The role of epigenetic mechanisms in the programming by early-life stress and nutrition in Alzheimer’s disease

The role of epigenetic mechanisms in the

programming by early-life stress and

nutrition in Alzheimer’s disease

Date 07-06-2015

Student Steffie Szegedi Student number 5781892 Supervisor dr. A. Korosi Co-Assessor dr. G. van Wingen

Education MSc in Brain and Cognitive Sciences, University of Amsterdam Track Cognitive Neuroscience

Abstract

Alzheimer’s disease (AD) is a very debilitating disease and the most common form of dementia. Age is the greatest risk factor for the development of AD. Because of the ageing trend of populations western societies the costs will significantly increase which may jeopardize the sustainability of the current health care resources. Therefore research into the etiology, diagnosis and treatment of AD is needed. Although certain genes have been found that are involved in AD they do not explain the etiology of AD completely and therefore other factors are thought to be important as well. The field of epigenetics attempts to bridge

environmental and genetic factors explaining pathologies. Early life is a sensitive and critical period in the development of humans. Stress induced epigenetic changes on the glucorticoid system, BDNF and Reelin will be discussed and its possible relation to Alzheimer’s disease. The influence of nutrition, such as caloric restriction and a high fat diet, on epigenetic changes will be addressed and its possible relation to Alzheimer’s disease. The hormone leptin is strongly related to nutrition and there is a high density of leptin receptors in the hippocampus, therefore the possible role of leptin in the etiology of Alzheimer’s disease will be discussed as well. The relation between epigenetic changes that are associated with increasing age will also be discussed. This paper indicates that early life is a sensitive and determining period in human development. Besides the critical period during early life there seems to be a critical period in the later stage of life as well. The hippocampus is an area in the brain that is quite sensitive to the effects of life adversities (e.g. stress and malnutrition) especially during early development. These life adversities can have detrimental effects on hippocampal functioning and therefore might lead to memory deficits. Taken together AD could result from different underlying causes. Especially, in sporadic AD, which is the largest group of patients, factors as life adversities (e.g. stress and malnutrition), unhealthy life style (e.g. obesity,

Table of contents

1. Introduction

1.5 Non-genetic factors that could contribute to AD 8-9

2. Discussion of the studied literature

2.1 Early life stress 10

2.1.1 Stress inducing paradigms 10-11

2.1.2 Epigenetic changes and glucorticoids 11-14 2.1.3 Epigenetic changes, BDNF and Reelin 15-16

2.1.4 Summary 16

2.2 Early life nutrition 16

2.2.1 DNA methylation 17

2.2.2 Effects of caloric restriction 17-18

2.2.3 Leptin 18-20

2.2.4 Summary 20

2.3 Aging 20

2.3.1 Epigenetic changes 21-22

2.3.2 Summary 22

3. Personal critical opinion

4. Conclusion

1. Introduction

1.1 Alzheimer’s Disease

Alzheimer’s disease (AD) is a very debilitating disease characterized by an insidious onset, a progressive disease course, memory deficits and deficits in at least one other cognitive domain (e.g. aphasia, apraxia, agnosia and executive functioning) (Bateman et al., 2012; Dubois et al., 2010; Eikelenboom et al., 2008). Altogether, this impairs the patient to function in everyday life and to participate in social activities (Bateman et al., 2012; Dubois et al., 2010; Eikelenboom et al., 2008). AD is the most common form of dementia (Alzheimer Association, 2011; Eikelenboom et al., 2008; Richard et al., 2012; Selkoe, 2001); prevalence estimates of AD have been reported varying between 1 and 13 percent in people between the ages 65-70 years and between 25 and 43 percent in people older than 85 years (Eikelenboom et al., 2008; Alzheimer’s Association, 2011). The prevalence of AD is expected to increase each year, because the proportion of the population which is 65 years and older continues to increase (Alzheimer’s Association, 2011, Brookmeyer et al., 2011). In particular, the increase in AD has great financial impact on society; the worldwide costs of dementia were estimated at US$ 604 billion worldwide in 2010 (Gillespie et al., 2013). Moreover, the ageing trend of populations in most (western) societies will significantly increase these costs (Comas-Herrera et al., 2011; Gillespie et al., 2013; Bateman et al., 2012) which may jeopardize the sustainability of the current health care resources (Comas-Herrera et al., 2011; Gillespie et al., 2013). Not surprisingly, research into the etiology, diagnosis and treatment of AD is gaining momentum (Alzheimer Association, 2011), as it has significant consequences for public health policies.

On a neurological level the most pronounced abnormalities found in the brains of AD patients are β amyloid plaques, neurofibrillary tangles (Alzheimer’s Association, 2011; Dubois et al., 2010; Selkoe, 2001; Van Duijn et al., 1994; Zawia et al., 2009) and atrophy in the medial temporal lobe (Dubois et al., 2010; Zawia et al., 2009). A number of genes and proteins are identified which are thought to be involved in Alzheimer disease; including APP, PS1, PS2 and ApoE4 (Hardy & Selkoe, 2002 Van Duijn et al., 1994). Although research has identified

genes that are involved in AD (Bertram et al., 2007; Hardy & Selkoe, 2002, Van Duijn et al., 1994) and has led to more insight into the disease, the cause or even causes of AD remains unknown, with the exception of certain rare inherited/familial forms of the disease (Alzheimer Association, 2011). In these inherited/familial cases the relation between the clinical symptoms and both genes and neurofibrillary tangles/β amyloid plaques is quite strong. As, the etiology of the sporadic form of AD cannot be explained yet, other factors are thought to be important as well. A vascular hypothesis has been proposed which encompasses that the sporadic form of AD is a vascular disorder caused by an impaired cerebral perfusion (De la Torre, 2004). In addition other research has indicated that cardiovascular risk factors such as high cholesterol, diabetes mellitus type 2, hypertension, physical inactivity, smoking and obesity are associated with an increased risk of developing AD (Alzheimer Association, 2011). Stress has also been proposed as an important risk factor in the development of the sporadic form of AD (Devi et al., 2011; Rothman & Mattson, 2010). However, not everyone who has these risk factors develops the sporadic form of AD. Therefore the current consensus is that multiple genes and environmental factors contribute to the etiology of the sporadic form of AD (Alzheimer Association, 2011; Devi et al., 2011; Richard et al., 2012) and that more insight in the interaction between environmental factors and genes is needed in order to understand the etiology of the sporadic form of AD.

1.3 Epigenetics

The field of epigenetics attempts to bridge environmental and genetic factors explaining pathologies. The definition of epigenetics has changed overtime and it even had different meanings in different fields of research (Bird, 2007; Haig, 2004). However, since the 1990’s epigenetics is generally defined as heritable gene expression (phenotype) alterations, which are induced in the absence of changes to the DNA sequence itself (Berger et al., 2009; Choi & Friso, 2010; Haig, 2004; Kwapis et al., 2014; Moore et al., 2013; Whitelaw & Whitelaw, 2008). Examples of epigenetic mechanisms are DNA methylation, histone modification and non-coding RNA(Goldberg et al., 2003; Skinner et al., 2009).

1.4 Epigenetic mechanisms

DNA methylation is a process in which the addition of a methyl group may change gene expression and so influences cell and organism functioning (Zawia et al., 2009). The transfer of a methyl group from S-adenosyl methionine (SAM) to the 5th _{carbon of cytosine residue}

forming 5mC is mediated by DNA methyltransferases (Dnmt’s; Dnmt1, Dnmt3a and Dnmt3b; Moore et al., 2013; Pishva et al., 2014). Figure 1 shows the schematic representation of the DNA methylation process.

Figure 1. DNA methylation. A methyl group is transferred from SAM to cytosine and this process is mediated

by DNMT's. Adapted from Zakhari, (2013). Alcohol Metabolism and Epigenetic Changes.

DNA methylation influences gene activity in two different ways. (Mill et al., 2008). The first way, which is known as the methylation density model, encompasses that the proportion of methylated cytosines across a region controls chromatin conformation and this alters the transcriptional potential of a gene. The second way, which is known as the critical site model, encompasses that the methylation of specific cytosines at transcription-factor binding sites is critical for attenuating the binding affinity and therefore reducing the transcription of mRNA (Mill et al., 2008; Riggs et al., 1998). Histone modification, in particular the acetylation of histones, is another epigenetic mechanism and is mediated by histone acetyltranseferases (HAT’s) and histone deacetylases (HDAC’s). The activity of HAT and HDAC affect the chromatin state and therefore influences gene-expression (Bahari-Javan et al., 2014).

Figure 2. Histone modification. HAT's and HDAC's affect the chromatin structure which in turn influences

gene expression. Adapted from Gillet et al., (2007). Mechanisms of leukemogenesis induced by bovine leukemia virus: prospect for novel anti-retroviral therapies in human.

Besides acetylation of histones, the function of a histone can also be modified by methylation, phosphorylation, biotinylation, ubiquitination, sumoylation and ADP-ribosylation (Choi & Friso, 2010). And the last epigenetic mechanism discussed here is a subgroup of non-coding RNA’s called mircoRNA’s. MicroRNA’s are short RNA molecules, consisting of 18-22 nucleotides, which influences post-transcriptional control of gene

expression (Van den Hove et al., 2014; Mattick & Makunin, 2006).

1.5 Non-genetic factors that could contribute to AD

The period after birth, referred to as “early life” is a critical and sensitive period in the development of humans (Hoeijmakers et al., 2015; Korosi et al., 2012; Lupien et al., 2009; Modgil et al., 2014). Research has shown that early life stress may induce epigenetic changes (Lupien et al., 2009; Weaver et al., 2004). Maternal care changes the methylation states of the Glucocorticoid (GR) gene in the hippocampus of rodents (Weaver et al., 2004). In addition the amount of licking and grooming and arched back nursing a pup receives correlates with

both the hippocampal GR mRNA expression and the ability to induce long term potentiation (LTP) in the dentate gyrus later in life (Van Hasselt et al., 2012). LTP is considered an important cellular mechanisms that underlies learning and memory (Grigoryan et al., 2013). Interestingly, learning and memory is severely impaired in AD patients (Alzheimer Association, 2011). Taken together, this indicates towards a possible role of early life stress in the epigenetic programming of AD.

Another factor that is thought to alter gene expression is (early life) nutrition (Waterland & Jirtle, 2003). It has been reported that folate, vitamin B12 (Veyer, 2002; Vickers, 2014), betaine and zinc (Veyer, 2002) are important components in the methylation process of DNA and therefore influences gene expression. Interestingly, a meta-analysis based on 14 epidemiological studies concluded that proper folate/B12 and homocysteine levels have a beneficial influence on cognition (Hinterberger & Fischer, 2013). Research has shown that certain dietary patterns (DP) in middle life were associated with less cognitive decline (Kesse-Guyot et al., 2012) and seem to be protective for developing AD (Gu et al., 2010). On the other hand, individuals who eat trans fats exhibit a higher relative risk to develop AD compared to individuals consuming around less trans fats (Morris et al., 2003). In line with this, research has found that trans fats increases the expression of APP and that it also impairs the transport of APP to the plasma membrane (Grimm et al., 2012). In addition, it has been reported that a high cholesterol diet in combination with trace amounts of copper in the drinking water of rabbits induced an accumulation of β amyloid as well as the formation of senile plaques, which was accompanied by an impairment in the rabbit’s ability to learn a cognitive task (Sparks & Scheurs, 2012). Interestingly, in humans it has been reported that an increased copper intake was associated with a faster cognitive decline only in individuals who

were on a diet rich in saturated and trans fats (Morris et al., 2006). Taken together, this indicates towards a possible role of nutritional compounds in the etiology of AD.

Age is considered one of the most important risk factor in AD (Alzheimer Association, 2011) and prior research has shown that elderly are quite sensitive to deprivation of certain nutrients (Keyes et al., 2007; Li et al., 2010) and exposure to stress (Lupien et al., 2009). This might indicate that a second sensitive period exists later in life in which adversities such as stress and malnutrition can have severe effects. Therefore, it could also be very important to shed some light on the second sensitive period and important epigenetic changes associated with age which may lead to AD, yet the research community has a tendency to focus on the relatively younger AD patients, while AD is more prevalent at older ages (Schoenmaker & Van Gool, 2004). The aim of this literature thesis is to give an overview of the possible influence of (early life) stress and (early life) nutrition on the epigenetic programming of sporadic/late onset AD.

2. Discussion of the studied literature

2.1 Early life stress

An important system involved in the regulating the stress response is the hypothalamic-pituitary-adrenal (HPA) system (De Kloet et al., 1997). This system involves the corticosteroid hormone that is secreted by the adrenal gland. Corticosteroid is released as a reaction to stress and prepares the body to act properly in threatening situations. Besides this activating function, it also exerts a negative feedback to terminate the HPA activation (De

al., 1997). The hippocampus is an area that is important for learning and memory and encompasses a high density of GR’s (Yao et al., 2007). Exposure to stress can enhance the stress response (Teicher et al., 2003). Early in life the brain has a period wherein it is particularly sensitive to environmental influences such as stress (Andersen & Teicher, 2008; Bale et al., 2010; Lupien et al., 2009). Stress during early postnatal life, also known as an early-life-adversity, has been shown to have pervasive adverse effects. As stress may induce epigenetic changes (Devi et al., 2010; Lupien et al., 2009; Weaver et al., 2004), this may be one of the mechanisms these effects are manifested. Interestingly, the hippocampus, which is severely affected in AD (Dubois et al., 2010; Zawia et al., 2009), contains a high density of GR’s (Yao et al., 2007) and is very sensitive to the effects of stress (Bremner & Vermetten, 2001; Kim & Diamond, 2002). Therefore this section will describe the possible influence of early life stress on the epigenetic programming in AD.

2.1.1 Stress inducing paradigms

A common paradigm to induce stress in animal infants is maternal separation (MS) (Bernardi et al., 2013; Lupien et al., 2009). Adult MS rats have an elevated HPA stress response and increased hypothalamic corticotropin-releasing factor (CRF) mRNA levels after acute stress (Plotsky et al., 1993). Moreover, they have an increased sensitivity towards developing depressive and anxious behavior. Besides the (mere) presence of the mother, the amount of nurturing behavior of the mother is also important for the development of rats. An important part of nurturing behavior of rat mothers is the licking, grooming and arched back nursing (LG-ABN) of their offspring (Doan & Evans, 2011) and there are trait-like individual differences in the amount of LG-ABN behavior a mother performs (i.e. low vs high LG-ABN mothers, with low showing little LG-ABN and high show a lot of LG-ABN behavior). The offspring of high LG-ABN mothers are less afraid and demonstrate a more modest HPA

reaction to stress in adulthood than the offspring of low LG-ABN mothers (Doan & Evans, 2011). These differences in maternal care, which is accompanied by an altered HPA reaction later in life, could provide insight into the possible role of this alteration on the brain. Especially on brain areas that are known to be very sensitive to stress exposure such as the hippocampus.

2.1.2 Epigenetic changes and glucocorticoids

As mentioned previously, the hippocampus is an area in the brain that is very sensitive to stress exposure (Bremner & Vermetten, 2001; Kim & Diamond, 2002) and it is severely affected in AD (Dubois et al., 2010; Zawia et al., 2009). It has been reported that differences in maternal care alter the methylation states of the exon 17 promoter of the GR gene in the

hippocampus (this GR gene is methylated in the offspring of low LG-ABN mothers, but infrequently in the offspring of high LG-ABN mothers; Weaver et al., 2004). Moreover, when the offspring is cross reared (i.e. offspring of high LG-ABN is reared by low LG-ABN mothers and vice versa) they possess the methylation pattern that belongs to the parent that reared them (Weaver et al., 2004), showing that this is an environmental and not genetic effect. The amount of LG-ABN a pup receives during the first post-natal week correlates positively with both hippocampal GR mRNA expression and the ability to induce long term potentiation in the dentate gyrus (Van Hasselt et al., 2012). A study found that exposure to glucocorticoids in vitro increased the production of both APP and BACE 1 (β-secretase) which in turn resulted in higher C99 and β-amyloid levels, figure 3 shows the formation of amyloid β (Green et al., 2006). Furthermore, it was shown that glucocorticoids in the 3XTg-AD mouse model led to up regulation of both BACE and C99 which influenced the β-amyloid levels (Green et al., 2006). These mice have a knock-in mutation of presenilin 1 (PS1), the Swedish double mutation of amyloid precursor protein (APP) and a frontotemporal dementia

mutation in tau (tau) (Green et al., 2006). In addition, glucocorticoid treatment accelerates tau accumulation but is dependent on the presence of the APP transgene (Green et al., 2006), because the 2XTg-AD (these mice have the knock-in mutation of PS1 and the tau mutation, but lack the double APP mutation) do not have the accelerated tau accumulation after glucocorticoid treatment that is present in the 3XTg-AD mice (Green et al., 2006). So the accelerated tau pathology is thought to be a downstream consequence of the effects of dexamethasone on β-amyloid (Green et al., 2006).

Figure 3. Formation of amyloid β-42. Two pathways in processing the transmembrane protein APP, the a

secretase pathway and the secretase (BACE1) pathway. The secretase pathway leads to both the amyloid β-40 and the pathogenic amyloid β-42. Adapted from Citron, (2004). Strategies for disease modification in Alzheimer’s Disease.

Another study found that 21 days exposure to dexamethasone, which is a GR agonist, led to learning and memory impairments and is accompanied with histological damage in the CA3 of the hippocampus in elderly but not young mice (Yoa et al., 2007). Another AD mouse model (Tg2576) displayed higher glucocorticoid plasma levels in the evening (which is the onset of the active phase of these mice) compared to wild type mice at 4 months of age (Lanté et al., 2015). This implies that the HPA system dysregulation occurs at an early stage of the

AD pathogenesis in this mouse model (Lanté et al., 2015). In addition, they also performed the dexamethasone suppression test in order to determine the intactness of the negative feedback mechanism. Interestingly, the glucocorticoid levels did not change in the Tg2576 mouse model after dexamethasone administration in contrast to the wild type mice in which dexamethasone led to a significant decrease of glucocorticoid levels (Lanté et al., 2015). This suggests a disruption of the GR dependent negative feedback loop of the HPA system in Tg2576 mice. In addition, these Tg2576 mice performed less well on the “where” component of an object recognition task compared to wild type mice (Lanté et al., 2015). This deficit of the where component of episodic memory in the Tg2576 mice could be reversed by a four day administration of a GR antagonist (RU486) and it also reversed the enhanced NMDAR-dependent LTD in the hippocampus (Lanté et al., 2015). They proposed that because it took four days in order to reverse both the memory deficit and the LTD, this might indicate towards an underlying epigenetic mechanism.

The human orthologue of the GR gene (NR3C1) exon I7 promoter is the exon 1F promoter. In

parallel with the animal studies above, a study with human postmortem brain tissue showed increased methylation of the exon NR3C1-1F in the hippocampus of suicide victims with a

history of child abuse compared to controls and suicide victims without a history of child abuse (McGowan et al., 2009). Interestingly, AD patients treated with prednisone, which is a glucocorticoid used to attenuate inflammation, exhibit more cognitive decline compared to AD patients treated with a placebo (Aisen et al., 2000). Moreover, it has been reported that high levels of glucocorticoids lead to atrophy in the hippocampus in elderly and is accompanied with memory deficits (Lupien et al., 1998). This indicates that elderly, especially AD patients, are sensitive to glucocorticoids.

On a side note, other brain disorder that are associated with highly stressful events in childhood could be associated with the development of AD. For instance, exposure to highly stressful events in childhood is a risk factor for both major depressive disorder (MDD) (Shea et al., 2004) and post-traumatic stress disorder (PTSD) (Bremner et al., 1993; Shea et al., 2004). In both disorders dysregulation of the HPA system has been reported (Shea et al., 2004). Hyperactivity of the HPA system has been reported predominantly in MDD patient compared to controls (Holsen et al., 2013; Shea et al., 2004), however in PTSD the results are more mixed in which both hyper- and hypoactivity have been reported (Shea et al., 2004). Bahari-Javan et al. (2014) postulated a possible link between PTSD based on the findings that early life stress is associated with epigenetic changes which in turn increases the risk for the development of PTSD (Domschke, 2012) and sufferers from PTSD at a young age are almost twice as likely to develop AD in their lives (Yaffe et al., 2010; Burri et al., 2013). Interestingly, certain candidate genes in PTSD (Broekman et al., 2007) are also linked to AD: BDNF (Kunugi et al., 2001) and ApoE4 (Hardy & Selkoe, 2002). Although indirect

associations, the above underscores the importance of early life stress, its effects on both the HPA system and epigenetic changes which may increase the risk for developing AD.

2.1.3 Epigenetic changes, BDNF and Reelin

The brain derived neurotrophic factor (BDNF) gene has been implicated in numerous psychiatric disorders including PTSD (Broekman et al., 2007) and AD (Laske & Eschweiler, 2006). BDNF is a protein important for neuronal survival, function and plasticity in the central nervous system (Laske & Eschweiler, 2006), which includes the neurons in the hippocampus, cortical, basal forebrain and the entorhinal cortex, all of which are affected in

AD (Peng et al., 2009). Maltreatment in rodents (by an abusive rodent mother) during early life leads to methylation of the BDNF gene and this in turn reduces BDNF gene expression in the adult PFC (Roth et al., 2011). Both the behavior and the methylation pattern is transferred from one generation to the next (Roth et al., 2011), however this methylation pattern can be reversed by chronic administration of a DNA methylation inhibitor (Roth et al., 2011). This may be an interesting therapeutic intervention that could affect future generations, because this intervention restores the BDNF expression and might also influence the behavior as a mother and this will then be passed on to the next generation. An effect of β amyloid overexpression, such as in AD, is decreased BDNF levels (Peng et al., 2009) and this could lead to neuronal and synaptic dysfunction and even neurodegeneration.

Reelin is an extracellular matrix protein which is secreted by Cajal-Retzius cells in the marginal zone (Qiu & Weeber, 2007), and has an import role in the formation of cellular layers and the control of radial neuronal migration during the prenatal development of the brain (Zhang et al., 2013). Besides these prenatal functions, reelin is also important for neuronal maturation after birth; it affects synaptic strength and plasticity in the postnatal developing and adult hippocampus (Qiu et al., 2006; Qiu & Weeber, 2007). Mice exposed to repeated MS have lower levels of reelin in the developing hippocampus compared to control mice (Zhang et al., 2013). Therefore, this decreased reelin level is thought to alter plasticity in the hippocampus which in turn impairs memory function. In addition, research has shown that the exposure of rats to a period of early-life stress leads to late-onset, gradual decline of hippocampus dependent learning and memory function during adulthood and aging (Brunson et al., 2005).

In this section I shed some light on the possible contribution (early life) stress has on the development of the sporadic form of AD. Early life stress can change the methylation state of the glucocorticoid receptor and deregulates the HPA system its reaction to stress, which in turn leads to higher glucocorticoids. These increased glucocorticoids in turn can lead to increased β amyloid and tau accumulation and damage in the hippocampus on neurological and on a behavioral level to learning and memory impairments, which are the main characteristics of AD in humans. The overexpression of β amyloid can lead to diminished BDNF levels. In addition, early life stress seem to alter the methylation pattern of BDNF which in turn reduces the BDNF gene expression in the brain. So, both overexpression of β-amyloid and early life stress induce decreased BDNF levels which may lead to further neuronal and synaptic dysfunction and neurodegeneration. Reelin is another protein that’s affected by early life stress and is thought to lead to altering plasticity in the hippocampus and therefore might lead to memory impairment which is the main clinical characteristic of AD.

2.2 Early life nutrition

Insights into epigenetic mechanisms demonstrated the importance of certain (chemical and nutritional) compounds for the formation of chemical bonds for DNA methylation (Simeoni et al., 2014; Veyer et al., 2002; Vickers et al., 2014) and histone acetylation (Chouliaras et al., 2010; Simeoni et al., 2014). The combination of the importance of certain compounds in epigenetic mechanisms and the sensitive critical period in early post-natal life, led to the idea that nutrition in early (post-natal) life could alter gene expression (Waterland & Jirtle, 2003). In this section an overview will be given of nutritional compounds that influence gene expression and might contribute to the development of the sporadic form AD.

An import methyl donor is S-adenosylmethione (SAM) which is converted from methionine by an ATP driven reaction (Anderson et al., 2012). Methionine is an amino acid that is not produced in the human body, so it needs to be part of the diet. Various enzymes and co-factors are involved in the synthesis of SAM. It has been reported that folate, vitamin B12 (Veyer, 2002; Vickers, 2014), betaine and zinc (Veyer, 2002) are important components in the methylation process of DNA and therefore influences gene expression. Other important components are the Dnmt’s, they mediate the transfer of a methyl group from SAM to the 5th

carbon of the cytosine residue forming 5-methyl-cytosine thus DNA methylation (Anderson et al., 2012; Moore et al., 2013; Pishva et al., 2014). A number of Dnmt’s have been described (Chouliaras et al., 2010). Dnmt1 its function is to preserve the methylation patterns (Chouliaras et al., 2010). Deficiencies in the diet of any of substances mentioned above could lead to altered methylation patterns and so change gene expression.

2.2.2 Effects of caloric restriction

Caloric restriction is a diet intervention that is known to increase lifespan and this effect have been found in a variety of species including yeast, flies, worms, fish, rodents and rhesus monkeys (Fontana et al., 2010). Caloric restriction is a dietary regime in which the amount of calories is reduced (25 to 60% from ad libitum), but adequate intakes of essential nutrients are provided (Ingram et al., 1987; Chouliaras et al., 2011). Rhesus monkeys exposed to CR demonstrated less age associated brain atrophy in subcortical regions (caudate nucleus, putamen and left insula), midcingulate cortex, bilateral temporal cortex and right dorsolateral frontal lobe compared to rhesus monkeys exposed to a standard diet (Colman et al., 2009). Interestingly, human AD is associated with brain atrophy in especially the medial temporal lobe (Dubois et al., 2010; Zawia et al., 2009). In a mouse model of AD (Tg2576mice), caloric restriction almost entirely prevented the β amyloid plaque development, which was present in

the ad libitum group of mice (Wang et al., 2005). β amyloid is another characteristic of AD in humans (Alzheimer Association, 2011). In addition, on a behavioral level aged mice on a CR diet did not show the age-related decline in performance on the maze task ( a learning task) which was present in aged mice on a control diet (Ingram et al., 1987). Increasing age, which is one of the greatest risk factors for AD, is associated with altered Dnmt3a levels in the CA1,2 and 3 region of the hippocampus in mice (Chouliaras et al., 2011). The exact consequences of altered Dnmt3a is not completely known yet, however both Dnmt1 and Dnmt3a have a DNA methylation (maintenance) function in post mitotic neurons and are required for normal synaptic plasticity and therefore thought to be important for learning and memory (Feng et al., 2010). Interestingly, the age related alterations of Dnmt3a levels could be prevented by caloric restriction (Chouliaras et al., 2011), which might also positively affect cognition in elder mice.

2.2.3 Leptin

Substances in the human body with important regulating functions are hormones. A number of hormones like leptin, ghrelin and insulin are essential in the energy homeostasis (Gómez-Pinilla, 2008) and therefore strongly related to nutrition. Leptin, also known as the satiety hormone, is an adipocyte-derived hormone, and plays an important role in the regulation of appetite/food intake and body weight by activating the leptin receptor in the hypothalamus (Harvey, 2007). Interestingly, leptin receptors are also found in other brain regions, including the hippocampus, cerebellum and brainstem (Harvey, 2007; O’Malley et al., 2007). Therefore leptin is thought to have other functions as well.

Leptin has been shown to increase both the motility and the density of dendritic filopodia of hippocampal neurons and this increase was associated with the formation of new synaptic

connections (O’Malley et al., 2007). Moreover, hippocampal CA1 neurons exposed to leptin led to an increased facilitation of NMDA receptor-dependent synaptic plasticity (Shanley et al., 2001). In addition, leptin increases hippocampal neurogenesis by increasing cell proliferation in adult mice (Garza et al., 2008). Moreover, leptin also increases hippocampal neuron survival by the JAK2-STAT3 and PI 3-kinase-Akt pathways (Guo et al., 2008). A mouse strain (SAMP8) has been found to exhibit APP overexpression, cholinergic deficits, an excess of β amyloid protein which is associated with age related impairments in learning and memory (Flood & Morley, 1998). The combination of these deficits makes it an appealing model for AD. Research demonstrated that leptin enhances memory processing in avoidance paradigms (Farr et al., 2006). They also found memory improvement in SAMP8 mice after leptin administration (Farr et al., 2006). In humans higher levels of leptin at baseline were associated with less cognitive decline in elderly in the following years (Holden et al., 2009). However, another study found that AD participants have higher CSF leptin levels compared to mild cognitive impairment (MCI) participants and control participants (Bonda et al., 2014). Interestingly, the increase of CSF leptin levels correlated with Braak stages, which is a scoring system of the amount of tau pathology in postmortem brain tissue (Bonda et al., 2014). In addition, they also found a trend towards lower leptin levels in MCI group compared to controls (Bonda et al., 2014). Taken together they reasoned that leptin is important for cognitive functioning and less leptin leads to diminished receptor binding which in turn impairs cognitive functioning (Bonda et al., 2014). However, as the disease progresses (more neurofibrillary tangles), the neurofibrillary tangles impair leptin receptor binding which is accompanied with more free leptin in the CSF and diminished cognitive functioning (Bonda et al., 2014). Moreover, it has been reported that nutrition early in life programs leptin concentrations in adolescence and is associated with obesity (Singhal et al., 2002). Interestingly, an high BMI (>=27) in older individuals is associated with more cognitive

impairment at baseline compared to individuals with an lower BMI, however the progression of AD is slower in high BMI individuals compared to normal BMI individuals (Besser et al, 2014). Moreover, a diet high in saturated fat and glycemic index increases CSF LD β amyloid levels, while an healthier diet decreases this level (Hanson et al., 2013). Interestingly, another study found that an high fat diet changes the methylation pattern of the leptin promotor (Milagro et al., 2009).

2.2.4 Summary

Taken together this paragraph shed some light on nutritional related factors that might contribute to the development of AD. Caloric restriction, leptin and a non-poly saturated fat diet might protect the brain form damaging especially areas which are sensitive like the hippocampus.

2.3 Aging

Age is the greatest risk factor for the development of the sporadic form of Alzheimer’s disease also known as late onset Alzheimer’s disease (Alzheimer association, 2011). DNA methylation differences between monozygotic twins increase with age which is known as epigenetic drift (Fraga et al., 2005). These DNA methylation changes that co-occur with increasing age could lead to alterations in gene expression which in turn may lead to diminished functioning. This might be the case in AD, because the older you get the more (epi)genetic mistakes could have occurred and might explain the older age of onset of this disease.

2.3.1 Epigenetic changes

Remembering new information is severely impaired in Alzheimer’s patients. Prior research has shown that DNA methylation is crucial for memory formation (Miller & Sweat, 2007). In

late onset Alzheimer (sporadic AD) disease patients PSEN1 promoter is hypomethylated (Wang et al., 2008). This hypomethylation is said to induce overexpression of PSEN1 which in turn may result in an β amyloid production imbalance (Tanzi & Bertram, 2005). Another study reported that in the rodent hippocampus age associated DNA methylation changes of the Arc gene have been found (Penner et al., 2010). This Arc gene is involved in memory consolidation and enduring synaptic plasticity (Penner et al., 2010). In addition, another study found that CR has a beneficial impact on the DNA methylation changes in the hippocampus associated with aging (Chouliaras et al., 2012).

As described earlier glucocorticoids affect brain functioning. Interestingly, glucocorticoid hypersecretion have been reported in around 30% of the old rats and this correlated with both memory deficits and reduced hippocampal volume (Issa et al., 1990). In addition, exposure to exogenous glucorticoids led to memory deficits and hippocampal atrophy in older rats (Lupien et al., 2009). On the contrary, when the glucorticoid levels were kept artificially low in older rats, both the memory deficits and hippocampal atrophy were prevented (Landfield et al., 2007). Older rats exposed to chronic stress show signs of hippocampal aging and the excess of endogenous or exogenous glucocorticoids led to atrophy of the dendrites in the hippocampus and it inhibits neurogenesis (Landfield et al., 2007). In addition, older monkeys exposed to chronic higher glucocorticoid levels have an increased β amyloid pathology, which is an important neuropathological feature of AD in humans (Kulstad et al., 2005). Aged healthy humans have higher levels of cortisol than younger individuals (Raskind et al., 1994) and a negative correlation has been found between increased plasma glucorticoid levels over years and hippocampal volume and memory in older adults (Lupien et al., 1998). Interestingly, AD patients have higher basal glucocorticoid levels compared to controls (Giubilei et al., 2001).

2.3.2 Summary

Increasing age is associated with DNA methylation alterations, which can lead to increased β amyloid levels and impaired memory consolidation and enduring synaptic plasticity. Hypersecretion of glucocorticoid is quite prevalent in elderly and this correlates with memory deficits and hippocampal atrophy. Both the memory deficits and hippocampal atrophy are important characteristics of AD.

3. Personal critical opinion

This essay was written to shed light on mechanisms that might contribute to the development of sporadic AD. It has been proposed that different etiologies might lead to quite similar combination of symptoms and that early onset (i.e. familial) AD has a partly different etiology than late onset AD (Richard & Van Gool, 2012). However, most dementia research focuses on people aged between 65 to 75 years, while in the general population AD is more prevalent at older ages (Schoenmaker & Van Gool, 2004). This leads to an overrepresentation of relative young demented individuals and underrepresentation of relative old demented individuals in clinical research (Schoenmaker & Van Gool, 2004). Interestingly, in relative young demented individuals the presence of these β amyloid plaques and neurofibrillary tangles is associated with cognitive impairment, however in later onset patients this association is decreased (Savva al., 2009). However, if increasing age is considered one of the most important risk factors to develop AD (Alzheimer Association, 2011) then it is rather peculiar to focus on the 5-10 % youngest patients because 1) the relatively younger AD patients are less representative for the AD population and 2) age itself is considered to be an important part in the etiology of the disease (Richard et al., 2012; Schoenmaker & Van Gool, 2004). This might imply that earlier onset of what is currently considered AD (familial AD)

could possibly be caused by something else than what is currently considered AD (sporadic AD) as well in older patients. So in the case of the sporadic form of AD, besides genetics, environmental influences such as (early life) stress, (early life) nutrition and aging are thought to be important contributors to the disease by altering gene expression epigenetically as has been described in the previous sections.

Although increasing age is considered one the most important risk factors for AD (Bahari-Javan et al., 2014) there is still no consensus whether AD is a disease of the elderly or that it starts earlier in life with no (apparent) clinical symptoms (Braak & Braak, 1997; Zawia et al., 2009). More research is needed to distinguish between the possible different subtypes of Alzheimer’s disease in order to create therapeutic interventions suitable for each subtype. Because, focusing on the β amyloid plaques and the neurofibrillary tangles as an therapeutic intervention would probably be beneficial for the relatively younger AD patients, this intervention would probably not resolve the cognitive deficits completely for the older AD patients (whose prevalence is much greater than the relatively younger AD patients).

Another factor that makes unraveling the etiology of sporadic AD hard is because AD is described on both a clinical level (i.e. episodic memory impairment, impairments on other cognitive domains and skills) and on a neuropathological level (i.e. neurofibrillary tangles and β amyloid plaques). These neuropathological investigations cannot be performed during life, so in practice a tentative diagnosis is based on the presence of the clinical symptoms (Dubois et al., 2010). The dichotomy in the use of the word AD to describe AD either on a clinical or on a neuropathological level could lead to confusion (Dubois et al., 2010), especially considering the studies which found AD-like neuropathological changes without the clinical symptoms of AD (Bennet et al., 2006; Knopman et al., 2003; Thal et al., 2002).

In my opinion, AD research could benefit by distinguishing more between subtypes and even change the name in some cases to Alzheimer’s syndrome. Because a disease is defined as an disorder in which the underlying etiology is known. In the case of Alzheimer’s Disease, the word disease is used partly correct, since some patients have the clinical combination of symptoms of AD without the neuropathological markers that are considered the cause of AD. In these cases of AD the etiology is not known yet and therefore it might be more correct to name this combination of symptoms Alzheimer syndrome as a syndrome is a set of clinical symptoms which often co-occur with an unknown etiology (1).

In the familial AD, which accounts for around 1% of the total AD cases (Bateman et al., 2012), genes have been found that contribute greatly to the development of the disease (Wang et al., 2008). However, in the sporadic form of AD other factors as: early life adversities (e.g. early life stress and early life nutrition), unhealthy life style (e.g. obesity, hypertension, hypercholesterolemia (Richard et al., 2012)) are thought to be important contributors to the disease. As mentioned in the discussion of the studied literature section, research has shown that early life experiences and or adversities influence gene expression epigenetically. Moreover, there are also indications that alterations in gene expression could also be transmitted from one generation to the next (Nilsson et al., 2008; Roth et al., 2011; Whitelaw & Whitelaw, 2008). This process is known as transgenerational epigenetic inheritance. Transgenerational epigenetic inheritance means that an epigenetic feature is passed on from parent to offspring over generations. In order to determine that an epigenetic phenomenon is truly transgenerational inherited, this feature should be present in the third generation offspring (F3), since in theory a certain compound could directly influence the F2. Increased knowledge regarding the relation between certain early life adversities and epigenetic

changes, could eventually help to improve early diagnostics and to create prevent strategies. Especially in the cases when epigenetic changes are passed on transgenerationally, early preventions could be undertaken. In the case of AD it has been postulated that neuropathology precedes clinical symptoms by many years even decades (Braak & Braak, 1997; Knopman et al., 2013). Although early postnatal life is considered a critical and sensitive timeframe for early life adversities like stress and certain nutritional compounds or lack of them (Hoeijmakers et al., 2015), studies have shown that elderly are quite sensitive to deprivation of certain nutrients (Keyes et al., 2007; Li et al., 2010) and stress (Lupien et al., 2009). This points towards a possible sensitive period later in life as well for life adversities as stress and malnutrition.

In general, adverse effects been reported regarding (early life) stress such as depressive behaviors, deficits in social interaction, impaired memory and loss of behavioral/cognitive control (Gapp et al., 2014). However stress early in life can also increase behavioral/cognitive flexibility (Gapp et al., 2014), which is a very important behavioral trait in making someone more capable of coping with adversities later in life. Moreover, this study also showed that this adaptive behavioral trait induced by early life stress is present in their offspring/progeny as well. So it would also be interesting to what extent early life experiences have a positive or protective impact on the genome. There might also be experiences or environmental influences that could prevent developing AD or postpone it which could be passed on to future generations.

Another factor that adds to the complexity is that aging, (early life) stress, (early life) nutrition interact with each other. An example of this is the association that has been found between the stress of maternal separation and increased weight gain, food consumption, abdominal fat and

2013). In this study the rats were also either exposed to a diet with an adequate amount of long chain polyunsatuared fatty acids (PUFA) or a PUFA deficient diet (calorically and nutritionally balanced). An interaction effect had been found between MS stress and a PUFA deficient diet which led to insulin resistance and alterations in leptin serum levels (Bernadi et al., 2013). This might be the case for many other environmental influences.

4. Conclusions

This essay was written to shed some light on the possible influence of early life stress and early life nutrition on the epigenetic programming in AD. Although some candidate genes have been identified, it does not explain the etiology of AD completely (the role of genetics is more clear-cut in the familial type of AD) nor does it explain the etiology of AD in a sub group of patients. Especially, in the late onset sporadic AD patients the connection between genetics and the neuropathological features of β amyloid plaques and neurofibrillary tangles is less strong (Savva et al., 2009). This paper indicates that early life is a sensitive and determining period in human development. Besides the critical period during early life there seems to be a critical period in the later stage of life as well. Life adversities in both the early stages and later stages can alter gene expression of multiple genes. Some of these alterations seem to contribute to the susceptibility to develop psychopathologies. The hippocampus is an area in the brain that is quite sensitive to the effects of life adversities (e.g. stress and malnutrition) especially during early development. These life adversities can have detrimental effects on hippocampal functioning and therefore might lead to memory deficits. Interestingly, atrophy of the hippocampus and memory deficits are important characteristics of AD. Taken together AD could result from different underlying causes. Especially, in sporadic AD, which is the largest group of patients, factors as life adversities (e.g. stress and malnutrition), unhealthy life style (e.g. obesity, hypertension, hypercholesterolemia) could together cause the clinical symptoms of AD. Therefore, more insight in these processes is

needed in order to create therapeutic interventions, to advise on life style changes and to engineer medication that could slow down or even reverse the disease process in the largest of group of patients.

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