Role Of Chromosome 21 In Alzheimers Disease Biology Essay

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Down syndrome is a genetic disease that caused by trisomy of Human chromosome 21. Down syndrome is common chromosomal disorder of mental retardation in humans. It is caused by the three types of chromosomal abnormalities namely, free trisomy 21, translocation Down syndrome and mosaic Down syndrome. Most of the Down syndrome individuals experience Alzheimer-like neuropathology like dementia, neurofibrillary tangles and many others. Genes that are in Chromosome 21 which includes SOD-1, DSCR1, APP gene and S100B, are highly involved in the relationship between Down syndrome and Alzheimer disease. Besides the genes involved, other factors like oxidative stress and hormone will be discussed in this review too.

There are two different types of hypotheses associated with Down syndrome namely, "developmental instability" and "gene-dosage effect".

Introduction

Down syndrome is a common chromosomal disorder of mental retardation in humans. It is caused by the trisomy of chromosome 21. Down syndrome is named after John Laugdon Down in 1866.There is three different types of chromosomal abnormalities namely, free trisomy 21, translocation Down syndrome and mosaic Down syndrome. Over 90% of the time, non disjunction and failure to separate the chromosome pairs during meiosis are the principal cause of Down syndrome. Down syndrome is named after John Laugdon Down in 1866. The first person that published the relationship between Alzheimer's disease-type neuropathology to clinical dementia in adults with Down syndrome was Jervis in 1948 and the person to demonstrate this disorder is due to the trisomy of chromosome 21 was by Jerome Lejeune in 1959. The symptoms associated with Down syndrome are diminished muscle tone, congenital heart disease, small skull, slanting eyes and retarded growth and development. Individuals with Down syndrome usually have the tendency of developing neuropathological changes like Alzheimer disease. Down syndrome has an overall incidence of 1 in 1000 live births when the mother aged 30, increasing 9 in 1000 births when the mother is aged 40 (Hook et al., 1983).

Alzheimer disease is a neurodegenerative disease which maybe is found in Down syndrome individuals. This disease is named after a neuropathologist, Alois Alzheimer in 1906. Down syndrome individuals experience the Alzheimer-like neuropathology by their mid-40s. In the beginning, Alzheimer disease affects parts of brain like memory and languages. But after a period of time, this disease will progress and cause problems in all aspects of our life. Alzheimer disease has 2 forms, familial and sporadic forms. Familial Alzheimer disease is a rare disease which is genetically acquired. There are mainly 3 types of lesions that are observed in Alzheimer disease. It is then caused by the mutations in several genes like APP which will lead to the over production of the amyloid-beta protein. The most common form of Alzheimer disease is sporadic form which contributes to 90% of Alzheimer disease cases. The first type is the neuritic plaques, extracellular deposits of fibrillar beta amyloid surrounded by degenerating neuronal processes and terminals. The next type of lesions is intraneuronal neurofibrillary tangles, primarily composed of abnormally hyperphospholated tau protein and lastly, it is vascular beta-amyloidosis associated with fibrillar amyloid deposition within the vascular wall. Over time, these pathological processes contribute to synaptic and neuronal loss, deterioration of neuronal networks, brain atrophy and dementia (Victor & Ropper, 2001).

Nowadays, people have longer life span and hence the Alzherimer disease become much more worrying for us as it will become a major public concern. There were 26.6 million of people that are suffering of the Alzheimer disease in 2006 and this number will continue to grow. It is then estimated to affect 1 in 85 people worldwide by the year of 2050. In fact, it was not until 1985 that research explicitly focused on aging related changes in health status and cognition of adults with intellectual disabilities, and in particular those with Down syndrome, began in earnest (Janicki et al, 1985).

In Down syndrome, there are two different types of hypotheses associated namely, "developmental instability" and "gene-dosage effect". The "developmental instability" hypothesis indicated that the correct balance of gene expression in the development is being disrupted. But this hypothesis is being questioned since other autosomal trisomy syndromes do not lead to the same clinical pattern (Shapiro et al,2001). In another case, the "gene-dosage effect" hypothesis, specific gene that is over expressed is responsible for the Down syndrome phenotypic abnormalities which indicated is trisomy of the Chromosome 21 (Delabar et al,1993).

The Genes

In chromosome 21, the most critical part that affects Down syndrome phenotype is the long arm(q) of chromosome 21. The critical region in chromosome 21 that is important to Alzheimer disease are amyloid precursor protein (APP) located at Chromosome 21q21.3 , superoxide dismutase gene (SOD-1) located at Chromosome 21q22.11, Beta-site APP-cleaving 2 enzyme (BACE2) located at Chromosome 21q22.3, carbonyl reductase (CBR) located at Chromosome 21q22.1 and cystathionine beta-synthase (CBS) located at Chromosome 21q22.3 . The critical region in chromosome 21 that is important to Down syndrome are glycinamide formyl transferase (GART) located at Chromosome 21q22.1, SOD-1, Cu2+/Zn2+ superoxide dismutase, beta subunit of S100 calcium-binding protein (S100B) located at Chromosome 21q22.3, Down syndrome critical region gene 1 (DSCR1) located at 21q22.3 and Intersectin 1 (ITSN1).

The Amyloid precursor protein (APP)

APP gene is located on human chromosome 21 and codes for a transmembrane protein that is expressed in both neurons and astrocytes. This gene is important in the relationship between Down syndrome and Alzheimer disease. Overexpression of APP gene will lead to the increase production of amyloid-beta protein which is the main protein component of senile plaque. The cause of the familial Alzheimer disease is by the mutation n the APP gene.

The amyloid-beta protein is formed by the proteolytic cleavage of the large, type-1 integral membrane-spanning glycoprotein APP by secretases. It has two different pathways, the amyloidogenic pathway and the nonamyloidogenic pathway. The amyloidogenic pathway is beta-secretase cleaves APP to generate APPsB, a 100-kDa soluble NH2-terminal fragment and a 12-kDa membranebound carboxyl-terminal fragment. Hence, the nonamyloidogenic pathway is that cleaved within its amyloid-beta region (aminoacids 16-17), at the alpha-secretase cleavage site, to produce an N-terminal fragment, APPsa, and a C-terminal APP fragment of 83 amino acids (Kang et al,1987).

In normal mechanism of the brain, there is stable distribution of beta-amyloid in the brain and this intracellular beta-amyloid is essentially in the entire life indicated that beta-amyloid within neurons represents a product of normal metabolism. The two most common species of beta-amyloid are AB40 and AB42. Beta-amyloid will start to accumulate during younger times and with increasing in age, the amount will progressively increase. During middle ages like 35 years, beta-amyloid associated neuropathology will accelerate tremendously.

The soluble APP is the most toxic APP which can have neurotrophic activities and longer aggregating forms. The amyloid-beta protein at high concentration will lead to neurotoxic whereas at low concentration it can function as a neurotrophic factor. When amyloid-beta protein is oxidized, the solubility will decrease and hen will result in the accumulation of the intracellular microglial. This accumulation will increase the concentration of amyloid-beta protein and lead to more plaque formation. Amyloid-beta protein will also induce oxidative stress directly and activating microglia indirectly (Yankner et al, 1990).

Although it has been a strong standing that amyloid-beta protein contributes to the Alzheimer disease but there is evidence that amyloid-beta protein is very useful in our body. Amyloid-beta protein provides an important role in both synapse and in synaptic structure-functional plasticity that underlie learning and memory (Koudinov et al, 2001).

The autopsy studies in brains of older Down syndrome individuals showed that senile plaque and neurofibrillary tangles and in the brains and some indivuals show a much earlier onset. This maybe suggest that there is an apoptotic action happening and may result in the large amount of neuronal death in the brain.

It has been studies to show that APP metabolism in involved in the peripheral tissues. Changes occurs in APP metabolism is noted in the platelets, lymphocytes and fibroblasts in both Down syndrome and Alzheimer disease individuals. This change in APP showed that there is two to three fold of increase plasma concentration in both amyloid-beta protein(1-40) and amyloid-beta protein(1-42) in Down syndrome individuals and also increase of mRNA of APP.

The Beta-site APP-cleaving 2 enzyme (BACE2)

BACE is a transmembrane aspartyl protease and has a second protein called BACE2 that is 55% identical to BACE.BACE2 has two active site motifs of aspartic protinases which are located at residues 93 to 96 of DTGS and residues 289 to 292 of DSGT. BACE2 has a minor cleavage site at the beta-site of APP and also a major cleavage in the beta-amyloid region that is close to the alpha-secretase site.

BACE2 is said to contribute to the amyloid-beta protein production. Some authors investigate the expression of BACE2 in the frontal context of the Down syndrome patients and hence, the immunoreactivity of BACE2 in Down syndrome patients with Alzheimer disease and control is compared. The results show that in neurorofibrillary tangle-bearing neurons there is BACE2 but not in those Down syndrome patient without Alzheimer disease. So, this will give an indication that BACE2 contribute to the Alzheimer-type neuropathology of Down syndrome (Barbiero et al, 2002).

In Alzheimer individual platelets, there is a significant amount of reduction in the BACE2 which suggest that this BACE2 cause increase Alzheimer neuropathology.

The Down syndrome critical region gene 1 (DSCR1) and The Intersectin 1 (ITSN1)

The DSCR1 gene is located at the human chromosome 21 and it encodes for the calcipressin 1 which inhibit calcineurin activity by interacting with calcineurin A. So, phosphorylation of calcipressin 1 will inhibit the activity of calcineurin and this will allow the control the half life of calcipressin by increasing its degradation. To protect the cells from getting damaged, negative feedback mechanism of DSCR1 gene should be activated. In brain, heart and skeletal muscle, the DSCR1 is highly expressed. It was shown that DSCR1 is over expressed in the individual brain of the Down syndrome fetuses and post mortem and for those Alzheimer disease individuals, they also showed DSCR1 mRNA levels to be two to three times higher than the control.

Basically, overexpression of DSCR1 can affect two calcineurin-dependent pathways by blocking calcineurin activity. So, when there is an increase of DSCR1, it may disrupt endocytosis and the vesicle recycling because of the calcineurin-dependent dephosphin dephosphorylation. Next, the hyper

The ITSN1gene is located in human chromosome 21 and it encodes for endocytic protein ITSN1. In this gene, there are two major mRNA transcripts which divided into 6kb and 11kb, short and long isoforms. These isoforms are expressed in the brain but in different cell types. It has been detected in western blotting that long form is neuronal specific while the short form is in glial cells and for those Down syndrome individual, there is an over expression of the long isoform in the brain.

These genes are involved in the neruronal endocytosis in the pathology of the Down syndrome and Alzheimer disease. In neuronal endocytosis, it is very important for the neuronal repair and survival as the secretory vesicles need to be reuptake during the synaptic transmission after any neuronal damage.

The Minibrain-Kinase Gene

The gene minibrain-kinase maybe associated with Down syndrome. This gene is encoded to the Down syndrome critical region 21q22.2. There has been studies that showed that the over expression will cause congnitive impairments with Down syndrome and increases in apoptotic cell death and reduction in neuronal differentiation which altered neuronal plasticity and intellectual disability observed in Down syndrome (Murakami et al, 2006).

The Immune System

Astrocytes also play an important role in old Down syndrome patient's brain. Upon activation in the brain of the Down syndrome patient, it will express more of the S100B, an astrocyte-derived neurite growth-promoting factor. S100B is associated in dystrophic neurite formation and in plaque evolution and also in neurofibrillary tangle evolution in Alzheimer disease. S100B is secreted by astrocytes and increase the intraneuronal free calcium levels and stimulates the growth of neuronal processes. In the studies of S100B, it showed that the number of astrocytes expressing S100B in Down syndrome patient was about twice as that to the controls of all ages.

Another way to test for the relationship between Down syndrome and Alzheimer disease is by the complement cascade, C1q. C1q accumulates in amyloid-beta protein deposits in neurons within Down syndrome brain. In this case, the increase level of C1q will suggest that it is responsible for the acceleration phase of Alzheimer disease pathogenesis in Down syndrome patient (Stoltzner et al, 2000).

The Oxidative Stress

Another factor that is involved in both Alzheimer disease and Down syndrome is oxidative stress. As we all know that oxygen is very important for life but the byproducts are very harmful. These byproducts include reactive oxygen species like superoxide and hydroxyl and hydrogen peroxide and peroxynitrite (Andersen et al.,2004). The amyloid precursor protein and the cytoplasmic enzyme Cu2+/Zn2+ superoxide dismutase (SOD-1) are responsible for reactive oxygen species homeostasis. SOD-1 is responsible for the first line of antioxidant defense by catalyzing the dismutation of O2•- to molecular oxygen (O2) and H2O2, which can be converted by catalase (CAT) and by (selenium-containing) glutathione peroxidase (GPX) to water. Since SOD-1 is located at chromosome 21, so the trisomy of chromosome 21 will lead to accumulation of hydrogen peroxide because of the imbalance in the ratio of SOD-1 to CAT and GPX. Hence, this will lead to the increase of neuronal cell death which also contributes to the progressive mental decline in both Down syndrome and Alzheimer disease. In peripheral tissues, SOD-1 has 50% more in patients than normal in the immune system. Hence, it will disrupt the immune system to make the patients to be weaker (Benzi et al, 1997).

The E2F-1 Gene

The E2F-1 gene is located in human chromosome 20. It encodes a protein E2F-1 transcriptional factor E2F-1. This transcription factor plays major role in in the control of cell cycle, action of tumor suppressor proteins and DNA damage to apoptosis.

The ETS2 Gene

The ETS2 gene is located on human chromosome 21q22.2. This gene encodes for a protein Protein C-ets-2 which is a transcriptional factor of beta-APP gene. It will specifically bind to the beta-APP promoter and work with transcription factor AP1 (Wolvetang et al, 2003).

The Oestrogen Hormone

Oestrogen has a role of protecting neurons from the toxic effect by amyloid-beta , ameliorated the cerebral metabolism and also increase the level of acetylcholine in the basal forebrain and hippocampus. It also has the antioxidant effect which is very helpful towards Alzheimer disease. Other beneficial impacts include reduction of the lipid peroxidation, prevention intracellular peroxide accumulation and reduce the degradation of the neurons in the brain.

So, it is said that estrogens reduce the occurrence of Alzheimer disease of Down syndrome woman. Woman patients with Down syndrome may have an earlier occurrence or more serve form of Alzheimer disease when these women has early onset of menopause compared to those late menopause women (Schupf et al., 2006). But those post-menopause women that receive estrogen replacement therapy may have a lower occurrence in having Alzheimer disease.

The Apolopoprotein E Gene

Another factor that attribute to the late onset of Alzheimer disease is Apolopoprotein E (APOE) gene. This gene is located on chromosome 19 and has 3 types of alleles (Corder et al., 1993). The allele that is responsible for Alzheimer disease is APOE ε4 allele. It is found that patients with Alzheimer disease has higher frequencies of the APOE ε4 allele compared with those without other APOE genotypes and have a earlier onset of Alzheimer disease (Corder et al., 1993). Another allele that has good contribution towards Alzheimer's disease for adults with Down syndrome is APOE ε2. It is the least common allele but can reduce the risk of Alzheimer's disease for adults with Down syndrome (Schupf et al,1996).

Cholesterol is transported by high-density lipoproteins such as APOE, and these suggested of the hypothesis that the relationship between APOE and risk of Alzheimer's disease may be linked to cholesterol metabolism. Statins or HMG-CoA reductase inhibitors are currently the most widely prescribed class of cholesterol lowering medication. In a number of studies, it has been shown that the use of statin does reduced the risk of the Alzheimer's disease. So, for participants with a total cholesterol level of 200 mg/dL or more, the effect of statin significantly lower the risk of dementia compared to that of other participants with lower total cholesterol (Green, Jayakumar, Benke, & Farrer, 2002).

The Sortilin-related receptor-1 Gene

On chromosome 11 (11q24.1), there is this gene called sortilin-related receptor-1 gene (SORL1). It is a 250-kDa membrane protein that is expressed in the neurons of the nervous system. The SORL1 gene has the role of intracellular trafficking between membrane and hence, interacting with amyloid precursor protein (APP) in endosomes and golgi. This gene function to get rid the excess beta amyloid protein. So, when there is little expression of this gene, it will cause to the increase of beta amyloid protein hence it will lead to the accumulation of beta amyloid protein. Since there is already a large amount of beta amyloid protein in the brains of the Down syndrome patients, then it will have problem to decrease the amount of beta amyloid protein so it will increase the risk of having Alzheimer disease. (Rogaeva et al, 2007)

The Phorsphorylation

Phosphorylation is a mechanism that controls the activity of enzymes and receptors by switching on the regulation of the cell function. Constant activation of the phosphorylation mechanism will increase the accumulation of the of neurofibrillary tangles, abnormal twisted protein filaments that form within affected neurons and are composed mainly of hyperphosphorylated tau protein (Hardy et al, 1991).

So, the hyperphosphorylated tau protein in the brain of the transgenic mice with extra human minbrain-kinase gene also give us the indication of the overexpression of minibrain-kinase could contribute to the early onset of Alzheimer's disease associated with Down syndrome ( Wegiel et al, 2008).

The Age

There have been studies that suggest that overall dementia risk increases beginning in the late 40's or early 50's and even some twenty years earlier than it does within the general population. However, there is still some individuals vary on the onset age. A small minority of adults with Down syndrome begin to experience substantial declines in cognition before age 50, yet another minority is able to mature well into their late 60's or early 70's without experiencing signs or symptoms of Alzheimer's disease (Schupf, 2002).

There are studies on the different ages of mothers who give birth to their children to have risk of having dementia. The results showed a four-fold increase in risk of dementia among mothers who gave birth to their children with Down syndrome less than 35 years of age compared with mothers who were older than 35 years when their child with Down syndrome was born or compared with mothers of children with other intellectual disabilities (Schupf et al., 1994).

The Biomarkers

Biomarkers are used to monitor diseases progression so it is very useful in quantifying the effects of any available treatment regimen. Because biomarkers are strongly associated with disease risk, detection of early changes in biomarker levels provides an opportunity for early intervention to delay or prevent disease onset (Lesko & Atkinson, 2001).

To date, validated biomarkers for Alzheimer's disease in adults with Down syndrome have yet to be discovered. However, there are some biomarkers that have been investigated. These include measures of the quantity and type of beta amyloid protein found in blood plasma and telomere size in metaphase and interphase preparations as well as on individual chromosomes (Schupf, Patel et al., 2001).

There is a close relationship between Down syndrome and Alzheimer disease mainly cause by the overexpression of the APP gene and lead to the over production of the protein, amyloid-beta protein(1-40/42), the major contribution to Alzheimer disease pathogenesis in Down syndrome patient. It is reported in both cross-sectional and prospective analyses that beta-amyloid 1-42 levels increased in demented adults with Down syndrome but not beta amyloid 1-40 levels. For people who are nondemented but with high plasma beta-amyloid 1-42 levels were over two times as likely to develop Alzheimer's disease as those with lower levels (Schupf, Patel et al., 2001).

Telomeres are DNA sequences that located at the end of the chromosome which is a series of repeats of the TTAGGG nucleotide sequence. These DNA sequences undergo shortening with each cell division, serving as markers of a cell's replicative history and an indicator of cellular aging. Using quantitative telomere protein nucleic acid fluorescent in situ hybridization (FISH) analyses of metaphase and interphase preparations from age matched pairs of participants with Down syndrome with and without dementia, there are four observations being observed. The first observation is there are shorter telomeres in individuals with dementia. Next, the individual chromosomes 1 and 21 could be used alone and/or in combination to detect telomere shortening. The third observation is that the cells from individuals with dementia or MCI had reduced numbers of telomere signals when analyzed using a PNA telomere probe, and lastly the shorter telomeres in individuals with MCI (Jenkins, Velinov, Ye, Gu, Li et al., 2006).

The Conclusion

In conclusion, Down syndrome showed that it has a relationship with the pathology of Alzheimer disease. Triplication of chromosome 21that causes over expression of the amyloid-beta protein is the major cause towards the pathology of Alzheimer disease. Not only so, some other sub factors also contribute to it. After understanding the various causes that resulted in Down syndrome patients to have Alzheimer disease, it will be easier for us to invent more ways to treat all these symptoms and hence it will definitely benefit a lot of people that are associated with these diseases.

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