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. 2017 Jul 11;38(1):73–84. doi: 10.1007/s10571-017-0521-1

Brain Under Stress and Alzheimer’s Disease

Boris Mravec 1,2,✉, Lubica Horvathova 2, Alexandra Padova 1,2
PMCID: PMC11481981  PMID: 28699112

Abstract

Modern society is characterized by the ubiquity of stressors that affect every individual to different extents. Furthermore, experimental, clinical, and epidemiological data have shown that chronic activation of the stress response may participate in the development of various somatic as well as neuropsychiatric diseases. Surprisingly, the role that stress plays in the etiopathogenesis of Alzheimer’s disease (AD) has not yet been studied in detail and is therefore not well understood. However, accumulated data have shown that neuroendocrine and behavioral changes accompanying the stress response affect neuronal homeostasis and compromise several key neuronal processes. Mediators of the neuroendocrine stress response, if elevated repeatedly or chronically, exert direct detrimental effects on the brain by impairing neuronal metabolism, plasticity, and survival. Stress-induced hormonal and behavioral reactions may also participate in the development of hypertension, atherosclerosis, insulin resistance, and other peripheral disturbances that may indirectly induce neuropathological processes participating in the development and progression of AD. Importantly, stress-induced detrimental effects as etiological factors of AD are attractive because they can be reduced by several approaches including behavioral and pharmacological interventions. These interventions may therefore represent an important strategy for prevention or attenuation of the progression of AD.

Keywords: Amyloid β, Corticotropin-releasing factor, Glucocorticoids, Glutamate, Locus coeruleus, Norepinephrine, Neuroinflammation, Plasticity, Tau protein

Introduction

Alzheimer’s disease (AD) was recognized as a new clinical entity more than 100 years ago after a description of the famous patient Auguste D. by Alois Alzheimer (Kraepelin 1910). It occurs in two forms, a familial (early-onset) AD that are determined genetically, and a far more common sporadic (late-onset) AD that is determined multifactorially. Both forms result in severe cognitive decline and completely disable the patients in the latest stages. The sporadic form of AD represents the most common cause of dementia in elderly, currently accounting for more than 95% of all AD cases and affecting nearly 40 million people worldwide (Prince et al. 2013; Balin and Hudson 2014).

Primary etiological factors responsible for development of familial AD represent inherited mutations in the genes that encode amyloid precursor protein, presenilin 1, presenilin 2, and/or a small number of other genes (Selkoe 2001). In the case of sporadic AD, its etiology is multifactorial and not well understood despite tremendous effort and therefore efficient treatment is not yet available. However, there are two generally accepted main risk factors responsible for development of the sporadic form of AD, age, and the ApoE ε4 allelic variant (Strittmatter et al. 1993; Roses 1996; Launer et al. 1999). Moreover, there are several hypotheses concerning sporadic AD etiopathogenesis focusing mainly on the role of amyloid β40,42 and post-translational modifications of tau protein. Research on AD is focused on the role of amyloid plaques and neurofibrillary tangles in synaptic and neuronal loss that is accompanied by cognitive decline. The main constituents of extracellular amyloid plaque, amyloid β40,42, is produced by the cleavage of amyloid precursor protein (APP). Proteins from the APP family and their secreted proteolytic fragments exert a complex set of actions ranging from transcriptional regulation to synaptic functions (Muller et al. 2017). During physiological conditions, processing of APP is predominantly performed by α and γ secretases. However, if the cleaving of APP becomes predominantly performed by β and γ secretases, it results in the production of amyloid β40,42 proteins. These proteins will then aggregate and create the core of amyloid plaques (Chapman et al. 2001). On the other hand, neurofibrillary tangles are composed of aberrant tau proteins. Tau is a microtubule-associated protein with an important role in the stabilization of the neuronal cytoskeleton. During physiological conditions, the functions of tau protein are modulated by the activities of protein kinases and phosphatases that determine the extent of phosphorylation of this protein. However, if tau protein is hyperphosphorylated and truncated it may aggregate and form neurofibrillary tangles (Ballatore et al. 2007). In addition, the role of mitochondrial dysfunctions, defects of the endolysosomal and autophagic systems, neuroinflammation, oxidative stress, altered insulin signaling in the brain, and increased permeability of the blood–brain barrier in AD-related neuropathology has been investigated as well (Armstrong 2013; Ramanan and Saykin 2013; Peric and Annaert 2015).

The main weakness of above-mentioned hypotheses is the fact that they focus on pathological processes that are consequences, rather than primary etiological factors. It is likely that a combination of several factors (e.g. age-related changes at the level of gene expression, infectious agents, toxic compounds, and head trauma) affects the neuronal milieu and initiates neuropathological processes leading to the formation of toxic tau and amyloid β species, reduction of synaptic plasticity, and neuronal loss resulting into development of sporadic AD (Whitehouse 1986; van Leeuwen and Hoozemans 2015).

Chronic stress is considered a key factor participating in the development of various somatic and neuropsychiatric diseases (Chrousos 2009). Epidemiological studies performed in the last two decades indicate a possible relationship between chronic psychosocial stress and the onset of AD later in life, as well (Wilson et al. 2003; Johansson et al. 2010; Tsolaki et al. 2010). Interestingly, the role of neuroendocrine and behavioral consequences of the stress response in inducing or promoting AD-related neuropathologies has only recently been investigated in detail (Fig. 1; Machado et al. 2014). The aim of this review is to summarize the complex mechanisms and pathways interconnecting chronic stress and AD-related neuropathology.

Fig. 1.

Fig. 1

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Number of PubMed articles found when searching the phrase “Alzheimer’s and stress not oxidative not caregivers” (February 2017)

How We Started to Investigate the Effect of Stress on the Development of AD-Related Neuropathology

Richard Kvetnansky devoted his scientific carrier to investigation of mechanisms and pathways responsible for the neuroendocrine stress response. He focused mainly on changes in catecholamines and catecholamine synthesizing enzymes in the periphery and brains of animals exposed to different stressors (Kvetnansky et al. 1976, 2009; Kvetnansky and Sabban 1993). Richard also participated in seminal experiments, that contrary to Selye’s original hypothesis of the nonspecificity of the stress response, proved that rats’ neuroendocrine response to different stressors are specific to each one (Pacak et al. 1998).

During the last decade of his scientific work, Richard wanted to utilize his extensive knowledge in the field of stress research to elucidate the connection between stress and development of AD-related neuropathologies. I remember his enthusiastic return from the Society for Neuroscience meeting held in Washington during November 2008, where he was impressed by results of Robert A. Rissman, which strongly indicated a connection between repeated stress and tau protein phosphorylation. A few months later, we prepared a grant application focused on the effect of stress on neurodegenerative processes related to AD, particularly on tau hyperphosporylation. We were successful with the grant and during the following years under Richard’s supervision we investigated the effect of acute and chronic stress on the development of tau pathology in knock-out mice and transgenic rats.

This review is dedicated to Richard, our colleague and friend, who devoted his life to science. In the following text, we describe findings from our and other laboratories supporting Richard’s idea, that chronic stress represents one of the primary etiological factors activating a cascade of processes promoting development and progression of the sporadic form of AD.

Neuroendocrine and Behavioral Stress Response is Essential for Survival

The stress response represents a multistep process beginning with a stimulus (stressor) that induces a reaction in the brain (stress perception). Subsequently, activation of certain physiological systems in the brain and body follows, leading to the expression of behavioral and neuroendocrine stress responses. Adequate intensity and duration of the stress response is essential because it enables the organism to cope with external and internal factors threatening its homeostasis (Dhabhar and McEwen 1997).

The stress response is initiated by activation of certain brain structures, depending on nature of stressors. Physical stressors (e.g. high or low temperature of environment, blood loss, infection, and mechanical trauma) activate primarily brainstem structures with consequent, immediate systemic reactions. These brainstem structures processing stress signals and elaborating stress response include the diffuse projecting neuromodulatory systems of the locus coeruleus (LC). Noradrenergic neurons of the LC are necessary for facilitation of arousal and alertness as well as for activation of the neuroendocrine response to stressors. Response to psychosocial stressors (e.g. aberrant social interactions, unemployment) is based on previous experiences or innate programs and requires processing in the forebrain circuits, including corticotropin-releasing factor-synthesizing neurons (Ulrich-Lai and Herman 2009).

Two main neuroendocrine systems are activated in response to stressors, namely the sympathoadrenal system (SAS) and hypothalamic-pituitary-adrenocortical (HPA) axis. Whereas activation of SAS predominantly induces redistribution of blood flow to vital organs, enabling them to produce an adequate physical and mental reaction to the stressor; activation of the HPA axis is primarily responsible for the regulation of metabolism (Chrousos 2009).

Why is Stress Becoming Bad (for the Brain)?

In the evolutionary history of humans, neuroendocrine and behavioral stress responses represented inevitable factors responsible for survival of our predecessors. However, in the last centuries the repertoire, intensity, and duration of stressors affecting humans have changed substantially. In modern society, physical stressors are less frequent, but humans are exposed more frequently to psychosocial stressors. Moreover, the behavioral components of the stress response have changed significantly. For example, one of the most important components of the behavioral stress response, particularly physical activity, is reduced in modern society and therefore the neuroendocrine changes activated by stressors are not utilized by muscles and other tissues. Inadequate utilization of metabolites that are released during the stress response together with increased energy intake may alter functions of the brain and peripheral organs. Therefore, this originally essential stress response may induce maladaptive reactions in modern humans with consequent detrimental effects (Nesse et al. Nesse et al. 2007; McEwen 2008).

It is well documented that inappropriate intensity and duration of the stress response may participate in the development of somatic (e.g. hypertension, metabolic and gastrointestinal diseases) (Chrousos 2009; Purdy 2013) and neuropsychiatric disorders (e.g. anxiety, depression, PTSD) (Lupien et al. 2009; Lucassen et al. 2014). Importantly, recent studies have also elucidated mechanisms and pathways by which the stress response participates in the development of AD-related neuropathology (Tran et al. 2011; Baglietto-Vargas et al. 2015; Piirainen et al. 2017).

Allostatic Overload of Organs may Initiate or Potentiate Development of AD-Related Neuropathology

The stress response, if inappropriate in intensity or duration, may result in allostatic overload of virtually any organ (including the brain) and compromise its functions. These alterations may initiate and/or potentiate directly or indirectly neuropathological changes in the brain (McEwen and Wingfield 2003; McEwen 2012). It can be hypothesized, that in predisposed individuals (e.g. ApoE ε4 allelic variant carriers), allostatic overload may participate in the development of AD-related neuropathology, as well (Figs. 2, 3).

Fig. 2.

Fig. 2

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Development of Alzheimer’s disease phenotype as a consequence of a multistep-pathological cascade activated by primary etiological factors, including stressors, pathogens, toxins, age-related DNA alterations, and ApoE ε4

Fig. 3.

Fig. 3

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Signals related to stressors are processed by neurons synthesizing glutamate, corticotropin-releasing factor (CRF), norepinephrine (locus coeruleus), and other neurotransmitters and neuromodulators. Consequent activation of the hypothalamic-pituitary-adrenocortical (HPA) axis and sympathoadrenal system is accompanied by release of glucocorticoids and catecholamines, stimulating activity of peripheral organs (e.g. cardiovascular, gastrointestinal, and immune). Chronic stress may also induce allostatic overload of glutamatergic, CRF-synthesizing, and noradrenergic neurons with detrimental effects on the brain’s milieu. Moreover, allostatic overload of peripheral organs may participate in the development of pathological processes at the periphery (e.g. atherosclerosis, insulin resistance) with consequent detrimental effects on the brain. Centrally and peripherally-induced alterations of the brain’s milieu may also participate in the progression of neurodegenerative processes leading to the development of Alzheimer’s disease. Interactions between neuropathological processes in the brain are depicted by interrupted line (dashed lines). BBB blood–brain barrier, NFTs neurofibrillary tangles

Based on the concept of multilevel homeostatic mechanisms (Chovatiya and Medzhitov 2014), we hypothesize that repeated stress-related allostatic overload may affect brain function at three basic levels: (a) at the cellular level, it may compromise proteostasis (e.g. tau protein), organelles homeostasis, and induce epigenetic changes in neuronal DNA; (b) at the tissue level it may affect intercellular communication (synaptic contacts), number of cells (reduction of neuronal density), composition of the extracellular matrix (accumulation of amyloid plaques), and neuroinflammation; (c) at the systemic levels it may alter the brain’s regulation of behavior (cognitive decline).

We hypothesize that allostatic overload may also participate in the development of AD indirectly via induction of alterations in peripheral tissues and organs. Additionally, deregulation of immune function, insulin resistance, cardiovascular, and gastrointestinal disorders, as well as other pathological processes induced by chronic stress may also profoundly affect brain homeostasis.

Direct Effect of Stress on the Brain

Stressors induce complex activation of brain pathways accompanied by the release of various neurotransmitters and neuromodulators. Moreover, some signaling molecules (hormones) are released into the periphery and are transported to the brain via humoral pathways.

Coordinated action of neurotransmitters, neuromodulators, and hormones released in stressful situations creates the basis for adequate neuroendocrine and behavioral stress response. However, as described below, alterations in the release of these compounds may lead to development of brain neuropathology.

Glutamate Excitotoxicity and Neuronal Loss

l-glutamate, the main excitatory neurotransmitter in the central nervous system is released from more than 50% of the synapses in the brain. Glutamate participates in virtually all brain activities, including formation of memory. Moreover, glutamate also plays a role as an intermediary metabolite in the detoxification of ammonia and as a precursor for the synthesis of proteins. Tissue homeostasis of extracellular glutamate levels is precisely maintained, because exaggerated glutamate release into the synaptic cleft induces an excitotoxic effect resulting in the death of postsynaptic neurons. This effect is prominent especially in acute insults like ischemic stroke, traumatic brain injury, hypoglycemia, and status epilepticus (Popoli et al. 2012; Lewerenz and Maher 2015).

Besides acute excitotoxicity, in vitro and in vivo experiments have shown that even a 10% chronic increase in extracellular glutamate concentration reduces neuronal survival, particularly in the context of aging. This chronic excitotoxic effect may by driven by multiple factors such as sensitization of NMDA receptors, a decrease of glutamate reuptake capacity, and increases in glutamate release. Importantly, altered glutamatergic neurotransmission accompanies the development of AD. For example, there is a stimulatory effect of amyloid β on NMDA receptors (Tu et al. 2014; Zadori et al. 2014; Lewerenz and Maher 2015).

Both acute and chronic stress enhances glutamate release within the brain, specifically in the prefrontal cortex and hippocampus. Whereas the enhancing effect of acute stress is mediated mainly by glucocorticoids activating presynaptic glutamatergic nerve endings, chronic stress exerts its effect most probably via altering regulation of glutamate release termination (Popoli et al. 2012). Interestingly, memantine, a drug approved for the treatment of AD exerts its beneficial effect via modulation of glutamatergic neurotransmission. Memantine acts as an inhibitor of intra- and extra-synaptic NMDA receptors and reduces tonic over-activity of these receptors, therefore protecting neurons from damage and death (Parsons et al. 2007). Further experiments are necessary to determine whether memantine may be used for prevention of AD-related neuropathology in chronically stressed individuals.

Reduced Brain Norepinephrine Levels Compromises Brain Milieu

Norepinephrine (NE) is a neuromodulator with complex functions in the brain. The main function of NE in the brain is to modulate the transmission of signals between neurons. This modulatory influence plays an important role in the orchestration of stress responses (Ulrich-Lai and Herman 2009). However, NE also significantly participates in the maintenance of brain tissue homeostasis by modulating synaptic plasticity, neurogenesis, activity of astrocytes and microglia, energy metabolism, cortical perfusion, and permeability of the blood–brain barrier (Marien et al. 2004; Hertz et al. 2010; Bekar et al. 2012; O’Donnell et al. 2012; Toussay et al. 2013). The main source of NE in the brain is the locus coeruleus (LC) (Freedman et al. 1975; Robertson et al. 2013).

It is suggested that reduced tissue levels of NE in the brain participates in the alteration of the above-mentioned homeostatic regulation and therefore may participate in the development of AD-related neuropathology. This assumption is supported by several facts: (a) LC neurons undergo significant degeneration in AD; (b) lesions of the LC exacerbate neuropathology in animal models of AD; (c) some treatment strategies affecting noradrenergic transmission in the brain exert beneficial effects on cognition (for review see (Mravec et al. 2014).

Activity of the LC neurons is accompanied by re-synthesis, release, and degradation of norepinephrine. If NE is localized to the neuronal cytoplasm, it may be metabolized to toxic compounds that are detoxified by neuronal enzymatic machinery (Rosenberg 1988; Burke et al. 2001). However, chronic, stress-induced repeated activation of the LC may lead to an allostatic overload of the de-toxicant capacity of LC neurons. Consequently, degeneration of these neurons may significantly reduce NE levels in the brain, followed by deterioration of brain homeostasis and development of AD-related neuropathology. Therefore, it can be hypothesized that the use of drugs to exaggerate noradrenergic neurotransmission in the brain may represent a new strategy for AD treatment.

Corticotropin-Releasing Factor in the Brain Modulates Tau Pathology

Corticotropin-releasing factor (CRF) is released by neurons of the hypothalamic paraventricular nucleus into capillaries of the eminentia mediana and regulates activity of HPA axis by triggering the release of adrenocorticotropic hormone from the anterior pituitary, which consequently stimulates the synthesis and secretion of glucocorticoids from the adrenal cortex. Whereas the majority of CRF-synthesizing neurons are located in the hypothalamic paraventricular nucleus, CRF neurons are also located in the septal region, amygdala, cerebral cortex, hippocampus, and brainstem (e.g. LC) (Merchenthaler et al. 1982; Henckens et al. 2016). Therefore, besides regulating HPA axis activity, CRF neurons are involved in regulating activity of several brain structures, including the LC. Interactions between CRF-synthesizing and NE-synthesizing neurons are essential for modulation of stress response (Chrousos 1998; Lehnert et al. 1998). Moreover, it has been found that CRF affects phosphorylation of tau protein (Rissman et al. 2007; Campbell et al. 2015).

We have found that CRF potentiates tau phosphorylation during acute stress, whereas in animals exposed to chronic stress, CRF exerts an opposite effect (Kvetnansky et al. 2016). This effect is dependent on type 1 CRF receptors. Furthermore, CRF-induced phosphorylation of tau protein interferes with neuronal energetics as it impairs axonal transport of mitochondria (Le et al. 2016).

Exaggerated Activity of the HPA Axis Reduces Hippocampal Plasticity

Glucocorticoids, the effector molecules of the HPA axis, exert complex effects in the periphery as well as in the brain. They regulate metabolism, development, and immune functions, as well as play a crucial role in neuroendocrine stress response (Charmandari et al. 2004). Glucocorticoids also exert central effects, including regulation of glucose utilization by brain tissue, appetite and feeding, and memory formation (Sapolsky et al. 2000). In the brain, a high density of glucocorticoid binding receptors is found in hippocampus, a structure that undergoes significant neurodegenerative changes in AD (Braak and Braak 1991).

Whereas glucocorticoids primarily act to maintain homeostasis, persistently elevated glucocorticoids levels during chronic stress may reduce synaptic plasticity and the number of neurons in hippocampus (Suri and Vaidya 2013; Lucassen et al. 2015). This effect is mediated by several mechanisms, including attenuation of brain-derived neurotrophic factor. In addition, published data indicate that glucocorticoids also reduce synaptic plasticity by activation of glycogen synthase kinase-3 (GSK-3). It is suggested that GSK-3 induces synaptic weakening by phosphorylation of tau protein (Yi et al. 2017). Moreover, in contrast to the classical view of glucocorticoids as potent anti-inflammatory compounds, recent findings have shown that glucocorticoids could induce or potentiate neuroinflammation (McEwen 2008; Vyas et al. 2016). Even if the mechanisms responsible for this effect are only partially elucidated, it is suggested that glucocorticoids induce production/release of danger signals, such as HMGB-1 in the brain, with consequent activation of the NF-kB pathway in microglia (Frank et al. 2016).

Indirect Effects of Stress on the Brain

Maintenance of appropriate brain functions depends on an adequate supply of oxygen and nutrients. However, chronic stress may compromise activity of peripheral tissues and organs and may consequently affect the brain.

Cardiovascular Alterations Affect Exchange of Substrates and Waste Products Between the Blood and the Brain

The cardiovascular system represents one of the most important effectors of the neuroendocrine stress response. During stressful situations, the cardiovascular system provides delivery of substrates, especially for the brain and muscles, enabling the organism to perform appropriate cognitive and motor activity (Kyrou and Tsigos 2007).

Epidemiological studies have clearly demonstrated that chronic psychosocial stress may increase risk of cardiovascular diseases (Timio et al. 1997; Esch et al. 2002; Steptoe and Willemsen 2004; Esler 2016). It is suggested that stress promotes development of atherosclerosis by facilitating low-grade vascular inflammation via elevation of plasma levels of pro-inflammatory cytokines (Lu et al. 2013; Lagraauw et al. 2015). Stress-induced repeated damage of tissues (e.g. kidney) and elevation of renin–angiotensin–aldosterone system activity, along with endothelial, brainstem, and hypothalamic dysfunction induced by low-grade inflammation and vascular remodeling represent factors that may participate in the development of hypertension (Oparil et al. 2003; Hall et al. 2012). Atherosclerosis and hypertension also compromise perfusion of the brain, alter function of the blood–brain barrier, and may participate in the development of AD (Kalaria et al. 2012; Arvanitakis et al. 2016).

Brain hypoperfusion may be accompanied by excessive release of glutamate, inducing an excitotoxic effect on neurons (Lewerenz and Maher 2015). In addition, hypoxia increases phosphorylation of tau protein by activation of GSK-3 (Zhang et al. 2014). Moreover, atherosclerosis- and hypertension-related alterations at the level of the blood–brain barrier compromise clearance of amyloid β from brain tissue potentiating AD neuropathology (Chakraborty et al. 2016; Daulatzai 2017).

Peripheral Insulin Resistance Induces Diabetes Type 3

Abdominal obesity and type 2 diabetes are disorders exerting deleterious effects on various organs, including the brain. These metabolic disorders significantly increase risk for cognitive decline and the development of AD (Jayaraman and Pike 2014). Furthermore, chronic stress-induced activation of HPA axis increases glucocorticoids levels leading to orexigenic effects, abdominal fat accumulation, insulin resistance, dyslipidemia, hyperglycemia, and hypertension (Jauch-Chara and Oltmanns 2014).

Obesity and diabetes may participate in AD pathogenesis by dysregulation of insulin signaling in the brain, induction of hyperphosphorylation of tau protein, amyloid β formation, and neuroinflammation. It has been hypothesized that AD represents a metabolic disease and is subsequently referred to as “type 3 diabetes” (Jayaraman and Pike 2014; Kandimalla et al. 2016). It is suggested that insulin’s effects in AD-related neuropathology is based mainly on pathological modification of tau protein. Hyperphosporylation of tau protein induced by altered insulin signalization in the brain is mediated by increased activity of GSK-3 and lack of dephosporylation by protein phosphatase 2A. Additional factors interconnecting insulin resistance and AD include increased levels of specifically phosporylated insulin receptor substrate 1, insulin resistance-related increased vulnerability to oxidative stress, coexpression of AD- and insulin resistance-related genes, and insulin-modulating degradation of amyloid β (Diehl et al. 2017).

Gastrointestinal Alterations Induce Neuroinflammation

The gastrointestinal tract (GIT) contains over 100 trillion microorganisms (microbiota) that participate in multiple physiological host functions. During physiological conditions, the potential pro-inflammatory effect of gut microbiota is strictly restricted. However, chronic stress induces changes in permeability of the GIT barrier leading to release of microbiota pro-inflammatory molecules into the blood stream (Rieder et al. 2017). Signals related to systemic inflammation modify brain metabolism and behavior (sickness behavior), mainly by affecting functions of microglia. During physiological conditions these changes are transient. However, if microglia exert a primed phenotype as a consequence of altered brain homeostasis (e.g. in aged individuals), systemic inflammation may induce neuroinflammation in the brain (Perry 2010).

Neuroinflammation, specifically the subclinical inflammation of the nervous tissue, is a hallmark of AD. It can be initiated by various factors, e.g. infection, toxic metabolites, traumatic brain injury, autoimmune compounds, or by overactivation of neurons. At the beginning, this neuroinflammation is beneficial and serves as a defense mechanism. However, chronic neuroinflammation exerts harmful effect on the brain (Huang et al. 2017; Piirainen et al. 2017).

In addition, experiments employed germ-free animals indicate that host microbiota can regulate formation of amyloid plaques in the brain, as well (Fung et al. 2017).

Suppressed Activity of Immune System Leads to Reactivation of Latent Viruses

Stress exerts complex changes in activity of the immune system. Whereas some immune functions are exaggerated, others are attenuated. As mentioned above, stress may induce neuroinflammation by different mechanisms. However, chronic stress may also exert suppression of immune function within the periphery with several negative consequences; including reactivation of pathogens (Webster Marketon and Glaser 2008; Fleshner 2013; Moreno-Trevino et al. 2015). It has been suggested that some pathogens, including herpes simplex virus type 1, Cytomegalovirus, Chlamydophila pneumonie, spirochetes, and periodontal pathogens, may participate in the development of AD (Harris and Harris 2015; Lovheim et al. 2015; Itzhaki et al. 2016).

Alzheimer’s Disease-Related Neuropathology May Affect Stress Response

Research focusing on the relationship between stress and AD is focused mainly on the effect of stress on AD-related neuropathology. However, even if structures involved in regulation of SAS and HPA axis activity are affected within the brain of AD patients, the effect of neuropathological changes in AD on stress response is not the primary focus of AD research. This is a consequence of tradition in AD research because AD is considered to be an age-related disorder associated predominantly with memory impairment. Memory dysfunction is linked to neuronal loss in specific brain areas, including hippocampus and the association cortex. However, recent studies have shown that in AD other brain structures are also affected, including the LC and hypothalamus (Loskutova et al. 2010). As mentioned above, both the LC and hypothalamus play central role in modulation of neuroendocrine and behavioral stress response.

Recent data indicate that functions of the LC and hypothalamic nuclei might be severely affected in AD. For example, Braak’s findings indicate, that AD neuropathology starts in the LC. Moreover, a loss of neurons in hypothalamus has been described and it is suggested that this phenomena is mainly the consequence of endoplasmic reticulum stress resulting from neuroinflammation (Clarke et al. 2015).

In our experiments, we have found that immobilization-induced elevation of epinephrine and norepinephrine was significantly reduced in WKY transgenic rats over-expressing human truncated tau protein. These data indicate that tau pathology may compromise the activity of the sympathoadrenal system during stressful conditions (Lejavova et al. 2015).

Potential Clinical Implications

Even if there are several hypotheses related to the etiology of AD, there are only two unambiguously accepted risk factors, particularly age and the ApoE ε4 allelic variants. Accumulated evidences indicate that stress is another important risk factor. Modern society is characterized by the ubiquity of stress and is characterized by an inappropriate stress response. Importantly, the stress response is attractive as an important factor in the etiology of AD because it can be modified. There are several approaches that may help to reduce negative impact of inappropriate stress responses on the development of AD-related neuropathology. These include the spectrum of modifying factors, including physical activity, diet, and psychological processes (Baum and Posluszny 1999; Purdy 2013). Based on the above-mentioned data we suggest that stress-induced neuropathology may be reduced also by: (a) drugs normalizing glutamatergic neurotransmission in the brain (e.g. memantine), and (b) modified molecules of antidepressants that will improve noradrenergic neurotransmission in the brain and consequently ameliorate disruptions of brain homeostasis. These neuropharmacological approaches might be used as preventive or adjuvant therapy of AD.

Stress and AD: Why Still not so Clear Connection?

Curiously, the role of stress as one of many causative factors in the pathogenesis of neurodegenerative diseases, particularly AD, is described only vaguely. Available data indicate connections between stress, hyperphosphorylation of tau protein, cleavage of amyloid β, and neuroinflammation (Chong et al. 2005; Carroll et al. 2011; Ricci et al. 2012). However, even if experimental, clinical, and epidemiological studies indicate that the stress response may represent a risk factor for development of AD, it is necessary to note that there are several difficulties in the investigation of this topic. There is a need for long-lasting prospective clinical studies that might confirm the relationship between chronic stress and AD incidence. However, it is difficult to prove a causal relationship between a particular stressor/s and disease because of the long-term interval between exposure to stressors and the development of pathology, as well as because of significant inter-individual differences in the response and resilience to stressors. Therefore, further experimental and clinical research employing variety of stressors is necessary to uncover mechanisms interconnecting the stress and AD-related neuropathology.

Acknowledgements

This work was supported by the Slovak Research and Development Agency under the contract No. APVV-0088-10 and European Regional Development Fund Research and Development Grant (ITMS 26240120015). We wish to thank Dr. Ken Goldstein of ScienceDocs (www.sciencedocs.com) for the editing of this paper.

Authors’ Contributions

BM drafted the manuscript, LH and AP helped to revise and finalize the manuscript.

Compliance with Ethical Standards

Conflict of interest

We declare no conflicts of interest.

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