental and Clinical Pharmacology,
University of Catania, Viale Andrea Doria 6, 95125, Catania, Italy. Tel.: +39 095
7384236; fax: +39 095 7384238.
E-mail address: fdrago1@netzero.net (F. Drago).
of mental illnesses and a major cause of morbidity worldwide.
Estimates of prevalence range from 5 to 20% of the general population,
when people with mild depressive episodes are included (Fava and
Kendler, 2000; Kessler et al., 2005). Depression is associated with

0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejphar.2009.10.022
 F. Caraci et al. / European Journal of Pharmacology 626 (2010) 64–71
significant disability (Murray and Lopez, 1997) and with excess
mortality (Cuijpers and Smit, 2002) particularly from cardiovascular
disease (Rivelli and Jiang, 2007).
Current antidepressant drugs, which are directed against mono-
aminergic systems, provide a useful therapeutic tool, but approxi-
mately 30% of depressed patients failed to respond to these drugs
and antidepressants produce remission only in 30% of patients. This
can be explained by the fact that the pathophysiology of depression
has not been completely elucidated, and treatments have been
developed following the “monoaminergic hypothesis” of depression
without taking into account other mechanisms involved in the
pathophysiology of the disorder. The identification of these mechan-
isms represents a fundamental step for the identification of new
targets and the design of new antidepressant drugs. Recent studies
suggest that factors other than monoamine deficiency or imbalances
between various neurotransmitter systems must be considered when
describing the neurobiological basis of major depression, such as
alterations in mechanisms to resilience to stress, reduced synaptic
plasticity, impaired adult hippocampal neurogenesis and neurode-
generative phenomena in the hippocampus (Krishnan and Nestler,
2008).
Neurodegeneration is also the main histopathological feature of
Alzheimer's disease, a devastating disorder affecting more than 37
million people worldwide. It is mainly characterized by memory loss,
with disoriented behaviour and impairments in language, compre-
hension, and spatial skills. Neuropsychiatric symptoms, such as
depression, psychosis and agitation are also frequent in people with
Alzheimer's disease, and are a common precipitant of institutional
care (Ballard et al., 2008). Current drugs for Alzheimer's disease are
only symptomatic, but do not interfere with the underlying
pathogenic mechanisms of the disease (Klafki et al., 2006). Therefore,
recent efforts in Alzheimer's disease research are now directed to the
identification of new molecular targets for the development of
disease-modifying drugs able to counteract the degenerative pro-
cesses and the resulting memory loss in Alzheimer's disease patients.
Alzheimer's disease is characterized by the presence of ß-amyloid
in the senile plaques, intracellular aggregates of tau protein in the
neurofibrillary tangles, and progressive neuronal loss (Hardy and
Selkoe, 2002). Genetic studies and evidence from animal models
support a primary role for ß-amyloid in the cascade of events which
leads to neuronal death in Alzheimer's disease brain (Hardy and
Selkoe, 2002). Oligomeric species composed of aggregated ß-amyloid
are believed to exert toxic effects on synaptic and cellular functions,
finally leading to neurodegeneration (Cerpa et al., 2008). Different
mechanisms have been proposed to explain ß-amyloid neuro-
toxicity, such as oxidative stress (Butterfield et al., 2007), amplifica-
tion of N-methyl-D-aspartate (NMDA) toxicity (Hynd et al., 2004), cell
cycle activation in differentiated neurons (Giovanni et al., 1999;
Copani et al., 1999; Herrup et al., 2004; Copani et al., 2007), and finally
the sustained loss of the canonical Wnt pathway, a signalling pathway
essential for maintaining neuronal homeostasis (Caricasole et al.,
2004; Inestrosa et al., 2007).
Recent evidence, from epidemiology to neurobiology, suggests a
strong relationship between depression and dementia. For different
years depression and dementia have been considered completely
distinct clinical entities. The term “pseudodementia” is used to define a
clinical picture characterized by depression associated with cognitive
impairment and responsiveness to antidepressant treatment, as
opposed to depression as an early symptom of dementia, which is
instead unresponsive to antidepressants (Gualtieri and Johnson,
2008). Recent evidence suggests that depression can act as a risk
factor for dementia, in particular Alzheimer's disease, and, most
importantly, common pathophysiological mechanisms between these
two diseases have been identified, which might explain the progres-
sion from depression to Alzheimer's disease (Fig. 1). In the present
review we will examine this evidence, focusing on the common
65
Fig. 1. From depression to Alzheimer's disease: neurobiological links and hypothetical
pathophysiological mechanisms. Dysfunction of hypothalamic–pituitary–adrenal (HPA)
axis, chronic inflammation and deficit of neurotrophin signaling exert a central role both in
the pathophysiology of depression and Alzheimer's disease by increasing levels of
glucocorticoids and pro-inflammatory cytokines and also reducing brain-derived
neurotrophic factor (BDNF), and transforming-growth-factor-β1 (TGF-β1) levels. These
alterations might lead to an increased vulnerability to β-amyloid toxicity and hippocampal
atrophy, thus favouring the onset of cognitive deficit and finally the progression from
depression to Alzheimer's disease.
molecular pathways as new pharmacological targets for the treatment
of both depression and Alzheimer's disease.
2. The connection between depression and dementia:
epidemiological evidence
Different studies suggest that depressive disorder is associated
with increased risk of developing cognitive dysfunction (Kessing,
1998; Castaneda et al., 2008) and eventually dementia, in particular
Alzheimer's disease (Geerlings et al., 2000; Ownby et al., 2006).
Several groups have examined the temporal relationship between
depression and Alzheimer's disease to understand whether depression
is simply a prodromal symptom of Alzheimer's disease which precedes
the onset of cognitive deficits, or whether a history of depression might
represent an independent risk factor for the development of
Alzheimer's disease. The systematic meta-analysis from Ownby et al.
(2006) clearly shows that the interval between diagnoses of
depression and Alzheimer's disease is positively related to an
increased risk of developing Alzheimer's disease, suggesting that
rather than a prodrome, depression can be considered as a risk factor
for Alzheimer's disease. Interestingly, depression occurring early in life
(more than 25 years before the diagnosis of dementia) is associated
with a late development of Alzheimer's disease (Robert et al., 2003).
Kessing and Andersen (2004) have demonstrated that the risk to
develop Alzheimer's disease increases with every new affective
episode associated to mood disorders (Kessing, 1998; Kessing and
Andersen, 2004). In particular, the authors found that the rate of
dementia tended to increase by 13% with every episode leading to
hospital admission for patients with depressive disorder.
There is also epidemiological and clinical evidence suggesting a
strong relationship between depression and dementia. Late-life
depression is characterized by the onset of a depressive episode
after age 50 (Gualtieri and Johnson, 2008). Late-life depression
patients frequently exhibit a significant cognitive impairment
(Gallassi et al., 2006). In particular, deficits have been reported in
domains of attention, language, episodic recall, semantic recall,
visuospatial/visuoconstruction, working memory, and executive
66 F. Caraci et al. / European Journal of Pharmacology 626 (2010) 64–71
function (Elderkin-Thompson et al., 2003; Sheline et al., 2006; Köhler
et al., 2009). Several evidences suggest that patients with late-life
depression are at increased risk to develop dementia (Baldwin et al.,
2006; Thomas and O'Brien, 2008). A recent study has also demon-
strated an acceleration in age-related cognitive decline in patients
with depression compared to age-matched normal controls (Gualtieri
and Johnson, 2008). On the other hand, neurodegenerative phenom-
ena have been observed in different brain regions of depressed
patients, such as the hippocampus (Ballmaier et al., 2008), which is
also one of the first brain regions to be affected in Alzheimer's disease
brain. Furthermore, the presence of depressive symptoms promote
the conversion of mild cognitive impairment into Alzheimer's disease
(Houde et al., 2008; Modrego and Ferrández, 2004). Houde et al.
(2008) have found that the persistence of depression over two to
three years in mild cognitive impairment patients significantly
predicts cognitive deterioration leading to Alzheimer's disease.
Modrego and Ferrández (2004) have demonstrated that patients
with mild cognitive impairment and depression are at more than
twice the risk of developing Alzheimer's disease than those without
depression and, more important, patients with a poor response to
antidepressants are at an increased risk of developing Alzheimer's
disease. Finally, depression may occur in 30–40% of the Alzheimer's
disease patients (Assal and Cummings, 2002; Starkstein et al., 2005)
and it affects clinical evolution of Alzheimer's disease (Shim and Yang,
2006). Alzheimer's disease patients with major depression show a
greater and faster cognitive impairment than non depressed patients
(Lyketsos et al., 1997; Milwain and Nagy, 2005; Shim and Yang, 2006),
and, interestingly, neuritic plaques and neurofibrillary tangles, the
two major hallmarks of Alzheimer's disease brain, are more
pronounced in the hippocampus of Alzheimer's disease patients
with comorbid depression as compared with Alzheimer's disease
patients without depression (Rapp et al., 2008).
3. The neurobiological links between depression and
Alzheimer's disease
3.1. Stress and dysfunction of the hypothalamic–pituitary–adrenal axis
Epidemiological evidence supports a role for stress as a risk factor
both for depression (Pittenger and Duman, 2008) and Alzheimer's
disease (Bao et al., 2008; Simard et al., 2009). Several studies clearly
show that chronic exposure to stress and stressful life events may lead
to the development of major depression (Czéh and Lucassen, 2007;
Kendler et al., 1999; van Praag, 2004; Charney and Manji, 2004;
Pariante, 2003), and that elderly individuals prone to psychological
distress are more likely to develop dementia than age-matched non-
stressed individuals (Wilson et al., 2006; Simard et al., 2009).
Stress can be considered as a physiological response to a threat,
which usually activates a specific neuroendocrine pathway known as
the hypothalamic–pituitary–adrenal (HPA) axis (de Kloet et al., 2005).
Stressful stimuli activate the hypothalamus to release the peptide
corticotropin-releasing factor (CRF), which then promotes the release
in the pituitary gland of the adrenocorticotropic hormone (ACTH) into
the circulation. Finally ACTH stimulates the release of glucocorticoids
from the adrenal cortex. Glucocorticoids are steroid hormones that
readily cross the blood–brain barrier and bind to low-affinity
glucocorticoid receptors and high-affinity mineralocorticoid recep-
tors, exerting a negative feedback on HPA axis in the hippocampus and
regulating normal cellular metabolic activity finally influencing many
CNS functions, such as learning and memory (de Kloet et al., 2005).
Stress and HPA axis abnormalities have been demonstrated both in
depression and Alzheimer's disease, with an impaired negative feed-
back of glucocorticoids on the activity of the HPA axis, which results in
elevated cortisol levels (Krishnan and Nestler, 2008; de Kloet et al.,
2005; Davis et al., 1986; Masugi et al., 1989; Swanwick et al., 1998).
Interestingly, the dysfunction of HPA axis occurs early in Alzheimer's
disease (Gurevich et al., 1990; Belanoff et al., 2001b). High basal
cortisol levels are associated with more rapid cognitive decline in
Alzheimer's disease patients (Greenwald et al., 1986; Charles et al.,
1986; Davous, 1987; Carlson et al., 1999), and prednisone treatment
causes an impairment of cognition (Aisen et al., 2000).
Excess glucocorticoids may have a central role in the pathophys-
iology of both depression (Sheline et al., 2003; Krishnan and Nestler,
2008) and Alzheimer's disease (Landfield et al., 2007; Sotiropoulos
et al., 2008) via multiple mechanisms. High levels of glucocorticoids,
through the activation of glucocorticoid receptors, can reduce
neurogenesis in the hippocampal dentate gyrus (Krishnan and
Nestler, 2008), induce the retraction of hippocampal apical dendrites
(Sapolsky, 2000; Magariños and McEwen, 1995; McLaughlin et al.,
2007) and cause neuronal death in hippocampal neurons (Sapolsky,
1986; Yu et al., 2008). In particular, glucocorticoids trigger apoptotic
death in hippocampal neurons via the activation of glucocorticoid
receptors (Crochemore et al., 2005), and also can increase neuronal
vulnerability to different toxins, such as radical oxygen species (Behl
et al., 1997), excitotoxins (Elliott and Sapolsky, 1992) and β-amyloid
(Abraham et al., 2000; Goodman et al., 1996). All these events can
contribute to the reduction in hippocampal volume found both in
depression and early Alzheimer's disease. Interestingly, in animal
models of Alzheimer's disease stress-level glucocorticoid administra-
tion enhances β-amyloid formation by increasing steady-state levels
of amyloid precursor protein (APP) and the β-APP cleaving enzyme,
and also promotes the development of neurofibrillary tangles, a major
histopathological hallmark of Alzheimer's disease, that strongly
correlates with the clinical onset and severity of dementia (Green
et al., 2006).
All these data demonstrate a central role of HPA dysfunction and
high levels of glucocorticoids both in depression and Alzheimer's
disease pathogenesis and suggest the possibility that glucocorticoid
receptors might be a suitable target both for antidepressant and
antidementia drugs.
Clinical data in support of this view have been obtained with
mifepristone, a glucocorticoid receptor antagonist, which seems to be
efficacious in the treatment of psychotic depression, a subtype of
depression characterized by hypercortisolemia (Belanoff et al., 2001b;
Schatzberg and Lindley, 2008; Blasey et al., 2009). Mifepristone at
doses ranging from 600 to 1200 mg/day causes, in patients with
psychotic depression, a rapid improvement in depressive and
psychotic symptoms (Belanoff et al., 2001a; Belanoff et al., 2002).
Preliminary evidence suggests a potential role of mifepristone also in
Alzheimer's disease (Pomara et al., 2002; DeBattista and Belanoff,
2005; Dhikav and Anand, 2007). Mifepristone at the dose of 200 mg/
day showed a positive effect compared to placebo on global cognitive
function after 6 weeks, as assessed by Alzheimer's Disease Assessment
Scale (DeBattista and Belanoff, 2005). Unfortunately no studies have
been conducted yet in Alzheimer's disease patients to assess the
clinical efficacy and the safety of mifepristone after a long-term
treatment (e.g. 6 month), alone or in combination with cholinesterase
inhibitors. Large and long-term clinical studies will be necessary to
further validate this attractive putative drug target both in depression
and Alzheimer's disease.
3.2. Chronic inflammation in depression and Alzheimer's disease
Over the last two decades several studies have demonstrated that
chronic inflammation has a central role in the pathophysiology of both
depression and dementia (Maes et al., 2009; Adler et al., 2006;
Leonard, 2007; Rojo et al., 2008). An altered activation of the immune
system and the ensuing state of chronic inflammation seem to be
strictly correlated to the HPA dysfunction observed in depressed
patients (Maes, 1999). It has been hypothesized that both high cortisol
levels and the activation of immune system can be explained with the
development of glucocorticoid receptor resistance found in depressed
 F. Caraci et al. / European Journal of Pharmacology 626 (2010) 64–71
patients (Maes et al., 2009). Depressed patients have higher levels of
pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-
2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-
12), interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα)
(Schiepers et al., 2005), as well as increased acute phase proteins,
chemokines and cellular adhesion molecules (Maes, 1999). On the
other hand, reduced levels of anti-inflammatory cytokines, such as
interleukin-4 (IL-4), interleukin-10 (IL-10) and Transforming-Growth-
Factor-β1 (TGF-β1), have been found in the plasma of depressed
patients (Maes, 1999; Maes et al., 2009; Myint et al., 2005). Different
studies have demonstrated a positive correlation between the severity
of the symptoms of depression and the increase in the inflammatory
status (Maes, 1999; Owen, 2001; Maes et al., 2009). Pro-inflammatory
cytokines interfere with many of the pathophysiological mechanisms
that characterize the pathogenesis of depression, altering serotonin
metabolism, and reducing both synaptic plasticity and hippocampal
neurogenesis (Maes et al., 2009). Furthermore, pro-inflammatory
cytokines might also promote neurodegenerative processes both in
depression and Alzheimer's disease through the induction of
tryptophan 2,3 dioxygenase (TDO) and indoleamine 2,3 dioxygenase
(IDO) (Leonard, 2007). Activation of these two enzymes leads to an
increase in the synthesis of the neurotoxins 3-hydroxykynurenine (3-
OHK) and quinolinic acid (QA), which can induce neuronal apoptosis
activating the NMDA receptor (Myint and Kim, 2003; Leonard, 2007).
Chronic inflammation play a central role also in the cascade
of molecular events underlying Alzheimer's disease pathogenesis (Rojo
et al., 2008). Increased cerebrospinal fluid (CSF) levels of interleukin-1β
(IL-1β) (Cacabelos et al., 1991) and augmented plasma levels of IL-6
(Huberman et al., 1995; Singh and Guthikonda, 1997) have been found
in Alzheimer's disease patients. In vitro and in vivo studies have
demonstrated that ß-amyloid can activate the microglia to release pro-
inflammatory cytokines such as IL-1β, IL-6 and TNF-α (Maccioni et al.,
2009). Inflammatory responses elicited by elevated Aβ peptides play an
important role in the progression of Alzheimer's disease, and microglia
activation is an early event in Alzheimer's disease pathogenesis and
can be already detected in patients with mild cognitive impairment
(Okello et al., 2009). A direct correlation has been established between
ß-amyloid-induced neurodegeneration and cytokine production (Rojo
et al., 2008). Pro-inflammatory cytokines, such as IL-1β and IL-6,
contribute to reach the signal to trigger neuronal death in Alzheimer's
disease brain (Rojo et al., 2008). Pro-inflammatory cytokines can also
activate the cyclin-dependent kinase 5 (CDK5), one of the main kinases
involved in tau hyperphosphorylation, thus finally promoting neurofi-
brillary tangles formation (Rojo et al., 2008; Quintanilla et al., 2004).
These data demonstrate that chronic inflammation is a common
pathophysiological feature both in depression and Alzheimer's
disease and might explain why a history of depression, with the
following chronic inflammatory changes, can promote the develop-
ment of Alzheimer's disease (see Fig. 1). Furthermore, this new
evidence suggests that anti-inflammatory drugs might be considered
as a new tool for treatment of depression and Alzheimer's disease.
Antidepressant drugs exert immune-regulatory effects, reducing the
production of pro-inflammatory cytokines and stimulating the
synthesis of anti-inflammatory cytokines such as IL-10 and TGF-ß1
(Maes et al., 2009). Unfortunately these drugs produce remission only
in 30% of patients. Existing anti-inflammatory drugs such as non-
steroidal anti-inflammatory drugs (NSAIDs) could be selected in trials
aimed to augment the clinical efficacy of antidepressants. Interest-
ingly it has been demonstrated that acetylsalicylic acid (ASA)
accelerates the antidepressant effect of fluoxetine in animal model
of depression (Brunello et al., 2006), and also shortens the onset of
action of selective reuptake inhibitors (SSRI) in major depressed non-
responder patients (Mendlewicz et al., 2006).
The potential efficacy of anti-inflammatory drugs has also been
studied in Alzheimer's disease models, starting from the epidemio-
logical evidence that long-term use of NSAIDs reduces the risk of
67
developing Alzheimer's disease and delayed the onset of Alzheimer's
disease (Pasinetti, 2002; Imbimbo, 2009). The inducible cyclooxy-
genase-2 (COX-2) promotes amyloidogenic processing (Xiang et al.,
2002) and COX-2 has been found to be elevated in Alzheimer's disease
brain (Pasinetti, 2002). Interestingly in vitro and in vivo studies have
also shown that some NSAIDs, such as ibuprofen and indomethacin
and sulindac sulfide, decrease both β-amyloid 1-42 production and
aggregation by direct modulation of γ-secretase activity (Weggen
et al., 2003) independently from COX inhibition (Weggen et al., 2001;
Rojo et al., 2008). Unfortunately long-term, placebo-controlled
clinical trials with both non-selective and COX-2 selective NSAIDs in
Alzheimer's disease patients have produced negative results. New
studies should be conducted in high-risk populations such as
amnestic mild cognitive impairment patients carrying one or more
epsilon4 allele of the apolipoprotein E, with or without depression, to
assess the potential neuroprotective efficacy of these drugs. Alterna-
tively NSAIDs might be used in Alzheimer's disease drug discovery as
precursors for the development of new β-amyloid-lowering agents .
3.3. Impairment of neurotrophin signalling in depression and Alzheimer's
disease: the role of BDNF and TGF-β1
Neurotrophins are essential for the maintenance of neuronal
homeostasis and modulation of synaptic plasticity (Fumagalli et al.,
2008). Changes in the levels and activities of neurotrophic factors,
such as brain-derived neurotrophic factor (BDNF), and TGF-β1 have
been described both in depression and Alzheimer's disease (Karege
et al., 2005; Murer et al., 2001; Cotman, 2005; Myint et al., 2005; Lee
and Kim, 2006; Tesseur et al., 2006; Mocali et al., 2004).
Significant decreases in BDNF have been detected in stress-induced
animal models of depression (reviewed by Krishnan and Nestler,
2008) as well as in depressed patients (Angelucci et al., 2005; Karege
et al., 2005). Stress reduces BDNF-mediated signalling in the hippo-
campus, whereas chronic treatment with antidepressants increases
BDNF-mediated signaling (Duman and Monteggia, 2006). However,
recent studies suggest that chronic stress can also increase the amount
of BDNF in the nucleus accumbens (Berton et al., 2006), suggesting
the existence of region-specific alterations of BDNF signaling after
chronic stress. BDNF is also involved in the pathogenesis of treatment-
resistant depression, because an association has been found between
a genotype of BDNF that significantly impairs the intracellular traf-
ficking and activity-dependent release of BDNF (Egan et al., 2003),
and an increased risk to develop treatment-resistant depression
(Anttila et al., 2007).
An impairment of BDNF signalling has been demonstrated also in
Alzheimer's disease (Murer et al., 2001; Cotman, 2005). The levels of
BDNF and its receptor, tropomyosin receptor kinase B (TrkB), are
reduced in Alzheimer's disease brain, and a deficiency of BDNF
signalling has been related to synaptic dysfunction, neurodegenera-
tion and finally cognitive deficits (Murer et al., 2001; Cotman, 2005).
Pro-inflammatory cytokines, such as IL-1β, render neurons vulnerable
to degeneration by interfering with BDNF-induced neuroprotection
(Tong et al., 2008). In addition, β-amyloid oligomers reduce BDNF
signaling by impairing the axonal transport of BDNF in neurons of
Alzheimer's disease transgenic mice (Tg2576) (Poon et al., in press).
Interestingly, genetic variations of BDNF play a central role in
Alzheimer's disease-related depression (Borroni et al., 2009). For
example, the presence of the functional single-nucleotide polymor-
phism (G196A; Val 66 → Met 66), which impairs BDNF signaling,
significantly increases the risk to develop depression in Alzheimer's
disease patients (Borroni et al., 2009).
BDNF can also interact in the CNS with other neurotrophins such as
TGF-β1. TGF-β1 is an anti-inflammatory cytokine which regulates the
balance between T helper-1 and T helper-2 cytokines, but it can also
act as a neurotrophic factor in the CNS protecting neurons against a
diverse number of insults, including excitotoxicity, hypoxia, ischemia,
68 F. Caraci et al. / European Journal of Pharmacology 626 (2010) 64–71
and most importantly β-amyloid (Vivien and Ali, 2006; Caraci et al.,
2008a). TGF-β1 can also increase synaptic plasticity by enhancing the
expression of BDNF and TrkB (Sometani et al., 2001).
Plasma TGF-ß1 levels are reduced in major depressed patients and
show a significant negative correlation with the Hamilton Depression
Rating Scale (Myint et al., 2005; Lee and Kim, 2006; Sutcigil et al., 2007).
Interestingly, TGF-ß1 levels significantly increase after antidepressant
treatment (Myint et al., 2005), and SSRI drugs such as sertraline might
exert immunomodulatory effects in vivo through a decrease in the pro-
inflammatory cytokine IL-12 and an increase in the anti-inflammatory
cytokines such as IL-4 and TGF-β1 (Sutcigil et al., 2007). Similarly,
therapeutic concentrations of venlafaxine prevent microglial activation,
reduce pro-inflammatory cytokine secretion, and finally increases the
release of TGF-ß1 in an astroglia–microglia co-culture model (Vollmar
et al., 2008).
Recently an impairment of TGF-β1 signaling has been demon-
strated in Alzheimer's disease brain. Tesseur et al. (2006) have found
that the expression of TGF-β type II receptor in neurons is reduced
very early in the course of Alzheimer's disease, and this alteration is
specific for Alzheimer's disease. An impairment of TGF-β1 signaling
axis might exert a pathogenetic role in Alzheimer's disease, depriving
cortical neurons of trophic support, increasing β-amyloid accumula-
tion and finally promoting β-amyloid-induced neurodegeneration, as
observed in different in vitro and in vivo models of Alzheimer's
disease (Wyss-Coray, 2006; Caraci et al. 2008a). A loss of function
within the TGF-ß1 signaling pathway may also contribute to tau
pathology and neurofibrillary tangle formation in Alzheimer's disease
brain (Chalmers and Love, 2007). Finally, TGF-β1 has a constitutive
role in the suppression of inflammation, and several studies have
demonstrated that TGF-β1 reduces microglia activation and promotes
the degradation of β-amyloid by microglial cells (Wyss-Coray, 2006).
Therefore a failure of TGF-β1 signaling in Alzheimer's disease brain
may contribute to enhance both chronic inflammation and neuronal
vulnerability to ß-amyloid, thus accelerating the progression of
Alzheimer's disease (Fig. 1).
Accordingly a reduction of both the active (25 kDa) and inactive
(50 kDa) forms of TGF-β1 has been reported in plasma of Alzheimer's
disease patients (Mocali et al., 2004). A single nucleotide polymorph-
isms (SNPs) at codon + 10 (T(C) and +25 (G/C), that reduces the
levels of expression of TGF-β1, has also been associated with an
increased conversion of mild cognitive impairment in Alzheimer's
disease (Arosio et al., 2007).
Overall these data demonstrate that a deficit of neurotrophins such
as BDNF and TGF-β1 might be considered a common pathophysio-
logical event both in depression and Alzheimer's disease, suggesting
that the rescue of neurotrophin signaling pathways could be a new
strategy for the treatment of these two diseases.
Neurotrophic factor therapy represents a difficult challenge for
CNS drug discovery, because protein growth factors do not cross the
blood–brain barrier and require intracerebral administration to be
effective. Central administration of BDNF into the ventricles or the
hippocampus induce neurogenesis and exerts antidepressant-like
effects in different models of depression (Malberg and Blendy, 2005).
Recently, BDNF gene delivery has also been found to exert substantial
protective effects in Alzheimer's disease models and has been
proposed as a new potential therapy for Alzheimer's disease
(Nagahara et al., 2009). Nevertheless central delivery of neurotrophic
factors cannot be considered a suitable approach for general medical
practice. Alternatively new efforts might be directed to identify
centrally available drugs able to increase the local production of BDNF
and TGF-ß1.
Different drugs are known to induce the synthesis and the release
of BDNF and TGF-ß1 in vitro and in vivo (Table 1). Antidepressants
stimulate BDNF synthesis with a time course in line with the onset of
clinical efficacy (Duman, 2004; Groves, 2007). Induction of BDNF has a
central role in mediating the effects of antidepressant drugs. Mice
Table 1
Potential pharmacological approaches to rescue neurotrophin signaling in depression
and AD.
Drug Mechanism Authors
Antidepressants Increased TGF-ß1 and BDNF Groves (2007)
plasma levels in vivo and Sutcigil et al., 2007;
augmented neurogenesis Myint et al., 2005;
Vollmar et al., 2008
Aspirin Increased TGF-ß1 Redondo et al. (2007)
plasma levels in vivo
Glatiramer Induction of TGF-ß1 Aharoni et al., 2005;
and BDNF synthesis Tsai, 2007
Lithium Increased synthesis Leyhe et al., 2009;
of BDNF and TGF-ß1 Caraci et al., 2008b
mGlu2/3 receptor agonists Increased synthesis Bruno et al. (1998)
and secretion of
TGF-ß1 from glial cells
Valproate Increased synthesis of BDNF Walz et al. (2007)
heterozygous for a BDNF null mutation are resistant to the effects of
antidepressants in the forced swim test (Saarelainen et al., 2003).
Activation of the transcription regulator cAMP response element
binding protein (CREB) is essential for the induction of BDNF by
antidepressants (Krishnan and Nestler, 2008; Malberg and Blendy,
2005). Antidepressant drugs, as above discussed, induce in vitro ed in
vivo the synthesis of TGF-ß1. A recent study by Kessing et al. (2009)
shows that continued long-term antidepressants treatment is asso-
ciated with a reduction in the rate of Alzheimer's disease, suggesting
that it might be worth to assess whether TGF-β1 signaling is a
common target for both depression and Alzheimer's disease, and
whether antidepressant drugs exert their neuroprotective effects
against Alzheimer's disease via the rescue of TGF-β1 signaling.
Other psychotropic drugs such as lithium and valproate increase
BDNF contents in rat hippocampus and frontal cortex (Walz et al.,
2007). Lithium increases BDNF serum levels in Alzheimer's disease
patients, and additionally determined a significant decrease of
Alzheimer's disease AS-Cog sum scores in comparison to placebo-
treated patients (Leyhe et al., 2009). Prevalence of Alzheimer's disease
is lower in patients treated with lithium (Yeh and Tsai, 2008), and
lithium reduces the risk of developing Alzheimer's disease in elderly
patients with bipolar disorder (Nunes et al., 2007). Different molecular
mechanisms have been suggested to explain the neuroprotective
effects of lithium. Recently, we have found that lithium can strongly
induce the release of TGF-ß1 from glial cells (Caraci et al., 2008b).
Among anti-inflammatory drugs aspirin can promote the synthesis
and release TGF-ß1 in vivo (Redondo et al., 2007) and, as above
discussed, it increases the response to antidepressant drugs (Brunello
et al., 2006). Interestingly, aspirin is known to reduce the risk of
developing Alzheimer's disease (Broe et al., 2000). Further studies will
be necessary to assess whether this drug can exert its clinical and
neuroprotective efficacy by increasing TGF-ß1 signaling.
Glatiramer, a synthetic amino acid copolymer currently approved
for the treatment of multiple sclerosis (MS), induces in mice specific
suppressor cells of the T helper-2 type that migrate to the brain where
they express anti-inflammatory cytokines such as IL-10 and TGF-ß1 in
addition to BDNF (Aharoni et al., 2005). Several studies have shown
that peripheral administration of glatiramer increases neurogenesis in
rodent brain (Tsai, 2007). Glatiramer might exert antidepressant
effects by increasing central BDNF, stimulating neurogenesis or
alternatively through its anti-inflammatory action. Unfortunately no
studies have been yet conducted in depressed or Alzheimer's disease
patients to assess the potential neuroprotective effects of glatiramer.
Finally, the production of TGF-ß1 can be enhanced by agonists of
group II metabotropic glutamate receptors both in cultured astrocytes
(Bruno et al., 1998) and in the mouse brain (D'Onofrio et al., 2001).
Interestingly agonists of group II metabotropic glutamate receptors
shorten the latency of antidepressants drugs in animal models of
 F. Caraci et al. / European Journal of Pharmacology 626 (2010) 64–71
depression (Matrisciano et al., 2007). In addition, these drugs protect
cortical neurons against ß-amyloid toxicity (Copani et al., 1995). It is
significant that highly potent and centrally available group II
metabotropic glutamate receptor agonists, such as LY404039, are
under clinical development for the treatment of schizophrenia (Patil
et al., 2007). We suggest that these drugs are potential candidates as
neuroprotectant agents both in depression and Alzheimer's disease.
4. Conclusion
In the present review we have examined recent evidence on the
common molecular mechanisms and cascades between depression
and Alzheimer's disease. The above short review did not intend to
cover the vast amount of data in this field.
According to the discussed data we suggest that hyperactivation of
HPA axis, chronic inflammation and deficit of neurotrophin signaling
can be considered as common pathophysiological mechanisms between
depression and Alzheimer's disease (Fig. 1) and are potential new
targets for pharmacological treatment of these two disorders. These
common molecular pathways might be studied in the future for the
discovery of new biological markers which predict the progression from
depression to Alzheimer's disease, and for the identification of early
Alzheimer's disease patients eligible for disease-modifying therapies.
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