Chronic stress as a risk factor for Alzheimer's disease.

Rev. Neurosci. 2014; 25(6): 785–804

Alberto Machado, Antonio J. Herrera, Rocío M. de Pablos*, Ana María Espinosa-Oliva, Manuel Sarmientoa, Antonio Ayala, José Luis Venero, Martiniano Santiago, Ruth F. Villarán, María José Delgado-Cortés, Sandro Argüellesb and Josefina Canoc

Chronic stress as a risk factor for Alzheimer’s disease Abstract: This review aims to point out that chronic stress is able to accelerate the appearance of Alzheimer’s disease (AD), proposing the former as a risk factor for the latter. Firstly, in the introduction we describe some human epidemiological studies pointing out the possibility that chronic stress could increase the incidence, or the rate of appearance of AD. Afterwards, we try to justify these epidemiological results with some experimental data. We have reviewed the experiments studying the effect of various stressors on different features in AD animal models. Moreover, we also point out the data obtained on the effect of chronic stress on some processes that are known to be involved in AD, such as inflammation and glucose metabolism. Later, we relate some of the processes known to be involved in aging and AD, such as accumulation of β-amyloid, TAU hyperphosphorylation, oxidative stress and impairement of mitochondrial function, emphasizing how they are affected by chronic stress/glucocorticoids and comparing with the description made for these processes in AD. All these data support the idea that chronic stress could be considered a risk factor for AD.

Present address: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7LJ, UK b Present address: National Institutes of Health, National Institute on Aging, Biomedical Research Center, Laboratory of Neurosciences, 251 Bayview Boulevard, Baltimore, MD 21224, USA c Deceased. *Corresponding author: Rocío M. de Pablos, Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, c/o Profesor García González, 2, E-41012 Sevilla, Spain, e-mail: [email protected] Alberto Machado, Antonio J. Herrera, Ana María Espinosa-Oliva, Manuel Sarmiento, Antonio Ayala, José Luis Venero, Martiniano Santiago, Ruth F. Villarán, María José Delgado-Cortés, Sandro Argüelles and Rocío M. de Pablos: Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, c/o Profesor García González, 2, E-41012 Sevilla, Spain; and Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, E-41013 Sevilla, Spain a

Keywords: aging; amyloid-β; glucocorticoids; neuroinflammation. DOI 10.1515/revneuro-2014-0035 Received May 16, 2014; accepted July 11, 2014; previously published online August 29, 2014

Introduction Alzheimer’s disease (AD) is the most common cause of dementia among the elderly, affecting one in two individuals over the age of 85 (Masters and Beyreuther, 1998; Iqbal and Grundke-Iqbal, 2008). At autopsy, the brain of a typical AD patient reveals macroscopically visible cerebral atrophy affecting those brain regions involved in learning and memory processes. These regions include the temporal, parietal and frontal cortex as well as the hippocampus (HC) and the amygdala. AD is also characterized by a progressive failure of synaptic transmission. This begins as a localized decrease in synaptic function and over time progresses to a global impairment (Mesulam, 1999; Selkoe, 2002; Rowan et al., 2003). These processes involve an increased deposition of amyloid-β (Aβ)-40 and -42 proteins into extracellular plaques (β-amyloidosis), synaptic dysfunction and neuronal death (Kim et al., 1996; Nitta et al., 1997). Many theories have been proposed to explain these processes, including amyloid cascade, mitochondrial impairment, oxidative stress, inflammation, mutations in specific proteins, long-term response to injury or infection, and defects in normal brain maintenance as well as in the clearance of defective proteins. Taking into account the heterogeneity of factors and the poor correlation between β-amyloidosis and the degree of cognitive decline in early stages of AD (Tanzi, 2005), it is difficult to define the most important factor in the onset and progression of the disease. This is especially true in late-onset AD, which accounts for 95%–98% of all cases. Moreover, some risk factors that increase Aβ deposition, such as old age and genetic mutations (presenilin (PS) 1 and 2 genes and missense mutations in the amyloid precursor protein, APP), are well-established risk factors for AD (Masters and

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786 A. Machado et al.: Stress and Alzheimer’s disease Beyreuther, 1998). Evidence suggests that environmental factors, such as the presence of chronic stress, might also accelerate AD pathogenesis (Wilson et al., 2003, 2005, 2006; Csernansky et al., 2006). Psychological stress is perceived by the hypothalamuspituitary-adrenal (HPA) system. First, the hypothalamus responds to stressors by secreting the corticotrophinreleasing hormone, which triggers the pituitary gland into releasing adrenocorticotrophin into the bloodstream. This in turn produces the secretion of cortisol from the adrenal cortex. Corticosteroids act on many organs and brain areas through two types of receptors, the mineralocorticoid receptors and the glucocorticoid (GC) receptors (GCR), which have a specific and selective distribution in the brain (Reul and de Kloet, 1985). GCR have been found in numerous brain regions relevant to cognition and related to AD-type diseases, such as the HC, the amygdale and the prefrontal cortex (PFC). Since the HPA axis is responsive to both acute and chronic stress, corticoids are suitable biomarkers of stress (Nater et al., 2013). Cortisol can be reliably measured in biological samples to assess either current systemic concentrations (saliva, blood) or cumulative secretion over time (urine, hair). It was reported the increase of plasma cortisol associated with psychological stress in people who had experienced the recent death of a close relative (McClelland et al., 1991). Many epidemiological studies have been carried out to assess the relationship between stressful events and the development of AD and dementia. Wilson et al. (2003) carried out a study on the cognitive function of 806 elderly members of the Catholic clergy, examining the association of stress proneness with AD, cognitive decline and measures of AD pathology. During an average follow-up of 4.9 years, 140 individuals developed AD. Those high in stress proneness (90th percentile) had twice the risk of developing AD compared with those low in stress proneness (10th percentile). It was concluded that proneness to experiencing psychological stress is a risk factor for AD, an effect independent of pathologic AD markers such as neuritic and diffuse plaques and neurofibrillary tangles. A parallel study (Tsolaki et al., 2003) on 149 Orthodox monks and nuns from Greek and Cyprus monasteries provided further evidence that less stress might not prevent the appearance of dementia, but it delayed the onset of symptoms. Moreover, after examining a sample of 1271 patients with dementia for a period of 7 years, Tsolaki et al. (2010) described how most patients reported a history of stressful events (life-threatening diseases and death of a loved one) before the onset of dementia. Another very interesting work, undertaken by Johansson et al. (2010), examined the relationship between self-reported psychological

stress in midlife and the development of late-life dementia in a population-based sample of females followed for 35 years. The interest of these works lies in the fact that they indicate the possible relationship between long-term life stress (psychological stress) and the onset of dementia late in life.

Chronic stress enhances damage progression in animal models of AD There are some studies that show the effect of stress in different animal models of AD, all of them reporting that stress produced the acceleration of AD features. This is in agreement (and complementary) with the review by Rothman and Mattson (2010).

(A) Non-transgenic models (Table 1) These models are based on the toxic effect described for Aβ (for review see Yankner and Lu, 2009). Hence, infusion of Aβ in different brain areas or addition of Aβ in different kinds of cell cultures were used to study AD features such as learning and memory of animals, APP metabolism and amyloidogenic process under stress/GC treatment conditions, showing in all cases that stress and high concentration of GCs produced an increase of Aβ toxicity (see Table 1).

(B) Transgenic models (Table 2) These models are based on the use of transgenic mice or cell lines that overproduce APP and/or develop both Aβ and TAU pathologies consequent to the inclusion of one or more mutated genes that are responsible for the development of AD in humans. It is interesting to note that these models develop many AD features in an age-dependent manner, similar to the natural progress of the disease, providing a very interesting complementary alternative to non-transgenic animal models (Stephan and Phillips, 2005). Data from these models point out that behavioral stressors or GCs treatment increase the different features of AD studied, accentuating the production of Aβ and its incorporation into Aβ plaques, and also decreasing the time needed for the appearance of these features. All these results (Table 1) indicate that stress enhances the toxic effect produced by Aβ administration (by direct injection or by osmotic mini-pumps, for example), this


A. Machado et al.: Stress and Alzheimer’s disease 787 Table 1 Non-transgenic models of Alzheimer’s disease. AD model

Aβ infusion

Stress/GC treatment

Effects

Aged macaques

No Aβ infusion

Cortisol treatment

12-month-old mice

No Aβ infusion

Dexamethasone treatment

Rats

Aβ(1–42) injection into the cholinergic magnocellular nucleus basalis Addition of Aβ

Elevated GCs levels

Decreased degradation of Aβ through downregulation of IDE Impairment of learning and memory, neuronal cell apoptosis and increase of mRNA levels of APP, β-secretase and caspase-3 Increased susceptibility to Aβ(1–42)-mediated toxicity

Addition of CORT

Hippocampal neuronal cultures Murine microglial-like N9 cell line Rats

Addition of Aβ

Aβ infusion into rat brain

Rats

Intracerebroventricular infusion of a 1:1 mixture of Aβ1–40:Aβ1–42 (300 pmol/day)

Rats

Middle-aged rats

Intracerebroventricular infusion of Aβ1–42 (160 pmol/day) Intracerebral infusion of Aβ

Dexamethasone treatment Prednisolone treatment Chronic psychosocial stress

Stress/GC

Neuronal injury Aβ-induced is exacerbated Impeded degradation of Aβ peptides More compact Aβ plaques Greater impairment of learning, memory and E-LTP; reduction of protein levels of CaMKII and increase of calcineurin levels

Eventual production of C99 and Aβ and greater amount of amyloidogenic peptides; spatial memory deficits

References Kulstad et al., 2005

Li et al., 2010

Abrahám et al., 2000 Goodman et al., 1996 Harris-White et al., 2001 Harris-White et al., 2001 Srivareerat et al., 2009

Tran et al., 2010

Catania et al., 2009

Aβ, β-amyloid; APP, amyloid precursor protein; CaMKII, calcium/calmodulin-dependent protein kinase II; C99, peptide C-terminal fragment 99; CORT, corticosterone; E-LTP, early-phase long-term potentiation; GC, glucocorticoid; IDE, insulin-degrading enzyme.

latter has been suggested as the toxic effect that develops the degenerative process in AD. Moreover, stress induced an earlier and more intense appearance of specific AD markers on transgenic mouse models of the disease (Table 2). This suggests that stress accelerates the specific AD process expressed in these animals.

Effect of chronic stress on the inflammatory process and glucose metabolism Chronic stress enhances the sensitivity to inflammatory processes of the brain areas affected in AD There are many features that strongly suggest the relationship between inflammation and AD (Ricci et al.,

2012). Immunohistochemical studies have shown that the plaques and tangles of AD are heavily infiltrated with activated cell types, such as reactive microglia displaying inflammatory/immune markers and molecules known to be associated with inflammation (McGeer and McGeer, 1998). The expression of such molecules has been shown to be strongly upregulated in AD. A study performed on transgenic animals suggests that neuroinflammation plays an important role in the cerebral amyloid deposition process (Guo et al., 2002). It has been shown that inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) or interferon-γ (IFN-γ) can augment APP expression (Buxbaum et al., 1992; Hirose et al., 1994) and Aβ formation (Blasko et al., 1999). It was also reported that cytokines are able to upregulate the transcription of β-secretase (the rate-limiting and necessary enzyme to synthetise Aβ deposits; Vassar, 2001; Sastre et al., 2003; Figure 1A). Kitazawa et al. (2005) described that microglia became activated in a progressive and age-dependent manner in the brain of a triple


788 A. Machado et al.: Stress and Alzheimer’s disease Table 2 Transgenic models of Alzheimer’s disease. AD model

Tg

TG2576 (Mouse)

Aberrancies in HPA function Restraint stress and homeostasis of blood glucose level Aβ deposits in cortical and Isolation stress (6 months) limbic regions, inflammation, behavioral deficits and impairments in hippocampal LTP (9–12 months of age)

Tg2576 (Mouse)

Tg2576 (Mouse)

TG2576 (mouse)

Envirommental stress

Restraints for 2 h during 16 days.

Corticosterone 1–3 days Restrain/isolation over 1 month

Isolation over 3 months

APPV717I-CT100 Increases in the long (Mouse) amyloidogenic form of Aβ (6–12 months of age).

Tg+stress

Reference

Hypoglycemia, death after food restriction and elevation of GCs levels Decreased hippocampal cell proliferation and accelerated age-dependent deposition of Aβ associated with an increased expression of GR and CRFR1 (6 months) Increased levels of Aβ plaques deposition, and Aβ levels, tau hyperphophorilation, and neuritic atrophy of cortical neurons (10–14.5 months). Dowregulation of MMP-2 Increased Aβ levels, supressed microglial activation, and worsened spatial and fear memory. Increased ISF Aβ levels.

Pedersen et al., 1999; Pedersen and Flynn, 2004 Dong et al., 2004, 2008

Restrain stress over 3 h Infusion of CRF Isolation and 6 h/day of immobilization stress 4 days/ week for 8 months (3–11 months).

Chronic mild social stress over 6 weeks

3XTg-AD (Mouse)

Develop both Aβ (insoluble) Dexamethasone 7 days and tau pathologies in an age-dependent manner (6–9–12 months), HPA dysragulation and increased corticosterone level N2A (cell line) Dexamethasone or corticosterone PC12-htau (cell Express the human ortholog Dexamethesone 24–48 h line) of the tau protein. More vulnerable to the toxic effect of Aβ and GC treatment

transgenic AD model (3xTg-AD). This activation correlated with the onset of fibrillar Aβ-peptide plaque accumulation and TAU hyperphosphorylation. When these animals were treated i.p. with lipopolysaccharide (LPS, which is known to increase inflammation on the CNS), they found a significant induction of TAU hyperphosphorylation. The

Lee et al., 2009

Carroll et al., 2011

Kang et al., 2007 Jeong et al., 2006

Accelerated cognitive impairment, increased number and density of vascular, intraneuronal and extracellular deposits of Aβ and APP-CTFs, elevated neurodegeneration and tau phosphorylation levels (11 months) Increased anxiety, elevated levels Rothman et al., 2012 of Aβoligomers and intraneural Aβ and decreased BDNF levels Increased levels of BACE, APP, Green et al., 2006 Aβ (soluble and insoluble) production, tau accumulation (4 months)

Increased levels of Aβ, APP and BACE levels 72 h Increased in APP misprocessing, Sotiropoulos et al., generation of amyloid peptides 2008 and tau phosphorilation through cdk-5 and GSK3 protein kinase. Altered tau trafficking and stability

same study also showed that the increase in inflammation (microglia activation) exacerbated key neuropathological features such as tangle formation. The areas of the CNS show different sensitivities to the inflammation induced by the highly proinflammatory compound, LPS. We have studied the inflammatory


A. Machado et al.: Stress and Alzheimer’s disease 789

Figure 1 Amyloidogenic and non-amyloidogenic pathways, and accumulation of β-amyloid peptide depending on stress and age. (A) The amyloid precursor protein (APP), an integral cell membrane protein, is cleaved by α-secretase in a region within the β-amyloid peptide (Aβ) initiating the non-amyloidogenic pathway. α-secretase produces two peptides, a large amylid precursor protein ectodomain (sAβPPα) and a carboxyl terminal fragment (CTFα), which is also cleaved by γ-secretase yielding two more fragments: the extracellular p3 and the amyloid intracellular domain (AICD). Alternatively, β-secretase beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1, represented here as β) cuts APP, releasing a soluble shorter version called sAβPPβ and initiating the amyloidogenic pathway. The new carboxyl terminal fragment (CTFβ) is a substrate for γ-secretase; cleavage occurs within the cell membrane, producing Aβ and AICD. (B) Accumulation and deposition of Aβ in the brain correlates with alterations of cognitive functions, ranging from mild cognitive impairment (MCI) to the severe state characterizing Alzheimer’s disease (AD). Stress makes accumulation of Aβ to increase far beyond the level produced by normal aging in unstressed individuals.

response to the injection of LPS in various areas of the CNS and found that the substantia nigra (SN) was the most sensitive (Castaño et al., 1998, 2002; Herrera et al., 2000; de Pablos et al., 2014). This might be due to the relative abundance of microglia in the SN, 4–5-fold compared

with other brain structures (Qin et al., 2007). However, some authors have suggested that inflammation is not the most important factor in the progression of Parkinson’s disease, but microglial activity correlates with the amount of α-synuclein placed in the SN (Croisier et al., 2005). Other areas, including those related to AD, such as the PFC and HC, were significantly less affected by LPS (Kim et al., 2000; de Pablos et al., 2006; Espinosa-Oliva et al., 2011). These findings, along with the special sensitivity of the dopaminergic neurons in this process, enable us to emphasize the importance of inflammation in the development of nigro-striatal dopaminergic system degeneration and its possible implication in Parkinson’s disease (Castaño et al., 1998, 2002; Herrera et al., 2000, 2005, 2008; Kim et al., 2000; Carreño-Müller et al., 2003; Tomás-Camardiel et al., 2004; de Pablos et al., 2005, 2006, 2014; Hernández-Romero et al., 2008; Villarán et al., 2009; Argüelles et al., 2010). However, taking into account the above mentioned significant importance of inflammation in AD, we hypothesize that the main areas of the CNS involved in AD, which respond poorly to proinflammatory compounds such as LPS, might increase their responsiveness under some specific circumstances. Therefore, we studied how these areas (PFC and HC) responded to LPS under chronic stress. In these conditions, both areas showed a significant increase in the inflammatory response along with the degeneration of neurons (de Pablos et al., 2006; Espinosa-Oliva et al., 2011). De Pablos et al., (2006) have shown that chronic stress significantly affects the induction of an inflammatory process in the PFC caused by LPS injection. Chronic stress reinforces the changes induced by LPS: microglial activation and proliferation, shown as a stronger reaction of OX-6 (marker of microglia activation) along with a significant increase in the levels of the proinflammatory cytokines TNF-α, IL-1β and IL-6, and a greater loss of astroglia. This pattern is maintained in the neuronal populations, showing a greater loss of NeuN (marker of neuronal nucleus) positive neurons in the stressed animals along with the loss of cells expressing glutamic acid decarboxylase-67 and NMDA receptor 1A mRNAs, which coexpressed in PFC GABAergic neurons. The increased neuronal damage produced by LPS in stressed animals could indicate a cooperative (synergistic) effect of chronic stress and inflammation. Espinosa-Oliva et al. (2011) showed that even though HC is insensitive to strong inflammatory stimuli such as LPS injections (Kim et al. 2000), a dramatic inflammatory effect occurs when LPS is injected into animals that are then subjected to chronic stress for 9 days. This effect is shown by activated


790 A. Machado et al.: Stress and Alzheimer’s disease microglia together with astrogliosis and a greater increase in the expression of the proinflammatory cytokines IL-1β and TNF-α, and in the neuronal and inducible nitric oxide synthses, which are also synergistically involved in the inflammatory processes. Moreover, NeuN immunostaining demonstrated a loss of about 50% of CA1 pyramidal neurons under these conditions, whereas FluoroJade B histochemistry demonstrated the presence of degenerating cells in most of the CA1 area. All these data strongly suggest the importance of inflammation in AD development and progression. Moreover, in a recent study our group has showed that chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons after the injection of LPS (de Pablos et al., 2014). Our hypothesis, instead of presenting inflammation as a primary cause for AD, proposes that the formation of plaques and tangles stimulates a chronic inflammatory reaction that aims to clear cellular debris. However, instead of achieving this goal, such prolonged inflammation causes damage to host tissue, turning a relatively benign condition into a malignant process. Moreover, the results described above show that chronic stress enhances the inflammation induced by a pro-inflammatory compound in PFC and HC cooperatively (synergistically). It is interesting to note that chronic exposure to high doses of GCs exacerbates the kainic acidinduced expression of the pro-inflammatory cytokines IL-1β and TNF-α increasing the inflammation process (MacPherson et al., 2005). Moreover, Li et al. (2014) described that microglia of the high-anxiety strain naïve DBA/2J mice polarizes more to the M1 phenotype, and that this polarization is even more prominent after a systemic proinflammatory challenge. However, a possible effect of stress on the anti-inflammatory cytokines in the brain has not been described. GCs are generally regarded as anti-inflammatory, and indeed have a variety of actions that inhibit inflammation. Thus, it was hard to discuss that GCs increased inflammation under chronic stress, as has been perfectly shown by Sapolsky’s group (Sorrells et al., 2009). It is known that the temporal relationship between GC treatment and immune challenge may be an important factor determining whether GCs exhibit pro- or anti-inflammatory properties. Here, we try to summarize other results that also point out that chronic stress/GCs enhances or induces neuroinflammation. Stress and GCs (as dexamethasone, a potent synthetic member of the GC class of steroid hormones that acts as an anti-inflammatory) seem to be particularly harmful by increasing extracellular accumulation of glutamate, which seems to be produced through two pathways: the increase of glutamate release

and the decrease of clearance by the excitatory amino acid transporter in neurons and astroglia (Leza et al., 1998; Madrigal et al., 2006). These effects, along with others described on mitochondrial function (Du et al.; 2009), produced overload of cellular calcium (Magarinos and McEwen, 1995; Adachi et al., 1998) and could justify some of the harmful effects of GCs. Moreover, as we have described above, stress increases pro-inflammatory cytokines (Dunn et al., 1999). TNF-α increase by stress seems to be due to a direct effect through the activation of the TNF-α converting enzyme (TACE). Madrigal et al., (2002) showed that the increase of TNF-α produced by immobilization stress was prevented by pretreatment with BB1101, an inhibitor of TACE activity. At the same time, the anti-inflammatory protective effect on dopaminergic neurons of the SN exerted by GCs through CGR has been pointed out by Ros-Bernal et al. (2011), who showed that GC repressed the nuclear factor κB (NF-κB) transcriptional activity essential for the inflammatory process that induces the degeneration of dopaminergic neurons. Conversely, the activation of NF-κB by stress has also been described (Madrigal et al., 2006). In addition, we should not forget that chronic high levels of GCs compromise immune functions, in part by down regulating GCR (Pace et al., 2007), suggesting that its protective effect could be compromised. In this case, the protective effect could have changed to a more inflammatory effect, with the induction of apoptosis (Baker et al., 1996). Moreover, it could be possible that the increased concentration of other molecules in chronic stress may turn the protective effect of GCs into a toxic inflammatory effect. We suggest that GCs (e.g., dexamethasone) increase oxidative stress through the induction of monoamine oxidase (MAO) enzymes. We described (Argüelles et al., 2010) the fact that dexamethasone enhanced the degeneration of rats dopaminergic neurons induced by the intranigral injection of thrombin, a serine protease that induces inflammation through microglia proliferation. The damaging effect of dexamethasone was produced through the increased oxidative stress by induction of MAO, as it was protected by MAO inhibition (tranylcypromine). The induction of MAO by GCs has been described (Youdim et al., 1989; Manoli et al., 2005) and this effect is inhibited by the GCR inhibitor RU486 (Carlo et al., 1996). More over, involvement of reactive oxygen species (ROS) in the toxic effect of dexamethasone was shown in other cell types (Baker et al., 1996), being prevented by antioxidant compounds (as N-acetylcysteine and ascorbic acid) or enzymes (as superoxide dismutase and catalase), both in vitro and in vivo (Orzechowski et al., 2002, 2003; Iuchi et al., 2003; Oshima et al., 2004).



Diminution of glucose metabolism A low glucose metabolism in the affected areas of the CNS is a typical feature described in AD that might be involved in the degenerative processes. Moreover, the decrease of glucose metabolism has been described in different areas of the CNS during aging (Kuhl et al., 1982). Patients with AD show a regional cerebral glucose hypometabolism as measured by positron emission tomography (de Leon et al., 1983a,b; Marcus and Freedman, 1997; Rapoport, 1999). These decreases in cerebral metabolism are especially observed in the frontal-temporal-parietal association cortices (Ibáñez et al., 1998; Yasuno et al., 1998), and correlate with several memory impairment measurements (Desgranges et al., 1998; Berent et al., 1999) and hippocampal atrophy (Yamaguchi et al., 1997; Meguro et al., 2001). This is in agreement with the fact that mild hypometabolism in the parietal associated cortex is already present in presymptomatic mutation carriers in familiar AD (Perani et al., 1993; Kennedy et al., 1995). Thus, the cholinergic deficit, the nerve cell atrophy and the amyloid accumulation in the brain are secondary phenomena caused by the 50%–70% decline in glucose metabolism in sporadic AD (Meier-Ruge and Bertoni-Freddari, 1996). The decrease in 2-desoxiglucose uptake in different areas of the CNS at different ages have also been described in APP transgenic mice overexpressing a mutated form of the human APP (mutation V717F) gene (Games et al., 1995; Rockenstein et al., 1995) associated with familial AD (Dodart et al., 1999). Exposure to stress levels of GCs produces physiological responses that are characteristic of type 2 diabetes, such as peripheral insulin resistance; corticosterone (CORT) administration has been shown to impair insulin signaling in the rat HC (Piroli et al., 2007). These effects may contribute to the deleterious consequences of hypercortisolemic/hyperglycemic states observed in type 2 diabetes. On the other hand, it has been suggested that cognitive impairment in diabetes may be a GC-mediated effect because an elevation of circulating CORT is thought to be associated with memory impairments (Aisa et al., 2007; Coluccia et al., 2008; Abercrombie et al., 2011). Stress and insulin resistance have been suggested to contribute not only to age-related loss of neurons in the HC of rats (Sapolsky et al., 1985), but also to the development of lesions typical of AD (Dhikav and Anand, 2007). It prevents intracellular accumulation of several neurotoxins implicated in AD like A-β protein, hydrogen peroxide and glutamate, etc. The drug is able to prevent the loss of CA1 pyramidal hippocampus neurons 24 h after traumatic brain injury.

Among the different mechanisms that have been suggested as a cause of insulin resistance under stress (Amatruda et al., 1985), JNK seems to have a central role (Solas et al., 2013). The decrease of cerebral glucose metabolism (CMRglu) is induced by GCs (Brunetti et al., 1998), which inhibits glucose transport in HC (Horner et al., 1990; Virgin et al., 1991) and other areas (Landgraf et al., 1978; Kadekaro et al., 1988; Freo et al., 1992; Endo et al., 1994; Fulham et al., 1995). This is in agreement with de Leon et al. (1997), who used positron emission tomography to measure the rates of CMRglu, showing that glucose utilization was specifically reduced in HC, and that serum glucose levels increased after the administration of a pharmacological dose of cortisol in normal individuals. Furthermore, Pedersen et al. (1999) showed that transgenic mice expressing a mutant form of the human APP, that causes inherited early-onset AD, exhibited severe hypoglycemia and death following food restriction, as well as sustained elevations of plasma GC levels and hypoglycemia following restraint stress.

Chronic stress accelerates the rate of aging, which could be related to the onset of AD Aging is the first risk factor for the onset of AD. In fact, AD is highly age-dependent. In terms of the onset age, AD can be divided into two groups: familiar, with an onset age under 60, which is always produced by the mutation of some specific genes (for a review, see Bertram and Tanzi, 2008), and late onset ( > 60 years old), whose etiology is not yet completely understood, accounting for 95%–98% of cases. A study of the association between age and AD enables us to estimate that both incidence and prevalence increase exponentially. This means that the disease starts to occur in very late middle age and its occurrence doubles every 5 years (Jorm and Jolley, 1998; Pedersen et al., 2001), affecting a proportion as high as 50% of the population aged over 85 years (Hebert et al., 2003). Aging is a process that includes specific changes in mitochondrial functioning, perturbed energy metabolism, oxidative stress, accumulation of altered proteins, impaired ability of the organism to cope with adversity, etc. Many of these changes occur, and are even exacerbated, in AD. Although there is general agreement on the idea that chronic stress/GCs plays a role in aging (Goosens and Sapolsky, 2007; Landfield et al., 2007), there is little


792 A. Machado et al.: Stress and Alzheimer’s disease consensus regarding the precise nature of this relationship and its underlying mechanisms. Predictions on positive and negative relationships between stress and aging depend on the nature, time of exposure and intensity of stress. Health-related stressors can become chronic in daily life for older adults (Smith, 2003). It is known that one of the main effects of stress is the increase in GCs. Indeed, this increase has been suggested as the cause of many of the damaging effects. Several clinicians have indicated remarkable similarities between the symptoms of Cushing’s disease (hypercortisolemia) and the manifestations of an increase in the aging rate in humans, i.e., heart disease, hypertension, adult-onset diabetes, osteoporosis and muscle wasting (Pecori Giraldi et al., 2003). Moreover, it is important to indicate that Epel et al. (2004) have reported that psychological stress (studied in caregiving mothers) produced a significant increase in the aging rate as measured using the most important and established aging parameters (oxidative stress, telomerase activity and telomere length), which are also known determinants of senescence and longevity in peripheral mononuclear blood cells from healthy premenopausal women. The caregiving mothers were healthy premenopausal women who where biological mothers of a chronically ill child; women with a healthy child were used as control. Subjects from both groups were free of current or chronic disease, and had a similar use of oral contraceptives. Women from both groups completed a standardized questionnaire for the assessment of the level of stress perceived over the past month. The caregiving mothers showed higher oxidative stress, lower telomerase activity, and shorter telomere length in their peripheral mononuclear blood cells; on average, the shortening was equivalent to at least a decade of additional aging. All these data enable us to suggest that chronic stress could increase age by accelerating the rate of aging. To support this, we will try to indicate the possible connections between aging, AD and chronic stress conditions. Some recent reviews summarize the relationship between AD and aging (Bishop et al., 2010 for example), or establish a quantitative scale for measuring premature aging in neurodegenerative disease cohorts (Cao et al., 2010). In brief, in this study, global gene expression data were used to determine the age of a normal brain sample, and then as to whether samples from patients with neurodegenerative diseases look ‘older’ at a molecular level than their age-matched non-diseased counterparts. The authors examined neurodegenerative diseases that increase in incidence with age (e.g., AD), and also those in which the relationship between age and disease incidence is unclear (e.g., FTLD). They found that in specific regions of the brain in both

neurodegenerative diseases, some characteristics of accelerated aging appeared, suggesting some common mechanisms underlying the risk of developing these diseases. Thus, in these contexts we will especially try to introduce the idea that chronic stress affects the main processes that appear to be involved in aging and AD.

Aβ accumulation It is known that in the aging brain, almost all humans accumulate Aβ (Wang et al., 1999; Morishima-Kawashima et al., 2000; Figure 1B). Consequently, it has been suggested that an AD cascade could be initiated as a process of normal aging. In this context, the onset of AD (Aβ accumulation) would be the consequence of any factor increasing Aβ accumulation rate, such as: different mutations producing juvenile AD; Down syndrome, a condition caused by the duplication of a region of chromosome 21 that includes the app gene (Mehta et al., 2003), and any other factor that could increase the rate of brain aging. In this context, Catania et al. (2009) have shown that adult rats exposed to chronic unpredictable stress for 4 weeks displayed a slight increase in the expression of APP mRNA in the HC, although this exposure did not alter immature or mature APP-protein levels. However, a significant increase in the levels of the C99 fragment of APP in HC and PFC was found. This was associated with increased β-secretase beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) and nicastrin levels. Consequently, chronic stress was shown to drive APP processing along the amyloidogenic pathway.

TAU hyperphosphorylation TAU is a major microtubule-associated protein that plays a large role in the outgrowth of neuronal processes and the development of neuronal polarity (Gotz et al., 2013; Briones and Darwish, 2014). TAU promotes microtubule assembly and stability, and is present abundantly in the neuronal axons of the central nervous system. However, recent studies show that TAU is also expressed in glial cells (Fuster-Matanzo et al., 2012). The phosphorylation of TAU regulates microtubule binding and assembly, but hyperphosphorylation destabilizes microtubules by decreased binding of TAU to microtubules (Hashiguchi and Hashiguchi, 2013). This results in aggregation of the protein leading to the formation of neurofibrillary tangles (Gotz et al., 2013), a pathological feature in most neurodegenerative diseases, especially AD. Mounting



evidence strongly suggests that accumulation of abnormal TAU is mediated through spreading of seeds of the protein from cell to cell; it is also suggested that the involvement of extracellular TAU species is the main agent in the interneuronal propagation of neurofibrillary lesions and spreading of TAU toxicity throughout different brain regions in these disorders (Medina and Avila, 2014). Some interesting data demonstrate a correlation of aging and TAU phosphorylation, which might be connected with synaptic plasticity (Härtig et al., 2005, Briones and Darwish, 2014). An age-dependent increase in the phosphorylation of TAU and the formation of neurofibrillary tangles has, for example, been observed in aged bears (Cork et al., 1988), sheep, goats (Braak et al., 1994), bison (Härtig et al., 2000), mouse lemurs (Bons et al., 1995), baboons (Schultz et al., 2000) and various other mammals (Härtig et al., 2001). It is interesting to note that de Quervain et al. (2004) have described that a rare haplotype in the 5’ regulatory region (rs846911) of the gene encoding HSD11B1 (11ß-hydroxysteroid dehydrogenase type 1) was associated with increased sporadic AD risk. The authors suggested that the carriers of the rare haplotype with reduced HSD11B1 transcription may therefore show less inactivation of hydrocortisone, resulting in increased neuronal vulnerability to AD-associated neurotoxicity and, therefore, increased risk of the clinical manifestation of AD. This agrees with the fact that increased concentrations of circulating hydrocortisone have been consistently found in AD (Belanoff et al., 2001). Recently, Sotiropoulos et al. (2011) have shown that in wild-type, healthy middle-aged rats (14 months old), chronic stress and GCs induce abnormal hyperphosphorylation of TAU in the HC and PFC, with contemporaneous impairments of HC- and PFC-dependent behaviors. This phosphorylation took place in at least two of the phospho-TAU epitopes (pThr231 and pSer262) upregulated by stress that were strongly implicated in the neuropathology of AD (Kimura et al., 2007; Mazanetz and Fischer, 2007; Sotiropoulos et al., 2008). Cui et al. (2012) showed that chronic noise exposure causes persistence of TAU hyperphosphorylation and formation of neurofibrillary tangles in the rat HC and PFC. Moreover, Filipcik et al. (2012) found TAU protein phosphorylation in diverse brain areas of normal and CRH deficient mice that was up-regulated by stress. Thus, lifetime stress/ GC exposure may have a cumulative impact on the onset and progress of AD pathology, with TAU hyperphosphorylation serving to transduce the negative effects of stress and GC on cognition.

Oxidative stress There is a general consensus on the idea that aging is produced/developed by the increase and accumulation of oxidative damage. In the context of AD, this links the pathophysiology of the disease directly to aging by an increase in its rate. There are many supporting data since general oxidative stress has been shown in AD by measuring F2-isoprostanes (Praticò et al., 1998). The oxidative damage described in AD seems to be higher than in aged subjects (Calingasan et al., 1999). In addition, oxidative damage to mtDNA is greater in brain tissue samples from patients with mild cognitive impairment and AD compared with samples from age-matched control subjects (Shao et al., 2008). These results could be related to the fact that oxidative stress biomarkers are elevated in the early stages of AD, suggesting that this could be an early event in the development of AD pathology (Nunomura et al., 2001; Praticò et al., 2001; Lovell and Markesbery, 2007). This is also consistent with the fact that levels of oxidative stress in the brain show a gradual increase (brains from normal aging subjects; subjects with mild cognitive impairment; a transition stage between AD and normal aging; AD, the most oxidized stage; for example, see Sultana and Butterfield, 2009), which is consistent with the notion that oxidative stress could be an early event in the progression from mild cognitive impairment to AD. It is interesting to note that the increase in oxidative stress is closely linked to Aβ accumulation and neurofibrillary tangle pathology in the brains of AD patients (Butterfield et al., 2001). The relationship between both processes has been noted, since oxidative stress increases the activity of some enzymes involved in Aβ production. It is also interesting to note that Aβ induces the formation of ROS, which can then cause lipid peroxidation and protein oxidation (Hensley et al., 1994; Mark et al., 1997; Butterfield et al., 2001; Matsuoka et al., 2001). In turn, the resultant Aβ triggers oxidative stress, creating a vicious cycle that might be involved in the development of AD pathology, particularly in the early stages. Chronic stress has been described as one of the main factors stimulating numerous intracellular pathways leading to increased free radical generation. Numerous reports have shown that restraint stress results in an imbalance of the antioxidant status, leading ultimately to increased oxidative stress, thereby resulting in oxidative damage (for example, see Radak et al., 2001). Chronic stress increases oxidative stress markers in the brain, including lipid peroxidation, protein carbonyls, DNA damage and nitrite levels (Liu et al., 1996; Fontella et al., 2005; Pajović et al., 2006; Sahin and Gumuslu, 2007a,b;


794 A. Machado et al.: Stress and Alzheimer’s disease Atif et al., 2008; Singh and Kumar, 2008; Lee et al., 2009), and it also depletes endogenous enzymatic as well as nonenzymatic antioxidants (Atif et al., 2008). This increase in oxidative stress could be related to the fact that stress decreases the activities of various free radical scavenging/ metabolizing enzymes (Radak et al., 2001) such as catalase (Kashif et al., 2003), which could lead to increased post-stress superoxide and H2O2 formation (Ward and Till, 1990). Other glutathion-related enzymes, such as glutathione S-transferase and glutathione reductase, that play a significant role in the detoxification of foreign molecules (Ceballos-Picot et al., 1992), have been found to decrease in HC, striatum and frontal cortex after restraint stress (Atif et al., 2008). These effects are also produced by CORT, since its exogenous administration causes an increase in oxidative stress in brain (Zafir and Banu, 2009). With regard to these data, there are works suggesting a strong relationship between the antioxidative capability of the mitochondria and lifespan, with especial consideration of catalase (Schriner et al., 2005; Jang and Remmen, 2009). Chronic stress induces Aβ formation through the increase in oxidative stress, with an increase in its accumulation rate and its effects. Moreover, it is also important to note that one of the main primary source of ROS, and the source of widespread oxidative damage found in both AD brains and mouse models of AD, is the reactive microglia through the NADPH oxidase activity (e.g., see Abramov and Duchen, 2005), along with the secretion of many proinflammatory molecules. Taking into account that, as we described before, stress increases the susceptibility to the proinflamatory agent LPS (de Pablos et al., 2006, 2014; Espinosa-Oliva et al., 2011). Similar effects could be produced in aging when Aβ, one of the main activators of microglia in AD, begins to accumulate and consequently to increase ROS production.

Mitochondrial impairment Probably, oxidative stress cannot be separated from mitochondrial function since this is the main site of free radical production (Moreira et al., 2007; Pamplona and Barja, 2007; Gibson et al., 2008; Starkov, 2008). Moreover, and in spite of some experimental exceptions (Copeland et al., 2009), there is general consensus that mitochondrial function is related to the aging rate and to lifespan, its ‘efficiency of function’, in relationship to oxygen consumption, energy and free radical production (Sanz et al., 2006; Rea et al., 2007; Bishop et al., 2010; Figure 2). The reduction of mitochondrial function during aging is due to

the loss of some enzymes by inactivation or by a reduction in their expression, (Lu et al., 2004; Yankner et al., 2008) which seems to be greater in AD (Liang et al., 2008; Loerch et al., 2008; Miller et al., 2008). Many of the biochemical, genetic and pathological features of sporadic AD could be explained, at least in part, by the ‘mitochondrial cascade’ hypothesis (Mancuso et al., 2008). Overproduction of ROS and high oxidative stress are characteristics of brains from AD patients (Atamna and Frey, 2007). Moreover, evidence of mitochondrial dysfunction along with a decrease in cyclooxygenase activity, mitochondrial membrane potential, mitochondrial mobility and motility, increased oxidative stress, caspase-3 overactivation, and increased Aβ production in AD pathogenesis have been indicated with the cybrid model (Khan et al., 2000; Cardoso et al., 2004). In a recent study, Selvatici et al., (2013) showed that in vitro mitochondial failure and oxidative stress mimic biochemical features of AD, wheareas, Cuadrado-Tejedor et al. (2013) found age-related mitochondrial alterations without neuronal loss in the HC of a trangenic model of AD. Moreover, many studies have shown that energy production, handling of energy metabolism and membrane fluxes fail in neurons from animal models and patients of AD. However, other factors, such as a reduction in the number of mitochondria and a decrease in energy metabolism are among the earliest detectable defects in AD brains (Hirai et al., 2001; Mosconi et al., 2005). Some of these data suggest that a primary damage to mitochondria, such as abnormal expression or inactivation/inhibition of mitochondrial proteins, should be observed in AD before the appearance of Aβ plaques, and that they would be responsible for the development of AD. This has been observed in AD-like transgenic mice. Gillardon et al. (2007) have shown that embryonic neurons derived from 3xTg-AD mice HC exhibited significantly decreased mitochondrial respiration and increased glycolysis, a condition that continues in females throughout the reproductive period and is noticeably exacerbated during reproductive senescence. Du et al. (2009) have described an important effect of GC that can explain, at least in part, some of the effects described for chronic stress or chronic treatment with GCs related to the increased rate of aging. These authors found that chronic high GC levels produced an attenuation of various aspects of the mitochondrial function. They studied mitochondrial oxidation, one of the important mitochondrial functions involved in ATP synthesis and described that cortical neurons showed a significant reduction in mitochondrial oxidation after long-term, high-dose CORT treatment. They also studied membrane potential, showing that it decreased after a 3-day exposure



Healthy Gluc

Gluc Bc1-2

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nDNA

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PDH

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ATP e-

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Aged Gluc

Ca2CaT

O2

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Protein oxidation Lipid peroxidation

Gluc Bc1-2

Cytc

nDNA

Pyr α-KGDH PDH ADP + Pi ATP

mPTP

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mitDNA H2O+ROS Ca2AO

OXPHOS OXPHOS

Aβ oligomer

CaT Ca2-

O2

Ca2CaT

Figure 2 Energy metabolism and free radicals production in healthy and aging. In healthy cells, glucose metabolism(left to the dashed-dotted line) through the tricarboxilic acid cycle (TAC) provides electrons (e-)to the oxidative phosphorylation (OXPHOS) machinery to yield ATP. Although a little amount of reactive oxygen species (ROS, right to the dasheddotted line) is produced in this process, antioxidant system (AO) eliminate them. Calcium homeostasis is maintained by the calcium transport (CaT) systems. The mitochondrial permeability transition pore (mPTP) opening is inhibited by Bcl-2. In aged, glucose metabolism and ATP production, as well as AO, decrease; unbalanced production of ROS and reactive nitrogen species (RNS) leads to protein oxidation and lipid peroxidation, also affecting mitochondrial DNA (mitDNA). The activity of β-secretase increaes, leading to the production of β-amyloid (Aβ); the oligomerization of this peptide leads to senile plaques.

to high-dose CORT. Both effects were confirmed by the study of calcium holding capacity, since it is known that mitochondrial function is especially involved in buffering intracellular calcium (Murphy et al., 1996). Moreover, they also described that the highest CORT doses reduced B-cell leukemia/lymphoma-2 (Bcl-2) levels in the mitochondria. It is interesting to remember that the Bcl-2 protein is the principal cytoprotective protein in mitochondria, reducing the production of ROS and thus preventing permeability

transition pore opening and mitochondrial depolarization (Zamzami et al., 1998). The increased mitochondrial calcium uptake made the cells resistant to the deleterious influence of elevated intracellular calcium. These effects were lost with the highest concentrations of CORT. These results suggest that chronic stress, as well as high levels of CORT, produce an impairment of mitochondrial function similar to that described in aging and also in AD (Figure 3). Likewise, mitochondrial dysfunction (decrease


796 A. Machado et al.: Stress and Alzheimer’s disease sporadic AD (Velliquette et al., 2006), and consequently a factor in preclinical AD (see Petrie et al., 2009).

of mitochondrial bioenergetics) has been demonstrated to cause amyloid production and nerve cell atrophy (MeierRuge and Bertoni-Freddari, 1997; Velliquette et al., 2005). It is important to note that diminution of glucose metabolism together with the impairment of mitochondrial function could produce a synergic diminution of brain energy metabolism (Figure 3). This has been suggested as one of the earliest proamyloidogenic events in the pathogenesis of

Gluc

This review points out that chronic stress is a risk factor for AD. The HPA axis seems to be the first mechanism by


Stress/GCs Gluc

Conclusion

GC

Bc1-2

Cytc

nDNA

Pyr mPTP

α-KGDH

Bc1-2

PDH ADP + Pi ATP

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mitDNA H2O+ROS

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OXPHOS

CaT

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GC

Gluc

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AD

Aβ oligomer

CaT

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GC


Gluc Bc1-2

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α-KGDH PDH ADP + Pi ATP

TAC

mitDNA H2O+ROS

e-

Ca2AO

OXPHOS OXPHOS

Aβ oligomer

CaT Ca2-

O2

Ca2CaT

Figure 3 Energy metabolism and free radicals production in stress and Alzheimer’s disease. Stress increases the release of glucocorticoids (GCs), which inhibit glucose transport to the cell as well as OXPHOS machinery; as the AO systems are negatively affected, production of ROS/RNS overcome cell capacities, resulting in increased damage. After binding to their receptors (GCR), GCs increase the production of secretases. Expression of the Bcl-2 protein decreases and the mPTP opens, leading to cell death. Most of these effects are produced by GC/GCR complexes which are also translocated inside the mitochondria. All these effects are overcome by RU486, an antagonist of GCR (not shown). If these effects were added to those of aging (Figure 2), accumulation of Aβ and its effects would be significantly increased. In AD, the effects described for the aged (Figure 2) are reinforced, resulting in a lower energy production by the reduction of glucose consumption along with the inhibition of some enzymes as pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH) complexes, more ROS/RNS (with the consequent oxidative damages), Aβ inclusions into the mitochondria, more senile plaques, and the imbalance of calcium homeostasis.



which chronic stress is able to produce its effect. In this context, and as has already been described, the increase in GC levels would appear to be the ultimate consequence of stress and there are many data, reviewed here, suggesting that such an increase provokes many of the effects of stress. All these data indicate that chronic stress/GCs enhances the main processes that appear to be involved in aging, such as the impairment of mitochondrial function, the decrease in energetic metabolism and the increase in oxidative damage, enhancing cell vulnerability, especially in those brain areas with a high GCR concentration. These processes seem to be involved in the increase and accumulation of Aβ, the main feature of AD. These entire data enable us to indicate that chronic stress/GCs should be regarded as an important risk factor for AD. In this context, it is worth mentioning the relationship of life psychological stress over a long period (Johansson et al. 2010) and post-traumatic stress disorder (Burnes and Burnette, 2013) with the onset of dementia late in life. For that, chronic stress condition along with GC concentration should be taken into account in the onset and development of AD. Therefore, a short-term objective should be the development of an accurate method for measuring stress levels, taking into account individual differences in the response to stress and in the vulnerability to stress-induced effects in both human and animal populations. Such a method would, therefore, enable the development of strategies that may help to protect the brain against long-term damage. It is also possible that chronic stress is not merely a response to environmental circumstances, but it is also a response to endogenous conditions such as the individual’s awareness of their own age and health status, and their associated limitations. Moreover, it should be interesting to broaden our knowledge about the regulation of HPA axis and its relationship with age. It is known that many of the damaging effects described for stress/GC were prevented by GC antagonist treatment. RU486, a GCR antagonist, prevents the intracellular accumulation of several neurotoxins involved in AD, such as the Aβ protein, hydrogen peroxide and glutamate (Behl et al., 1997) and the neuronal vulnerability (McCullers et al., 2002; Ghoumari et al., 2003; de Pablos et al., 2006; Espinosa-Oliva et al., 2011; Du et al., 2009; Mailliet et al., 2008; Baglietto-Vargas et al., 2013). As can be followed from this review, a challenge for the future would be to maintain low GC levels, or understand that GC will produce a low effect using safe and effective agents that block the action of GC and their impact on brain functions, including memory, as has been reported for RU486. Such agents could benefit people suffering from acute

and chronic stress, preventing the brain changes associated with aging, chronic stress and stress-related neuropsychiatric diseases. RU486 is the first and unique GCR antagonist available. It was initially considered mainly as a ‘contraceptive’ pill due to its antiprogestin activity. However, and probably for this other action, it has some secondary effect. Moreover, there is little information on its use, except for the treatment of Cushing’s syndrome. There is a review from Schatzberg and Lindley (2008) revising the effect of RU486 on cognitive disorders, including AD, and showing that exist limited data on it. All this allows suggesting the interest of GCR study along with the search for other GC antagonists without side effects. In recent years there has been a growing interest in complementary and alternative medicine approaches aimed at treating the acute symptoms of depression and anxiety associated with psychological stress; of special interest are the Mindfulness-Based Stress Reduction techniques (Edenfield and Saeed, 2012). However, little is really known about the effect of these techniques on the perception and effect of psychological stress. Acknowledgments: This work was supported by grant SAF-2012-39029 from the Spanish Ministry of Economy and Competitiveness and P10-CTS-6494 (Proyecto de Excelencia of Junta de Andalucia). Conflicts of interest statement: The authors declare that they have no conflicts of interest.

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