Causes And Impacts Of Down Syndrome Biology Essay

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Although no one knows for sure why DS occurs and there's no way to prevent the chromosomal error that causes it, scientists do know that women age 35 and older have a significantly higher risk of having a child with the condition. At age 30, for example, a woman has about a 1 in 900 chance of conceiving a child with DS. Those odds increase to about 1 in 350 by age 35. By 40 the risk rises to about 1 in 100.

Low muscle tone (called hypotonia) is also characteristic of children with DS, and babies in particular may seem especially "floppy." Though this can and often does improve over time, most children with DS typically reach developmental milestones - like sitting up, crawling, and walking - later than other kids.

At birth, kids with DS are usually of average size, but they tend to grow at a slower rate and remain smaller than their peers. For infants, low muscle tone may contribute to sucking and feeding problems, as well as constipation and other digestive issues. Toddlers and older kids may have delays in speech and self-care skills like feeding, dressing, and toilet teaching.

Down syndrome affects kids' ability to learn in different ways, but most have mild to moderate intellectual impairment. Kids with DS can and do learn, and are capable of developing skills throughout their lives. They simply reach goals at a different pace - which is why it's important not to compare a child with DS against typically developing siblings or even other children with the condition.

Kids with Down syndrome are also at an increased risk of developing pulmonary hypertension, a serious condition that can lead to irreversible damage to the lungs. All infants with Down syndrome should be evaluated by a pediatric cardiologist.

Approximately half of all kids with DS also have problems with hearing and vision. Hearing loss can be related to fluid buildup in the inner ear or to structural problems of the ear itself. Vision problems commonly include amblyopia (lazy eye), near- or farsightedness, and an increased risk of cataracts. Regular evaluations by an audiologist and an ophthalmologist are necessary to detect and correct any problems before they affect language and learning skills.

Alzheimer's Disease:-

Alzheimer's (AHLZ-high-merz) is a disease of the brain that causes problems with memory, thinking and behavior. It is not a normal part of aging.

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Alzheimer's disease (AD) is the most common form of dementia among older people. Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities.

AD begins slowly. It first involves the parts of the brain that control thought, memory and language. People with AD may have trouble remembering things that happened recently or names of people they know. Over time, symptoms get worse. People may not recognize family members or have trouble speaking, reading or writing. They may forget how to brush their teeth or comb their hair. Later on, they may become anxious or aggressive, or wander away from home. Eventually, they need total care. This can cause great stress for family members who must care for them.

AD usually begins after age 60. The risk goes up as you get older. Your risk is also higher if a family member has had the disease.

No treatment can stop the disease. However, some drugs may help keep symptoms from getting worse for a limited time

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Biochemistry of Alzheimers disease:-

NACP, a Synaptic Protein Involved in Alzheimer's Disease, Is Differentially Regulated during Megakaryocyte Differentiation:-

Non-amyloid-β component precursor (NACP) is a presynaptic protein which may play a role in amyloidogenesis in Alzheimer's disease (AD). Since an abnormal function of platelets has been demonstrated in AD, platelets could be used as a model to investigate the role of NACP in this disease. We characterized the patterns of NACP and β-synuclein expression in a megakaryocyte-platelet system (K562).

In this hematopoietic cell line, NACP expression was up-regulated during phorbol ester-induced megakaryocytic differentiation, while β-synuclein was down-regulated. Consistent with this, NACP but not β-synuclein was abundantly expressed in platelets. Immunogold electron microscopy of platelets showed that NACP is loosely associated with the plasma membrane, the endomembrane system and, occasionally, with the membrane of secretory α-granules. These findings suggest that coordinate expression of the synuclein family members may play a critical role during hematopoietic cell differentiation. Additionally, expression of the synuclein family members may be developmentally regulated during neural differentiation.

star, openAbbreviations: AD, Alzheimer's diseaseAβ, amyloid β; APP, amyloid precursor protein; BSA, bovine serum albumin; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; NAC, non-Aβ component of AD amyloid; NACP, NAC precursor; PBS, phosphate-buffered saline; PKC, protein kinase C; TBS, Tris-buffered saline; TPA, 12-o-tetradecanoylphorbol-13-acetate;

Neurodegenerative diseases are characterized by the presence of filamentous aggregates of proteins. We previously established that lithostathine is a protein overexpressed in the pre-clinical stages of Alzheimer's disease. Furthermore, it is present in the pathognomonic lesions associated with Alzheimer's disease. After self-proteolysis, the N-terminally truncated form of lithostathine leads to the formation of fibrillar aggregates. Here we observed using atomic force microscopy that these aggregates consisted of a network of protofibrils, each of which had a twisted appearance.

Electron microscopy and image analysis showed that this twisted protofibril has a quadruple helical structure. Three-dimensional X-ray structural data and the results of biochemical experiments showed that when forming a protofibril, lithostathine was first assembled via lateral hydrophobic interactions into a tetramer.

Each tetramer then linked up with another tetramer as the result of longitudinal electrostatic interactions. All these results were used to build a structural model for the lithostathine protofibril called the quadruple-helical filament (QHF-litho). In conclusion, lithostathine strongly resembles the prion protein in its dramatic proteolysis and amyloid proteins in its ability to form fibrils.

Cont...

Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques

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In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport systemhttp://www.rndsystems.com/DAM_public/5213.jpg

modles are available to researchers to study Alzheimer's:-

1-Alzheimer's Rat Model

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The Samaritan Alzheimer's Rat Modelâ„¢ is a chemically induced rat model designed for the study of non-genetically linked Alzheimer's disease, which accounts for the vast majority

The Taconic Samaritan Alzheimer's Rat Modelâ„¢ is the

Its rapid time to disease state enables researchers to accelerate the discovery of drugs to combat neurodegenerative disease. Through the induction of oxidative stress, it provides investigators with a deeper understanding of how the disease progresses.

of the disease instances. This unique, groundbreaking model offers several significant advantages over other options previously available for the study of neurodegenerative

diseases Researchers studying familial Alzheimer's have turned to Taconic for many years for our highly reliable, genetically modified model that is bred to develop the disease over time. To provide researchers with an equally reliable tool for the study of sporadic Alzheimer's, Taconic now offers a chemically induced model for this specific purpose.

Taconic's highly trained surgical technicians chemically induce the onset and progression of Alzheimer's disease in a Long Evans rat via the slow release of ferrous sulfate heptahydrate, LButhionine-( S,R)-sulfoximine, and Beta-Amyloid peptide. The model reaches the disease state extremely fast - in just 4 weeks - exhibiting memory impairment and Tau protein levels in the cerebral spinal fluid and developing the amyloid deposits that are characteristic of Alzheimer's.

The process also induces oxidative stress, allowing investigators to explore the vital link between such stress and the development of amyloid deposits in the brain. In tests conducted with this model, Samaritan Alzheimer's rats and a control group were both trained to retrieve an underwater platform. Four weeks after the chemical induction was performed, both groups were tested again and the Samaritan Alzheimer's Rat Modelâ„¢ showed much longer platform retrieval rates, indicative of memory loss.

Advantages of the Samaritan Alzheimer's Rat Modelâ„¢

Accelerated timeline

The model requires a much shorter time to disease state than a comparable transgenic model: just 4 weeks. So it enables researchers to conduct drug target screening on a faster timeline, saving time and money.

Not genetically linked

The model mimics the onset and progression of sporadic Alzheimer's that does not have a genetic link, allowing researchers to study a disease state that accounts for 95% of all Alzheimer's cases.

Advantages of the Samaritan Alzheimer's Rat Modelâ„¢

Demonstrated pathology

The model has demonstrated the main pathologies indicative of the disease, including memory impairment, hyperphosphorylated Tau protein levels in the cerebral spinal fluid, and key histological alterations.

Physiologically relevant

The disease state is simulated in a rat model, which is physiologically closer to humans than

a mouse model.

2- Drosophila as a model to study age-related neurodegenerative disorders: Alzheimer's disease.

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Alzheimer's Disease (AD) is the most common cause of dementia in the aging population. Although a variety of drug treatments can delay the onset of disease or temporarily reduce its severity, there is currently no cure or effective long-term treatment. This therapeutic void in part reflects an incomplete understanding of the biochemical pathogenesis of this disease. Model organisms, including invertebrates, have been extensively utilized to gain insight into the molecular and cellular mechanisms underlying disease. Here, we will describe how Drosophila has been used to study the function of genes associated with AD and to develop models of this devastating disease

3-Metabolism model :-http://www.sciencecodex.com/aggregated-images/brain/tW89m8SPj28S6560.jpg

Bioengineers from the University of California, San Diego developed an explanation for why some types of neurons die sooner than others in the brains of people with Alzheimer's disease. These insights, published in the journal Nature Biotechnology on November 21, come from detailed models of brain energy metabolism developed in the Department of Bioengineering at the UC San Diego Jacobs School of Engineering.

The Alzheimer's insights demonstrate how fundamental insights on human metabolism can be gleaned from computer models that incorporate large genomic and proteomic data sets with information from biochemical studies. UC San Diego bioengineering professor Bernhard Palsson and his students and collaborators first developed this "in silico" modeling approach for E. coli and other prokaryotes, and later extended it to human tissues.

The Nature Biotechnology paper describes the first time this modeling approach has been used to capture how the metabolism of specific human cell types affect the metabolism of other cell types.

"In human tissues, different cells have different roles. We're trying to predict how the behavior of one cell type will affect the behavior of other cell types," said Nathan Lewis, a Ph.D. candidate in the Department of Bioengineering at the UC San Diego Jacobs School of Engineering and the first author on the Nature Biotechnology paper, which also includes authors from the University of Heidelberg, Massachusetts Institute of Technology, and the German Cancer Research Center (DKFZ).

Similar approaches can be used to identify potential off-target effects of drugs, provide insights on disease progression, and offer new tools for uncovering the underlying biological mechanisms in a wide range of human tissues and cell types.

Why Some Neurons Die First in the Alzheimer's Brain:?

In the brains of people with Alzheimer's disease, certain cells, such as glutamatergic and cholinergic neurons, tend to die in much larger numbers in moderate stages of Alzheimer's disease, while GABAergic neurons are relatively unaffected until later stages of the disease.

"There is a big question as to what is causing this cell-type specificity," said Lewis.

The researchers built computational models that captured the metabolic interactions between each of the three neuron types and their associated astrocyte cells. Next, the bioengineers knocked down α-ketoglutarate, a gene known to be damaged in patients with Alzheimer's disease, and let their models of brain metabolism run to see what happens.

The results from the models agreed with clinical data. When the bioengineers disrupted the α-ketoglutarate enzyme in the models for cholinergic and glutamatergic neurons, the metabolic rate of these neurons dropped, leading to cell death. "But then you have the GABAergic neurons that show no effect. So the cell types that are known to be lost early on in Alzheimer's show slowed metabolic rates," explained Lewis.

Analysis of their models then led the bioengineers to the biochemical pathways that allowed the GABAergic neurons to be relatively unaffected despite the disrupted gene.

"We looked at what upstream is allowing this and found a GABA-specific enzyme called glutamate decarboxylase," said Lewis.

When the researchers added this enzyme to the models of the other neuron types, the metabolic rates of these neurons improved as well. Thus the model allowed the researchers to identify a gene and how it contributes to the whole cell to potentially prolong the life of certain cells in Alzheimer's disease.

3-Neuron Membrane Model to Study Alzheimer'shttp://www.medgadget.com/archives/img/08CSTL011_thethered_mem_LR.jpg

NIST scientists have built a model of the membrane that surrounds neurons in the brain, a tool which should help to discover the mechanisms behind Alzheimer's onset.

The brain's neurons transmit nerve impulses down a long stem that is surrounded by a two-layer membrane. In the neuron's normal, "rest" state, this membrane actively sorts sodium ions to the outside of the cell and potassium ions to the inside. To transmit a nerve impulse, an electrochemical change ripples down the membrane in advance of the impulse, making it temporarily more permeable and allowing the ions to swap places. That in turn changes the electrical potential across the membrane, allowing the impulse to pass. Afterwards, the membrane returns to rest and begins sorting the ions again.

Medical experts have hypothesized for years that small polypeptides called amyloid beta peptides somehow create a "leaky" membrane that disrupts this balanced back-and-forth switching of the electrical potential and, in turn, normal impulse transmission. Alzheimer's disease-the progressive brain disorder that is the nation's sixth leading cause of death-is believed to start with such breakdowns. As the disease progresses, amyloid beta peptides clump together to form plaques that further destroy nerve function.

Studying the beginnings of Alzheimer's is nearly impossible in humans because by the time the disease is diagnosed, most patients have moved into its later stages. Researchers at NIST have developed a laboratory model that recreates a simplified version of the nerve cell membrane, allowing the study of Alzheimer's disease mechanisms at the molecular level.

A clever piece of molecular-level design, the system is built by first covering a silica surface with gold. Sulfur atoms, which bond well to gold, are then added to act as anchors to hold the bilayer membrane. The result is a stable, tethered membrane with an aqueous environment on both sides that accurately models the behavior of the nerve cell membrane.

A collaborative team of researchers from NIST, Carnegie Mellon University, the University of California-Irvine and the Biochemistry Institute (BCHI) in Vilnius, Lithuania, exposed the membrane model to different concentrations of a specific form of amyloid beta peptides comprised of soluble, tiny (5-6 nanometers, approximately twice the diameter of a DNA helix) chains. The researchers found increased cation movement across the normally strong barrier at the higher concentrations of the peptides.

The data support the hypothesis that membrane "leakiness" is not due to a permanent hole being formed but rather to an aggregation of amyloid beta peptides in the membrane that allows cations to be passed from peptide to peptide across the bilayer, like a baton handed off by relay runners.

Down Syndrome and Alzheimer's Disease Risk and How are Down Syndrome and Alzheimer's disease related

Down syndrome increases the risk of Alzheimer's disease. People with Down syndrome may experience health problems as they age that are similar to those experienced by older people in the general population. The presence of extra genetic material found among persons with Down syndrome may lead to abnormalities in the immune system and a higher susceptibility to certain illnesses, such as Alzheimer's, leukemia, seizures, cataracts, breathing problems, and heart conditions.

People with Down syndrome also experience premature aging. That is, they show physical changes related to aging about 20 to 30 years ahead of people of the same age in the general population. As a result, Alzheimer's disease is far more common in people with Down syndrome than in the regular population. Adults with Down syndrome often are in their mid to late 40s or early 50s when Alzheimer's symptoms first appear. People in the general population don't usually experience symptoms until they are in their late 60s.

The symptoms of Alzheimer's disease may be expressed differently among adults with Down syndrome. For example, in the early stages of the disease, memory loss is not always noted. In addition, not all symptoms ordinarily associated with Alzheimer's disease will occur. Generally, changes in activities of daily living skills are noted, and the person with Down syndrome may begin to have seizures when he or she never had them before. Changes in mental processes -- such as thinking, reasoning, and judgment -- also may be present, but they often are not commonly noticeable because of limitation of the individual's functioning in general.

How Common Is Alzheimer's Disease in People With Down Syndrome?

Estimates suggest that 25% or more of individuals with Down syndrome over age 35 show the signs and symptoms of Alzheimer's-type dementia. The percentage increases with age. The incidence of Alzheimer's disease in people with Down syndrome is estimated to be three to five times greater than that of the general population.

Why Do People With Down Syndrome Get Alzheimer's Disease?

Current research shows that the extra "gene dosage" caused by the abnormal third chromosome of Down syndrome may be a factor in the development of Alzheimer's disease. The early aging of the Down syndrome brain may also be a factor

Drug treatments for Alzheimer's disease

No drug treatments can provide a cure for Alzheimer's disease. However, drug treatments have been developed that can improve symptoms, or temporarily slow down their progression, in some people. This factsheet explains how the main drug treatments for Alzheimer's disease work, clarifies their availability, and sets out the most recent guidance from the National Institute for Health and Clinical Excellence (NICE) on their usage.

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What are the main drugs used?

There are two main types of drugs used to treat Alzheimer's disease. Aricept, Exelon and Reminyl all work in a similar way, and are known as acetylcholinesterase inhibitors. Ebixa works in a different way to the other three.

Aricept (donepezil hydrochloride), produced by Eisai and co-marketed with Pfizer, was the first drug to be licensed in the UK specifically for Alzheimer's disease.

Exelon (rivastigmine), produced by Novartis Pharmaceuticals, was the second drug licensed in the UK specifically for Alzheimer's disease.

Reminyl (galantamine) was co-developed by Shire Pharmaceuticals and the Janssen Research Foundation. Originally derived from the bulbs of snowdrops and narcissi, it was the third drug licensed in the UK specifically for Alzheimer's disease.

Ebixa (memantine) is produced by Merz and marketed in Europe by Lundbeck. It is the newest of the Alzheimer's drugs.

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How do they work?

Aricept, Exelon and Reminyl

Research has shown that the brains of people with Alzheimer's disease show a loss of nerve cells that use a chemical called acetylcholine as a chemical messenger (Pierre et al, 2004). The loss of these nerve cells is related to the severity of impairment that people experience.

Aricept, Exelon and Reminyl prevent an enzyme known as acetylcholinesterase from breaking down acetylcholine in the brain. Increased concentrations of acetylcholine lead to increased communication between the nerve cells that use acetylcholine as a chemical messenger, which may in turn temporarily improve or stabilise the symptoms of Alzheimer's disease.

All three cholinesterase inhibitors work in a similar way, but one might suit an individual better than another, particularly in terms of side-effects experienced.

Ebixa

The action of Ebixa is quite different to, and more complex than, that of Aricept, Exelon and Reminyl. Ebixa blocks a messenger chemical known as glutamate. Glutamate is released in excessive amounts when brain cells are damaged by Alzheimer's disease, and this causes the brain cells to be damaged further. Ebixa can protect brain cells by blocking this release of excess glutamate.

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