The Genetics Of Neurodevelopmental Defects Biology Essay


Down syndrome is a well-known and widely publicised disorder, being the most common genetic cause of intellectual disability today. It was first described in 1866 by John L. H. Down who described the characteristic physical features and mental retardation associated with the disorder, but the genetic cause of the disorder was not known until 1959 [24].

Down syndrome occurs in roughly 1 in 1000 live births, but this number does not represent the number of foetuses with this genetic abnormality as 94% of pregnancies with a prenatal diagnosis of Down syndrome are terminated. Of the 6% of pregnancies that are continued after diagnosis some will miscarry (2% of spontaneous abortions have been shown to have the Down syndrome genetic abnormality [6]), and some will be stillborn [7].

The risk of giving birth to a child with Down syndrome increases greatly as maternal age increases [2] with only 1% of pregnancies diagnosed with Down syndrome in mother's younger than 20 and 31% of pregnancies being diagnosed with the disease in mother's between the ages of 35 and 40 [7].

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Down syndrome occurs as a result of a triplication on chromosome 21 and therefore it's associated genes. Sometimes there is not a complete extra chromosome but only extra parts of chromosome 21; in these cases the person with Down syndrome may not show all the characteristics associated with the disease and it is study of these patients that has enabled research to narrow down specific chromosomal regions causing specific characteristics of the disease.

Down syndrome gives rise to a number of congenital developmental abnormalities involving a range of bodily functions and including the cardiovascular, endocrine and gastrointestinal systems [3] with the main feature of the syndrome being mental retardation [4]. Physically the brain of individuals with Down syndrome differs from normal in that its average weight is lower than that of the general population and following neurodegeneration in later years becomes smaller still. There are a number of specific physical abnormalities which can be seen post mortem, such as reduced size of the cerebellum and brain stem, a narrow superior temporal gyrus and decreased diameter of the fronto-occipital area of the forebrain. Other physical manifestations of this syndrome which can often be detected from birth, include short stature, hypotonia, a flat facial profile, brachycephaly (a "flattened" skull), redundant folds of nuchal skin (often used in prenatal diagnosis by ultrasound), upslanted eyes (due to oblique palpebral fissures), a protruding tongue and short, broad hands with a single palmar crease [19].

Whilst Down syndrome was originally associated with a very short life span (in the 1940's Down's children were only expected to live to approximately 12 years of age [45]), due to medical advancements in the last 20-30 years, particularly in the management and treatment of congenital heart disease, those suffering from Down syndrome are now expected to live to over 60 years of age. It is this prolonged life span which has brought to light other neurological defects associated with the disease which were not previously known, such as the development of early-onset Alzheimer's. This revelation has paved the way for new research into Alzheimer's disease with the prospect of narrowing down the cause of Alzheimer's disease to genes on chromosome 21.

Chromosomal Abnormalities

The growth and development of a human being is dependent entirely on their DNA - billions of base pairs, firstly arranged into genes, which are then arranged in a more orderly, linear structure onto chromosomes. A normal human karyotype has 46 chromosomes arranged into pairs and each chromosome contains a specific set of genes, which are arranged in a set order.

It is when there is abnormal chromosome numbers or characteristics that clinical problems occur. Many chromosomal disorders are associated with neurological defects, as the nervous system is dependent on the correct functioning of a variety of genes in different areas throughout the human genome. Chromosomal abnormalities can occur in many forms; there can be extra complete sets of chromosomes in the cell known as triploidy (69 chromosomes in each nucleus) or tetraploidy (92 chromosomes in each nucleus), or extra single chromosomes/partial chromosomes.

Triploidy most often occurs where a single egg is fertilized by two sperm, and although it is thought to make up approximately 15% of the chromosomal abnormalities during conception [8] it is not often seen as these embryos usually spontaneously abort. Tetraploidy is even rarer than triploidy and in both of these abnormalities, even if the pregnancy continues, the babies die shortly after birth.

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Aneuploidy is one of the more common chromosomal abnormalities and describes either missing or extra single chromosomes rather than additional full sets. It is not often compatible with life, accounting for approximately 50% of the spontaneous abortions that occur before the 15th week of pregnancy [23]. Monosomy - a missing chromosome, is nearly always lethal (with the only exception being Turner syndrome), and trisomy (the addition/partial addition of a chromosome) has only been shown to be compatible with life when occurring with chromosomes 13, 18 and 21. It is trisomy of chromosome 21 that causes Down syndrome; this most commonly occurs when the chromosomes do not disjoin normally either during meiosis 1 or meiosis 2(approximately 95% of cases [8]).

Development of Trisomy as a result of Non-disjunction.

Sourced from: [Accessed 20/3/10]

There have been many studies looking for the cause of non disjunction in both maternal and paternal gametes and it has been found that approximately 80% of cases can be attributed to errors in the maternal meiosis [25]. Of those, 75% were shown to occur during meiosis I and 25% during meiosis II [26], however Lamb et al., 1996 showed that non-disjunction during meiosis II is usually associated with recombination in meiosis I, indicating that it is meiosis I which is the main source of error in aneuploidy as a result of non-disjunction.

Mosaicism can also occur in individuals with chromosomal abnormalities - this is where there are some cells with trisomy 21 and some cells with the normal chromosome number; mosaicism often produces milder or fewer symptoms than individuals with all cells affected. Mosaicism can occur as a result of non-disjunction after fertilization whether there has been an error in meioisis or not.

Mosiacism in Down Syndrome

Sourced from: [Accessed 6/4/10]

Mosaicism as a result of Nondisjunction during meiosis:

Mosaicism as a result of Nondisjunction after fertilization:

Chromosome 21 is also one of only 5 chromosomes which can undergo a Robertsonian translocation. This occurs when the short arms of two different chromosomes are 'lost' during cell division and the long arms then fuse to form a single chromosome; because the genetic material of the chromosome is contained on the long arms this abnormality does not affect the individuals phenotype, however the offspring of this individual may inherit either a missing or an extra long arm of one of these chromosomes. This can be important in Down syndrome as Robertsonian translocations can occur with chromosomes 14 and 21which can result in either monosomy 14, trisomy 14, monosomy 21 or trisomy 21, and as it is only the long arm of the chromosome which contains the genetic material, trisomy 21 where there is only an additional long arm and not the full chromosome still produces the same genetic effects as full trisomy 21 produced by non-disjunction i.e. the affected individual will have Down syndrome. Robertsonian translocations are the cause of Down syndrome in approximately 5% of affected individuals [8].

Development of Trisomy as a result of a Robertsonian Translocation

Sourced from: [Accessed 20/3/10]

Chromosome 21

Chromosome 21 is one of the smallest chromosomes in humans, comprising approximately 1.7% of the human genome [9] and holding just 225 genes (127 known genes, 98 predicted and 59 pseudogenes) [10]. The density of genes varies along the long arm of chromosome 21 (21q) with the distal half containing 167 genes and the proximal half only 58 genes [20]. Genes on chromosome 21 have been shown to be responsible for 17 known disorders, with the number expected to rise as genetic research advances. These disorders include neurological disorders, congenital heart disease, autoimmune diseases, cancers and disorders in hearing and vision, many of which manifest themselves in Down syndrome when the gene they are linked to is over expressed.

Whilst it has already been established that Down syndrome is a result of trisomy 21 and more specifically, just the long arm of chromosome 21, a widely accepted theory now is that there is a critical region on 21q which holds many or most of the genes which account for the symptoms of Down syndrome, thought to be between the markers D21S17 and ETS2 [21] or 21q22.1 to 21q22.3 (containing 33 genes). This theory has come about from studies involving individuals with only partial trisomies of chromosome 21 and comparing the clinical manifestations of their genetic abnormality to those with different partial trisomies of chromosome 21.

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Some of the possible genes and their suspected roles are summarised below:


Suspected Role in Down Syndrome


This encodes the amyloid  precursor protein - thought to cause features of Alzheimer's Disease. (Individuals with partial trisomies not including the APP gene do not develop Alzheimer's). [8]


Encodes the CBS enzyme - overproduction causes disruption to metabolism and lymphocyte DNA Hypermethylation. [7]


Role in Amyotrophic Lateral Sclerosis - a form of motor neurone disease, sufferers of which can develop frontotemporal dementia.


Possible role in the development of heart defects [15]


Causes skeletal abnormalities, is a transcriptional regulator of APP [38]


Role in newly synthesized DNA and possible role in programmed cell death [16]


Possible involvement in brain development and may be the cause of mental retardation [17]


Possible involvement in Alzheimer-like pathology [38]


Possible cause of neurodegeneration [12]


Increases glucose metabolism in the brain. May cause cognitive disabilities [13]


Mediate excitatory neurotransmission and may have important roles in central nervous system disorders [11]


Possible cause of Cataracts [14]


Over expression may disrupt DNA synthesis and repair [14]


The gene for expression of Interferon, disruption affects immune system. [14]

There are many factors, not just the genes which code for neurological development which can have an influence on the growth and development of the brain in an individual with Down syndrome. For example, it has been suggested that abnormal growth of the skull in Down syndrome impedes brain growth (and as a consequence, development), leading to the abnormal shape and relatively low weight of the brain in individuals with Down syndrome [18] and the delayed myelination in early childhood (seen in 23% of Down Syndrome cases) is also increased to as much as 48% if the child also had congenital heart disease [18], these are important factors to consider as early and effective treatment for other conditions(such as the heart disease) may allow for much greater neurological development in the individual with Down syndrome than may have been possible otherwise.

There are however many "key" genes which are thought to be the direct cause of the neurodevelopmental defects in Down syndrome such as DYRK1A, PKFL and GLUR5 which are the focus of much research, as down regulation of these genes could help to increase neuronal development in children with Down syndrome. Down regulation of genes which are thought to be the main cause of the Alzheimer's pathology seen in Down syndrome such as APP, SOD1 and S100β could also help to slow or prevent the onset of neurodegeneration not only in people with trisomy 21 but other people with dementia - these genes will be looked at in more detail later on.

Alzheimer's Disease

Alzheimer's disease is a progressive, degenerative disorder of the brain which currently affects approximately 417,000 people in the UK [27] and accounts for around 60 - 70 % of all degenerative dementias [26]. This disease generally tends to affect the older population (one in 14 people over the age of 65 and one in six over the age of 80 suffer from Alzheimer's in the UK [27]) but some forms of Alzheimer's, particularly those with a familial link can have an onset as early as 40 years of age, and post mortem examinations of individuals with Down syndrome show Alzheimer's pathology from around 35 years of age.

Alzheimer's disease can only be diagnosed in the living through the symptoms of dementia with diagnosis only then being confirmed by observation of neuropathological markers in the brain post-mortem; specifically amyloid plaques and neurofibrillary tangles with an associated reduction in brain size. The hippocampus, amygdala and medial temporal lobes are particularly affected showing enlargement of the lateral and third cerebral ventricles, widening of the sulci and narrowing of the cortical gyri [28]. There are several hypotheses for the cause of these pathologies, some of them genetic, some environmental and some due to other predisposing disorders.

The clinical features of Alzheimer's include deficits in attention, orientation and memory often leading to language difficulties and in severe cases an individual suffering from this disease may eventually become mute. Psychiatric symptoms such as depression, delusions, hallucinations and distrust, sometimes with aggression. (often as a result of increasing confusion) occur in most cases and can be the reason for the initial diagnosis. There is a decline in motor coordination as well with loss of the ability to dress, eat or walk unaided being symptoms in the later stages of the disease. Death from this disease, if there are no other associated disorders is often due to sepsis following infection [30].

In approximately 10% of cases of early-onset Alzheimer's disease there has been shown to be an autosomal dominant genetic transmission of the disease. Research has shown that there are many factors and potentially many genes which can pre-dispose an individual to Alzheimer's, however there are no known genes to "cause" Alzheimer's disease as even individuals who possess the pre-disposing gene may still not develop the disease. Those genes that are known have been associated with the development of Alzheimer's pathology, but not necessarily the symptoms of dementia - this is particularly the case in Down syndrome. Late onset Alzheimer's disease is primarily associated with a gene located on chromosome 19 - ApoE and the early-onset forms have been linked to genes on chromosomes 1 (1q, 258, 259), chromosome 14 (14q, 255-257) and chromosome 21 (21q, 254) [29]. The genes on chromosomes 1 and 14 (PSEN-1 and PSEN-2) both indirectly affect amyloid-β deposition - it is the proteins coded for by these genes which cleave the amyloid-β precursor protein (APP) leading to it's accumulation and deposition in the brain. PSEN-1 also interacts with glycogen synthase kinase (GSK3b) and contributes to the phosphorylation of the Tau protein and therefore the formation of the neurofibrillary tangles. Mutations of the APP gene can lead to deposition of amyloid-β also - it was the APP gene on chromosome 21 which was the first to be discovered as much research into chromosome 21 was fuelled by the recognition of early onset Alzheimer's like symptoms in individuals with Down Syndrome.

The Amyloid Cascade

The amyloid-β hypothesis is a very popular one as there seems to be much evidence to support it, especially with the increased accumulation of the peptide in familial early-onset Alzheimer's disease, which has been linked to specific genes affecting the amyloid precursor protein. However the plaques of amyloid-β which form in patients with dementia are also found in the cortex of elderly people who have shown no signs of dementia [31] indicating that it is not presence of the plaques alone which are the cause of Alzheimer's, but that they are simply one of many contributing factors.

The amyloid precursor protein (APP) is a type of integral membrane glycoprotein which is expressed in several types of cells. It is known that APP can be cleaved by specific proteases - the α, β and γ secretases and it is thought to undergo three pathways [30]. There is the constitutive secretory pathway where the APP molecule is cleaved within it's Aβ region which prevents the formation of amyloid-β; an internal pathway where the APP moves inside the cell and into a lysosomal compartment, breaking it down into fragments which contain amyloid-β; and the pathway for the secretion of the amyloid-β from the cells, which then makes its way into the cerebrospinal fluid (this happens in both healthy individuals and those suffering from Alzheimer's disease). Therefore disruption to any of these pathways could cause over production, and associated increased deposition, of amyloid-β - hence the amyloid plaque pathology seen in Alzheimer's disease.

These pathways are not fully understood, nor is the function of APP within the body, however studies in mice which have been bred so that they do not have any APP have shown decreased locomotor functions indicating that APP is important for neuronal and possibly muscular function [30]. Other studies have linked APP to regulation of intraneuronal calcium [32], mediation of cell adhesion [33] and as a growth factor in fibroblast cultures [34], amongst other things. These are important findings as they indicate that any therapy which targets removal of APP as a treatment for Alzheimer's disease would have serious side effects and would therefore not be suitable.


The main component of the neurofibrillary tangles which are found post-mortem in the brains of individuals who suffered from Alzheimer's dementia are mainly composed of the "multifunctional microtubule associated" Tau protein [31]. These neurofibrillary tangles are mostly found in the hippocampus, amygdala and entorhinal cortex of the brain (an important memory centre). In the normal brain, Tau is important for the stability of the cytoskeleton of axons and therefore their structure, with stability of the cytoskeleton being directly related to the equilibrium between the phosphorylations and dephosphorylations of Tau [31]. It is hyperphosphorylation of Tau that occurs in Alzheimer's disease due to the action of a number of protein kinases including GSK3β and Cdk5. It has been shown that improper activation of Cdk5 can lead to neuronal death in the hippocampus [35] and therefore inhibition of Cdk5 can protect cells against neuronal death. It is thought therefore that it is Cdk5 which initially stimulates the Tau hyperphosphorylation but that this then modifies the GSK3β which in turn prevents Tau from functioning as it should as part of the cytoskeleton. This cascade which leads to the formation of the neurofibrillary tangles is thought to be triggered by the deposition of the amyloid-β described previously.

Alzheimer's Pathology in Down Syndrome

The prevalence of dementia in individuals with Down syndrome is different to that of the general population with 8% becoming demented between the ages of 35 and 49, 55% between the ages of 50 and 59 and 75% over the age of 60 years [31]. Whereas in the majority of the general population who develop Alzheimer's disease, onset is after the age of 65, with prevalence only increasing greatly over the age of 80. However, even though not all individuals with Down syndrome will display signs of dementia, post mortem their brains all show Alzheimer's disease pathology, and from a much younger age. Interestingly, even though in the general population there is a higher incidence of women developing Alzheimer's disease, in those with Down syndrome the incidence appears to be as much as three time higher in men [50]; the cause of this difference is unknown as yet.

One theory for the development of Alzheimer's has been that there is a "threshold effect", in that a certain amount of pathology (plaques, tangles and neuronal loss) must build up before clinical signs are seen [37] and the appearance of the pathology but not necessarily the symptoms in Down syndrome patients may indicate that for some reason trisomy 21 actually raises the threshold for which pathology causes dementia [38]. The ε4 allele of the APOE gene which has been shown to be a risk factor for Alzheimer's disease in the general population is located on chromosome 19 and therefore not triplicated in Down syndrome, however it is possible that the presence of the ε4 allele in Down syndrome also serves as a promoter for early onset of the disorder in Down syndrome individuals, but this link has yet to proven [51].

As previously discussed, the symptoms of Alzheimer's disease are thought to originate from/be associated with the formation of amyloid plaques and neurofibrillary tangles and whilst there has been much debate as to which of these is the more important in the development of the disease, the discovery of the APP gene on chromosome 21 and the prevalence of Alzheimer's pathology in individuals with Down syndrome and therefore an extra copy of this gene have led to increasing favour for the amyloid cascade hypothesis. This was also further supported by the case of a 78 year old woman [39] with Down syndrome but only a partial trisomy of chromosome 21 in which the APP gene was not triplictaed and this woman did not develop dementia nor did she have the pathological changes associated with Alzheimer's when examined post mortem.

Alzheimer's disease in Down syndrome has also been shown to be associated with an increase in epileptic seizures in later life thought to be due to the effects of the APOE ε4 allele. Interestingly it has been observed that where the onset of this epilepsy is later, the patient will develop Alzheimer's disease whereas in cases where there is an early-onset of epilepsy, Down syndrome patients do not develop dementia [52]. The seizures do not seem to have a detrimental effect on the prognosis of Down syndrome individuals even though seizures are usually associated with a poor outcome in the general population, it is possible therefore that genes within the Down syndrome critical region which cause the development of Alzheimer's pathology are also able to provide a protective effect against the onset of Epileptic seizures which may be a useful avenue to pursue in the search for causes and prevention of epilepsy.

The neurodegenerative symptoms and pathology seen in Down syndrome, whilst very similar in appearance to Alzheimer's disease may come about as a result of the trisomy of genes not usually associated with Alzheimer's disease. There are several 'candidate genes' on chromosome 21 which may be responsible for the occurrence of these features including DYRK1A, SOD1 and S100β.


The DYRK1A gene codes for the production of Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A and is known to be important in the development of the central nervous system. It's location at 21q22.13 places it inside the Down syndrome critical region and as it has been linked both to neurodevelopmental defects and to the development of Alzheimer's pathology in Down syndrome it has been a gene which has been very widely researched.

A study on this gene ("Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing DYRK1A (minibrain), a murine model of Down's syndrome" - Altafaj, 2001) was conducted using mouse models of Down syndrome - mice can often be used to study Down syndrome as chromosome 16 in mice has been shown to have over 110 genes orthologous to chromosome 21 in humans [21]. The mice in this study showed "retardation in neuromotor development, characterized by the persistence of immature locomotor patterns and a delay in maturation of gait" and this motor impairment also continued to have an effect during adulthood (although gait eventually became normal) suggesting that the overexpression of the DYRK1A gene is responsible for impairment of motor coordination seen in Down syndrome either due to impaired neurodevelopment or due to hypertonia. There was also shown to be a delay in their ability to learn new material - mainly spatial, although there was no dysfunction seen in their working memory indicating that this gene causes impairment of the hippocampus and prefrontal cortex.

The reason for these developmental abnormalities when there is an overexpression of DYRK1A is thought to be due to a halting of the cell cycle leading to early neuronal differentiation limiting the development and proliferation of these cells [22].

DYRK1A - Possible roles in the body

Sourced from: Prasher, V.P; Farrer, M.J; Kessling, A.M; Fisher, E; West, R.J & Barber, C. (1998). Molecular Mapping of I I v Alzheimer-Type Dementia in Down's Syndrome. Ann Neurol 43 380-383 [Accessed 24/03/10]

DYRK1A has also been shown to play a role in other neurological disorders such as Parkinson's Disease and Huntingdon's disease; as these are both neurodegenerative diseases it provides a clue that DYRK1A may also be associated with the neurodegeneration and Alzheimer-like dementia seen in Down Syndrome. DYRK1A is particularly associated with the formation of Lewy bodies in Parkinson's disease and these Lewy bodies are seen in the dementia associated with Down syndrome (a significantly greater number are seen than in individuals with dementia who do not have Down syndrome) [36]. DYRK1A has also been shown to hyperphosphorylate Tau which we have already seen is the cause of neurofibrillary tangles and to phosphorylate APP leading to the formation of amyloid-β plaques [37].


The SOD 1 gene encodes for a protein which binds copper and zinc irons, the function of which is to destroy free superoxide radicals in the body and particularly in the brain which is particularly susceptible to these. These free radicals are then converted to less harmful substances (oxygen and hydrogen peroxide) [36], as they can otherwise cause damage to DNA - it is DNA damage by free radicals which is currently one theory for why we age which is why they are an important consideration when looking at neurodegenerative diseases with age-related onsets; however if the hydrogen peroxide is not then quickly detoxified it can produce an even more damaging free radical (OH-).

O2- + O2- + 2H+ H2­O2 + O2

Fe2+ + H2­O2 Fe3+ + OH- + OH-

Normally the production of the OH- free radical is prevented from forming by conversion of the hydrogen peroxide into water by catalase or glutathione peroxidise [38] but when there is an overexpression of SOD 1 and therefore an increase in the first reaction (above), these reactions may become imbalanced leading to formation of these free radicals and consequently damage occurs to the DNA . It has been suggested that a way to combat this would be to treat people who have an overexpression of this gene with glutathione peroxidise which would rebalance the two equations and prevent free radical production. However, mutations of the SOD 1 gene have also been shown to decrease the SOD's ability to bind to zinc which then leaves copper to act as an oxidase [31] and so increases oxidative stress causing further DNA damage this way. Amyloid-β has also been shown to increase the concentration of free radicals and to reduce anti-oxidant levels further promoting the neurotoxicity of the plaques which it forms.

Studies on transgenic mice have shown that both the SOD1 and APP gene are required to causes neuronal cell death, not just APP. When both genes were present "Hippocampus, entorhinal, and cingulate cortex volumes were decreased by 8% to 25%" [44] but with only SOD 1 present there was no change in the hippocampus and with only APP present there was no change seen in any of these regions.

Conversely, it has been shown that overexpression of SOD1 actually decreases APP toxicity and therefore increases life span compared to if it were only expressed in the normal amount but still causes significant neuronal death which can be observed in the brain anatomy post mortem - further study would therefore need to be undertaken before suppression of this gene is attempted as a therapeutic intervention.


BACE is a gene which is found on chromosome 11 which codes for the enzyme β-secretase which, as described earlier, cleaves APP leading to the production of amyloid-β. There is a homologous gene, BACE-2 (an integral membrane glycoprotein), which is found on the long arm of chromosome 21 and therefore triplicated in Down syndrome. Whilst it would therefore be expected that there would be overproduction of the BACE-2 protein, it has been found that this protein is actually only found in the brains of Down syndrome patients with Alzheimer's pathology - i.e. not in those with a partial triplication that don't develop the pathology and not in people without Down syndrome. This indicates that once activated, BACE-2, like it's homologue, may have a role in the additional deposition of amyloid-β in Down syndrome, however more recent studies [40] have suggested that BACE-2 actually cleaves amyloid-β rather than APP and therefore would actually decrease the amount of amyloid-β deposited. If, however, both the APP and BACE-2 genes were present in the trisomy then the plaques would still be deposited (as they are) but they wouldn't be as amyloid-β-rich as the plaques seen in Alzheimer's disease in non-Down syndrome patients (this could account for the lack of neurological symptoms seen in Down syndrome patients who still have the Alzheimer pathology).


The calcium-binding protein produced and secreted by the astrocytes in the peripheral and central nervous system is coded for by the S100β gene. It plays an important role in a variety of neuronal functions such as differentiation and extension of neurites, but also has a role in programmed cell death [38]. S100β overexpression is thought to be the initial cause of the fast maturation and therefore advanced wasting of the dendritic cells seen in Down syndrome which is thought to be a cause of the impaired intellectual function in these individuals. It may also contribute to the overall picture of neurodegeneration in later life and is a potentially important gene in the development of the Alzheimer-like pathology in Down syndrome as overexpression of this gene could lead to increased neurite growth and the development of neuritic plaques [41] i.e. s100β could contribute to the increased number of plaques seen in the brain of Down syndrome patients post mortem. S100β has also been shown to increase APP levels [41] - further evidence for it's role in the development of senile plaques, with a direct link having been shown between the level of S100β and the amount of amyloid-β deposited in the brain[42].

S100β has also been shown to induce the expression of IL-1 [53], as has APP. Whilst IL-1 is not found on chromosome 21, it's upregulation as a result of triosmy 21 has been shown to have an important effect in the development of Alzheimer's in Down syndrome because IL-1 can also cause increased expression of APP; this may account for the appearance of Alzheimer's pathology in individuals with partial trisomies which do not include the APP gene. Overexpression of IL-1 is unfavourable because, as well as its effects on APP, it is also highly toxic to cortical neurones [42] which may account for much of the neurodegeneration seen in the later stages of Down syndrome.

Another link between S100β and neurodegeneration is it's role in increasing the expression of nitric oxide synthase by astrocytes and therefore increasing levels of nitric oxide which can have the neurotoxic effects discussed previously. More recent studies have also linked this gene to the hyperphosphorylation of Tau [43] which means that this gene could be a good one to target when looking for new ways to halt, or at least slow the progression of Alzheimer's disease in both Down syndrome patients and the general population as it seems to have a wide range of effects and it's inhibition could lead to a marked decrease in much of the pathology.


The ETS-2 gene is located on chromosome 21 at 21q22.3 and is therefore in the Down syndrome critical region and is triplicated in individuals with Down syndrome. It has previously been found that there is a three to four fold increase in the production of APP in individuals with trisomy 21 [46], which is unusual as a triplication of just the APP gene ought only to produce a 1.5 fold increase and it has since been shown that is it over expression of ETS-2 which causes this dramatic increase. However, levels of ETS-2 itself do not seem to be increased even when the gene is overexpressed indicating that there are other factors required for its activation - the transcription factor Fos (levels in the brain are increased in Down Syndrome) and the transcription factor Jun (levels of which are decreased in Down syndrome) and it has been suggested it is the disorder in the levels of these three transcription factors which cause the increased APP level. Wolvetang et al, [47] showed that ETS-2 transactivates the promoter of the β-APP by binding to specific sites on the protein and therefore increasing APP production and consequently amyloid-β production leading to Alzheimer's pathology.

The transcription factor ETS-2 is normally expressed in Human cortical neurones but it is when it is upregulated that problems can occur. It is thought that this upregulation is due to oxidative stress as a result of anti-oxidant imbalance (e.g. SOD 1) [49], which can occur (as has previously been discussed) in trisomy 21. ETS-2 is usually expressed in the neurones and astrocytes in the brain and increased expression has been linked to an increase in degeneration of these cells, therefore interventions targeting downregulation of ETS-2 might have an important therapeutic effect - it has already been shown that dominant-negative ETS-2 is able to reduce the degeneration of neurones in Down syndrome [48]. It is thought that the death of brain cells in response to oxidative stress where ETS-2 is overexpressed, comes about as a result of activation of an apoptotic pathway causing mitochondrial death.


The development of the Alzheimer-like pathology in Down syndrome is likely to be due to a number of factors, with several genes working together to produce both the symptoms of dementia and the pathology seen post-mortem. It seems likely that APP plays an important role in the development of this pathology, seemingly confirmed by the case of the woman without triplication of the APP gene where the Alzheimer-like signs were not seen; however whilst APP may only cause increased amyloid-β production and plaque formation, it is genes such as S100β and BACE-2 which can influence the toxicity of these plaques.

Oxidative stress is increasingly being recognised as an important factor in neurodegeneration and the development of dementia in both Down syndrome and non-down syndrome individuals. SOD-1 found on chromosome 21 which may increase oxidative stress in the brain could therefore play an important part in the neurodegeneration seen in elderly Down syndrome patients. The primary cause of oxidative stress and its consequential neurotoxic effects cannot solely be attributed to SOD-1 however as SOD-1 has also been shown to be a possible cause of the increased life span of Down syndrome individuals which is seen relative to the age of development of their Alzheimer-like pathology.

It should be noted that study of Alzheimer's disease, not only in Down syndrome individuals, but in all people who develop this disease is particularly difficult as confirmation that the dementia is Alzheimer's dementia can only be given post mortem. Due to limited availability (possibly due to reluctance of carers to consent for a Down syndrome patient to partake in studies), many of the studies conducted have relatively small sample sizes and are not age, gender, or intellectual ability specific. This could potentially have an effect on the results observed and care should be taken when assuming a causal effect between certain physiological changes and the prevalence of the disease.

The development of this dementia in Down syndrome patients, whilst yet another unpleasant symptom of their disorder, may yet be hugely beneficial to the understanding of Alzheimer's disease and other associated dementias in the general population. Treatment which targets these genes and aims to have a dampening effect needs to be researched thoroughly as the potential side effects of gene therapy can be severe and may have an adverse effect in earlier life, even before the onset of dementia.