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Alzheimer’s disease

1. Background – detailed description of the disease.

2. You need to present at least three available techniques to diagnose this disease.

3. Figures and tables are required for your Paper.

4. All references used in the Paper must be no earlier than 2010.

Alzheimer’s disease

Alzheimer’s disease (AD), a common disease among the older group of people, deserves worldwide attention. Closely related to this disease is the concern for its high prevalence among the aging population, which is a global phenomenon. According to the United Nation report (2011), it was estimated that the number of people aged 60 years or over will triple in forty years’ time, hence totaling two (2) billion by 2050. To add to this statistic, it is alarming that Alzheimer Disease (AD) affected 500,000 people in UK and 36.5 million worldwide (United Nation report on health, 2011). The world aging population, coupled with rampant cases of Alzheimer among the senior age group justifies the undertaking of this study to investigate the possible influence of prions on Alzheimer. This investigation will contribute to the more extensive long-term study towards identifying the cause, diagnosis and possible cure for Alzheimer. On a social consideration, this will give hope to the senior citizen to look forward to better quality of life for the remaining years of their life.
In this context, it is interesting to introduce the concept of “active ageing” which was first discussed in the 1970’s. Today, World Health Organization (WHO) made the re-emergence of “active ageing” possible. According to WHO, “active” refers to continuing participation in social, economic, cultural, spiritual and civic affairs by older persons (WHO, 2012). This study therefore attempts to add to a vast body of knowledge in an effort to ensure “active ageing” among the senior citizen.

It is vital to understand AD before the technicalities of this disease are discussed at length. The National Institute of Aging in America has defined Alzheimer Disease (AD) as an irreversible, progressive brain disease that will slowly destroy the memory and thinking skills, and will eventually affect the ability of the person to carry out even the simplest task. AD is found to be more prevalent among people above 60 years of age (Hebert, Liesi E., et al.). However, although it is rare, people below 60 years old are not excluded. The following figure shows the relationship between Alzheimer’s occurrence and age.

AD is widely reported to be the common cause of dementia. Dementia is classified as a serious loss of cognitive ability in a previously unimpaired person, which is beyond what is expected of normal aging. Dementia is manifested through a set of symptoms such as changes in mood, memory loss and difficulty in communicating with others and failure to reason things out. As the disease progresses, the symptoms will become more prominent. Dementia may inflict any person and it disregards neither a person’s social and economic status nor ethnic or geographical boundaries. Manifestation of symptoms of people with dementia is unique in every individual. However, it certainly is a matter of time that the AD patient will be unable to care for himself or herself and will need assistance in their daily lives. It is however unfortunate that to date there is still no concrete evidence of a cure for all types of dementia.
AD has been defined by the loss of neurons and synapses in the cerebral cortex. The subcorticol region is no exception. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and the parietal lobe. Studies using MRI and PET have documented reductions in the size of the brain regions among people with AD as they progressed from mild cognitive impairment to AD, in comparison to similar images of healthy adults.

To add to the above, both the amyloid and Neurofibrillary tangles could be seen by microscopy in the brains of the AD patient. Plaques are characterized to be dense, mostly insoluble deposits of amyloid-beta peptide and cellular material located outside and around the neurons. The Neurofibrillary tangles are aggregates of a microtubule-associated protein known as Tau. Tau will be hyperphosphorylated and will accumulate inside the cells themselves. Lewy bodies are sometimes found in the brains of Ad patients. In the early stage of this disease, protein plaques and tangles will form in the brain. This will then pilot the death of the brain cells. It has been reported that AD patient shows a lacking in vital chemicals in their brain. These chemicals are involved in the transmission of messages within the brain.

In this regards, AD has been widely associated to protein misfolding disease caused by the accumulation of abnormally folded amyloid beta. In addition, tau protein is also accumulated in the brain of AD patient. Plaques are then formed from small peptides called beta amyloid. Beta amyloid is a fragment of a bigger protein known as the amyloid precursor (APP). APP is a transmembrane protein that penetrates the membrane of the neurons. APP is essential for the growth, survival and repair injury of the neurons. The reason why APP cleaves into smaller fragments is still unknown. However, it is known that APP is cleaved into smaller fragments by an enzyme through proteolysis. The cleaving of these fragments results in the formation of fibrils of beta amyloid. The deposited beta amyloid will clump together outside the neurons in dense composition, which is recognized as senile plaques.
In some incidences, AD is considered as tauopathy. This is due to the unusual accumulation of tau protein. Every neuron has a cytoskeleton, an internal support structure made up of structures called microtubules. Microtubules are responsible for paving the path to pilot nutrients and molecules from the body of the cell to the other part of the cell. The changes in Tau protein will lead to the degeneration of microtubules in brain cells. Tau is responsible for stabilizing the microtubules when they are phosphorylated and is therefore called a microtubule-associated protein. In AD, Tau undergoes chemical changes and becomes hyperphosphorylated. Tau protein will then begin to pair up with other threads and this will generate Neurofibrillary tangles that will eventually block the neuron’s transport system.

The following literature explains the possible influence of prions protein on Alzheimer, a disease commonly associated with dementia among people above 60 years of age. Alzheimer’s disease, also known as the Creutdz-Feldt Jacobs Disease, CFD, has existed in most communities for a long time. Brundin et al., posit that it was common for people in most communities to develop dementia especially towards the old age, where their memory was greatly affected. In addition, similar diseases affected a number of animals, notably sheep, cats and cattle. However, the physiological conditions that led to the disease were largely unknown until researchers in medicine and molecular biology developed an interest in finding the abnormalities in the proteomics within the patients’ brains as compared to the normal brains.

Until late 1970s, the association of the dementia in old age and CFD/AD was merely understood, especially because most physicians did not understand the exact occurrence of the disease. It was however known that AD normally affected the old people and that it may run in certain families. Thus, the interest to determine the genetic link in the transmission of the disease from one family member to the other developed from this observation. Moreover, the observation that among the Forey people in south Papua New Guinea as well as the Libyan Jew communities had a higher prevalence of the disease proved to researchers that there were more than genetic factors in the transmission. Libyan Jews may prove that the disease could highly be genetically inherited, the transmission of Kuru among the Fore people proved that the transmission could also be from one person to another regardless of the genetic association between the two. Researchers therefore had to consider these issues from both the genetic and other forms of transmission to determine the exact nature and occurrence of the disease in humans as well as other forms of spongiform encephalopathy disease in animals.

Theory of Central Dogma of Molecular Biology

The theory of Central Dogma of Molecular Biology that was first articulated in 1958 by Francis Crick, provides the fundamental understanding of protein in a normal person (refer to Figure 1). The process of building protein is documented in this theory in its original form.
According to this theory, the flow of genetic information in all biological systems must follow the stepwise procedure that involves the use of information stored in the nucleic acid to synthesis proteins active in physiological systems. Generally, Watson and crick hypothesized that the genetic information must flow from the section of the DNA coding for the specific characteristic to the RNA and then to the protein. The DNA (Deoxyribonucleic acid) stores the information through encoding for the characteristic in all species. For the cell to use this information there must be a process of deriving it from the DNA to the active form, generally in protein nature (Brundin et al.).

Thus, convert Watson and Crick hypothesied that the DNA must firts to another nucleic acid form, the messenger Ribonucleic acid (mRNA), through transcription process. The mRNA thus acts as the carrier for the information from the DNA to the external part of the nucleus, where the information is then used to synthesis the specific protein or polypeptide. This process is known as the translation procedure, and each of the resultant polypeptide must function its specific function in the organism. Though it looks such simple, the process is highly complicated because a number of enzymes and other proteins are involved in the process in order to ensure that the information encoded in the DNA is used to make the specific protein. In addition, there are several errors that are prone to occur in the process, and if not corrected could lead to abnormal protein thus abnormalities in the cell, the organs and the entire organ system. Thus, a number of other proteins and processes proofread the transcribed mRNA as well as other post translation processes that provide assurance of the correct protein.

Such enzymes include the DNA polymerase enzyme, which is responsible for the recognition of the strand of DNA to be transcribed, making the DNA copy of the template. This procedure occurs in the replication stage of the central dogma of molecular biology. The enzyme ensures that each of the DNA strands in the double helix replicates to another complimentary strand, thus increasing the amount of DNA in the cell with an aim of conserving the information encoded therein. According to the theory of molecular biology, the replication procedure starts when there is need to produce the protein and thus the characteristic encoded in the DNA strand. In this case, the genes must be converted frits to the RNA through copying of the information in the DNA to the messenger RNA. At this stage, the main player is the RNA polymerase enzyme, which is responsible for the recognition of the specific gene on one of the strands of the parent DNA double helix strand.

The RNA is the exact copy of the DNA, thus will have all the information encoded in the gene. Normally, one gene is transcribed a number of times, resulting into a large number of mRNA molecules that are then used to produce a substantial volume of the protein. According to the theory, the next phase is the conversion of the information encoded in the mRNA to the specific protein. In this case, the ribosome organelles are the major players. They are large structure with a large number of ribosomal RNA (denoted rRNA) molecules. They recognize the mRNAs, read the code and then proceed to produce the protein through synthesizing a chain of amino acids as encoded on the mRNA. Transfer RNAs, tRNAs, are used to read the base pairs in groups of three nucleotides on the mRNA known as the condons. Moreover, each of the tRNAs carries a specific amino acid which in this case will correspond to the condon recognized. The sequential transfer mRNA then deliver the amino acids to the ribosome, where they are made into a chain representing the polypeptide.

Transcription of Prions

Whilst this theory holds true in all individual, the formation of prion protein defies this theory. Proteinacous infectious particles commonly known as Prions are defined as infectious and lethal glycoproteins. Prions are formed as a result of mutation of protein called prion proteins. Mutation of the prion will lead to the misfolding of the protein, which will eventually alter the shape, and structure of the prion protein leading to the early formation (origin) of infectious prions. The unique feature of prion protein is that it is able to replicate and induce infectivity without the presence of nucleic acid. Specifically, the prions are devoid of the nucleic acids because they are naturally proteins, thus they do not carry a genome in themselves yet they replicate.

According to Jack Jr, Clifford R., et al., the main secret of the prion replication is the fact that the information is stored within the structure of the prion protein or the aggregate. This information makes the prion aggregates to recruit and incorporate other normal protein from the cells to the prion, growing with time and inducing refolds into the pathological isoform. However, the growth of the prion is not sufficient for the replication because at one stage, one prion changes to two prions as a matter of the rule of replication.

Thus, researchers focused on the need to establish the precise method through which the prions replicate independent of the nucleic acids and against the central dogma of molecular biology. The kinetics through which the elongation and the breakage of protein have been found to be exponential over time, and that are different from the kinetics of nucleic elongation whatsoever. Since the disease begins with an introduction of an infectious prion protein, nucleation becomes rare and could be ignored in vivo. Even if the disease is spontaneous rather than introduced, the nucleation will not be interfered with because the intervention will actually be too late. With this in mind, researchers then developed a focus on the exponential growth of the prion rather than nucleation. From these research studies, it has been established that prions have a short to long incubation period that could range from days to decades.

In the laboratory, the incubation period of samples of prions is generally reproducible, meaning that to an extent, they could be represented as in vivo.
Prion Proteins and Related Diseases

Studies focusing on the several forms of transmissible spongiform encephalopathies have developed an extensive literature, where a number of these conditions have been described. In addition, they have identified a number of these diseases in both animals and human. Most of these diseases have certain similarities in their manifestation and transmission from one animal to another within any given community. All transmissible spongiform encephalopathies have an incubation period ranging from months to years and that their severity increases with time, leading to death over a period of months. Moreover, it has been shown that none of these diseases provokes or evokes an immune response in the affected people or animals, giving a clue that they may not be caused by infections like other diseases, rather by an abnormality within the body system itself. The diseases also share a common pathologic process of non-inflammatory conditioning, which is only restricted to the central nervous systems of the affected animals or persons (Brundin et al.).

A number of research studies developed since late 1970s largely confirmed that the only form of macromolecule associated with the occurrence of these disease whether in animals or human beings is the prion proteins, PrP. The prion proteins are highly transmissible and explicative, and appear to share a common process or mechanisms of transmission and pathogenesis, and perhaps a common origin. Some difference between these diseases, however, does occur and have been noted in a number of studies. For instance, some like the new-variant CFD and transmissible mink encephalopathy have spread across species, while others like kuru and bovine spongiform encephalopathy have reached epidemic status by affected the species through food chains. Moreover, others like the familial CFD, the fatal familial insomnia and the Gerstmann-Staussler-Scheinker disease have become more genetically inheritable within the species they reside. For instance, scrappie disease was observed to be transmissible from one sheep to another and affecting the brains of the oldersheep. However, it was only in 1936 that the disease was observed to be heritable in the family line of the affected sheep, with an incubation period of about one year. Although this notion gave an insight into the development and transmission of AD in humans, the exact natural mode of the disease transmission remained controversial for a long time until the discovery of the prion protein in all forms of transmissible spongiform encephalopathies.

Prion Protein and Alzheimer disease
Alzheimer’s disease affects more than 37 million people throughout the world, and is thus the most common form of dementia. It is further estimated that the prevalence of the disease will increase with the inclined rate of aging among the world populations. Thus, the socioeconomic demands will increase significantly because the rising number of patients will increasingly demand for care and treatment. One of the hallmarks of this disease is the formation of senile plagues that are majorly composed of the peptide amyloid-β as well as the neurofibrilliary tangles that are formed from the tau protein. The accumulation of the peptide in the brain, however, is the most critical aspect for the pathogenesis of the disease, and which forms the basis for a number of studies (Jack Jr, Clifford R., et al).
The prion protein, PrP, mediates the degeneration of the neurons in the patient’s central nervous system, especially in the brain region. This is effected through the conversion of this protein from the normal and non-infective form, the PrPC to the infectious PrPSc variety. This variety has been found to be the major causative agent of Alzheimer’s disease as well as other transmissible spongiform encephalopathies, TSEs, such as creutdzfeldt-Jacobs disease, CJD, Kuru, scrapie, bovine spongiform encephalopathies and other similar diseases in animals. The possible role of the molecular form PrPC has been established under investigative research.

Studies have indicated that the possibilities of having a number of genetic links and neuropathological comparisons between the prion proteins and Alzheimer’s disease could be real and found with good research studies. The coexistence between the pathology of AD in CJD patients and the amount of prion proteins co-localizes with the plagues having the Aβ-peptides. The PrPC- Aβ complexes are normally present in large amounts in most patients with CJC and especially those with associated alzheimers disease-type of pathology. PrPCpromotes the formation of the Aβ plague. There is a genetic relationship between prion protein precursor andAlzheimer’s diseases. This is also common in almost all patients. A number of researchers have used a meta-analysis of the Alzheimer’s gene association to confirm the genetic links in patients with the disease. Studies indicate that the human gene encoding for the PrPC could be the potential susceptibility gene for the disease. In addition, they revealed that the polymorphism of methionine/valine 129 in this gene is a risk factor that could cause an early onset of Alzheimer’s disease even among the people aged below 60 years (Jack Jr, Clifford R., et al).

Studies indicate that in its late onset, sporadic Alzheimer’s disease has its amyloidogenic processing of the APP increased due to increased activity of the protein levels and more importantly, the increased levels of BACE1. BACE1 is the rate-limiting step in the production of Aβ, then it follows that the increase in the expression of the protein, as well as its inclined activities, will have a very significant effect on the levels of Aβ. In addition, the activity of the γ-secretase could be enhanced in patients with Azheimers disease, especially because the levels of the presenilin-1 mRNA normally increase in the brains of these patients. Moreover, the Aβ degradation normally decreases because the levels of the Aβ-degrading enzyme are also reduced in this case, which further enhances the γ-secretase activity. Others in neurobiology of the people and animals affected by dementia causing diseases, the hippocampus are normally the most affected part of the brain.

PrPC regulates the β-Secretase Cleavage of APP
While these studies have contributed much to the knowledge that the abnormal folding of the prion proteins is one hallmark of Alzheimer’s disease in human beings, additional studies in the processes by which the enzymes are regulated in the cleavage and folding of the protein have been very crucial. In this case, a number of studies indicate that there is a defined role of the prion protein PrPc in the regulation of the process by which β-Secretase enzyme catalyses the cleavage of the peptide APP. In addition, PrPc levels decrease the amyloidoigenic processing of the peptide APP, which therefore was shown to have a direct decreasing effect on the levels of Aβ.

The researchers have shown that the induced over-expression of PrPc in nuroblastoma cell line in human beings has a direct role in the decline of the levels of both Aβ and PrPc. Moreover, their studies on the murine neuroblastoma cell lines have shown that the depletion of the PrPc, mediated by siRNA or by a genetic knock out procedure normally results into an incline in the levels of Aβ. An increase in the levels of Aβ occurs in homozygotes for Met129 and the role of polymnorphism in the exposure to AD, the risks of developing the disease is quite high in the met129 homozygote.

According to (McKhann, Guy M., et al.), currently, there is no single test that can be used to confirm a person is suffering from Alzheimer’s disease. A complete assessment of patient’s general health is necessary in order to diagnose the disease’s possible cause. The first method of diagnosing Alzheimer’s disease is the use of medical history and physical examination. Diagnosis starts by reviewing the patient’s medical history during a workup. The healthcare provider enquiries about past and current illnesses and any medication the patient is taking. The doctor also enquires about the medical conditions of close members of the family and whether any of them has a known case of Alzheimer’s disease or related dementias. The physician enquires about the patient’s diet, nutrition and alcoholic use. The physician also asks the patient to bring a list of all medication he or she is using including any supplement and over-the-counter drugs, in order to review medications. The blood pressure, pulse rate and temperature of the patient are checked. Physical test also includes assessing overall health such as listening to lungs and heart, taking samples of blood and urine for laboratory testing. The results from lab test and physical can help identify symptoms of dementia.

Genetic testing can be used to diagnose Alzheimer’s disease or another dementia. The presence of certain genes in the body increases the risk of developing Alzheimer’s. Genetic testing can be done through blood test for the risk gene called APOE-e4 primarily used in clinical trials to determine people at higher risk of developing Alzheimer’s. Deterministic genes are used to diagnose familial Alzheimer’s or autosomal dominant Alzheimer’s disease (ADAD). ADAD begins earlier in life and is known to run family thus causing anxiety to close family members of a patient diagnosed with the condition (Montine et al.).
Neurological exam is a diagnostic technique for Alzheimer’s that assess a person for problems that might indicate brain disorder other than Alzheimer’s. The physician looks for signs of strokes, fluid accumulation on the brain, brain tumors, Parkinson’s disease, and other diseases that result in memory impairment. The physician tests a person’s speech, reflexes, sensation, eye movement, coordination, muscle strength and tone. A brain imaging may also be carried out during neurological examination using brain scans such as magnetic resonance imaging (MRI) or computer tomography (CT). These tests (MRI and CT) can be used to distinguish Alzheimer’s from other diseases with similar symptoms.

Alzheimer’s disease treatment
Currently, the cure for Alzheimer’s disease has not been found. However, several medications for the treatment of Alzheimer’s symptoms such as sleep problems, behavior changes, and memory loss are available (Mace, Nancy and Peter 15). These medications can slow down the disease’s symptoms progression for months or years. These drugs are not free of side effects that are more pronounced in elderly patients. Some of the medication for Alzheimer’s therapy includes antidepressants such as citaloprame and sertraline which treat mood disorders. Anxiolytics (lorazepam and oxazepam) treats restlessness and anxiety. Antipsychotic (aripiprazole, haloperidol, and olanzapine) treat aggression, delusions, and hallucinations. Non-drug therapies are also used by Alzheimer’s patients to cope with the disease’s symptoms. Vitamin E is among the earliest known therapy for Alzheimer’s. Although its use has declined due lack of scientific evidence, it was believed to have antioxidant characteristics that protect nerve cells from damage. Hormone replacement therapy (HRT) especially among women was considered as Alzheimer’s therapy. The recommendation for use of HRT was based on studies that suggested that HRT among postmenopausal women lowered the risk of developing Alzheimer’s. The female hormone (estrogen) was believed to interfere with the production of beta amyloid- the protein responsible for the development of Alzheimer’s. However, a recent study suggests HRT do not lead any inhibition of Alzheimer’s progress. The study also shows that HRT may increase the risks for breast cancer, stroke, and heart attack.

The cure for Alzheimer’s has not been found, and many people with the disease continue to lose their memory and its capacity to function. Recent census data indicate that the United States’ population is getting older, and the cases of Alzheimer’s are increasing day by day (Hebert et al. 1779). It is estimated that, in the next 50 years, Alzheimer’s incident may quadruple and almost two percent of the American population. This calls for a spirited effort among scientists in order to come up with a possible cure for Alzheimer’s. The available therapies that try to treat Alzheimer’s symptoms and help patients to cope with the disease are also inadequate. The side effects associated with the available Alzheimer’s therapies creates a big concern since they seem to complicate the caregivers’ efforts. While this study increased the need for further studies to investigate these aspects of the AD, they have increased the available knowledge. This is especially in the genetic association of the expression of the abnormally folded prion proteins and the occurrence of the disease.

Work cited

Brundin, Patrik, Ronald Melki, and Ron Kopito. “Prion-like transmission of protein aggregates in neurodegenerative diseases.” Nature Reviews Molecular Cell Biology 11.4 (2010): 301-307.
Hebert, Liesi E., et al. “Alzheimer disease in the United States (2010–2050) estimated using the 2010 census.” Neurology 80.19 (2013): 1778-1783.
Jack Jr, Clifford R., et al. “Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers.” The Lancet Neurology 12.2 (2013): 207-216.
Mace, Nancy L., and Peter V. Rabins. The 36-hour day: A family guide to caring for people who have Alzheimer disease, related dementias, and memory loss. JHU Press, 2011.
McKhann, Guy M., et al. “The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.” Alzheimer’s & Dementia 7.3 (2011): 263-269.
Montine, Thomas J., et al. “National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach.” Acta neuropathologica 123.1 (2012)

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