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Alzheimer’s Disease Biological Causes

Alzheimer’s disease is driven by two processes: extracellular deposits of beta amyloid and intracellular accumulation of tau protein.[9] “It is characterized by accumulation of amyloid-? peptide, generated by proteolytic processing of the amyloid precursor protein (APP) by ?- and ?-secretase.”[10p554] The APP gene provides instructions for making APP. This protein is found in many tissues and organs including the brain and the spinal cord. It plays a role in cell growth, formation of new synapses, differentiation of neurons, cell adhesion, calcium metabolism, and protein trafficking.[10] The length of APP varies between 695 to 770 amino acids. Protein breakdown generates A?, a 39- to 42-amino acid peptide. This form is the primary component of amyloid plaques found in the brains of AD.[10] APP may be processed via a non-amyloidogenic pathway that prevents A? formation or through a toxic, amyloidgenic pathway, resulting in A? plaque formation.
In the non-amyloidogenic pathway, APP is processed in peripheral cells. In this pathway, APP is cleaved by an enzyme called ?-secretase followed by ?-secretase. These are integral membrane proteins where cleavage by ?-secretase occurs within the A? domain. Cleavage by ?-secretase prevents A? formation and releases the extracellular secreted APP ? fragment.[11] Research shows that secreted APP ? protects neurons, regulates stem cell production, plays a role in brain development, and promotes the formation of synapses and cell adhesion. The remaining C-terminal fragment of APP then undergoes either lysosome degradation or ?-secretase cleavage, which generates p3 and the APP intracellular domain.[11]
In the amyloidogenic pathway, APP is primarily processed in neuronal cells. Within this pathway, APP is cleaved by ?-site APP cleaving enzyme 1 (BACE1), followed by ?-secretase. BACE1 initiates the production of the toxic A? that plays a crucial role early in the pathogenesis of AD.[11] Cleavage of APP by BACE1 releases the extracellular secreted APP ? fragment which is thought to assist with axon pruning and cell death.[12] BACE1 cuts APP to produce a membrane-bound C-terminal fragment C99 that is further processed by ?-secretase to generate A?. The site of ?-secretase cleavage within the transmembrane domain of APP can vary and determines the type of A? that is produced, A? 39-42. Once produced, A? is usually secreted into the extracellular space via exocytosis.[12]
A? is a major component of plaques that are found in both intracellular and extracellular locations. A?42 is considered to be one of the main causes of these plaques because it clumps together more quickly than other isoforms, forming clusters and fibrils.[10] In individuals with AD, elevated concentrations of A? plaques can lead to many cellular dysfunctions. The presence of A? plaques alone is not enough to diagnose AD since many people without cognitive decline have plaques.
Tau is a protein in the microtubule-associated protein family. It has several physiological functions in healthy axons including microtubule assembly and stability, vesicle transport, neuronal outgrowth and neuronal polarity. This protein consists of 352 to 441 amino acids and presents in various isoforms in the brain.[10] In AD, tau protein is hyperphosphorylated, causing disruption in microtubule transport and loss of neuronal transmission. Tau phosphorylation is the addition of phosphate to a tau protein through regulation of tau kinases. In humans, the tau gene is positioned on chromosome 17. In a normal brain, there are two to three moles of phosphate per one mole of tau, indicating that this amount of phosphorylation is necessary for tau to perform its normal biological functions. When tau becomes hyperphosphorylated, the ratio of phosphate to tau increases three to four fold compared to normal phosphorylation levels. This increased amount of phosphate alters the function of tau, making it insoluble and lacking affinity for microtubules. This leads to the degradation of the microtubules and neuronal cell death.[10]
The main risk factor for developing AD is increasing age, with those aged 65 and older at greatest risk.[10] Younger individuals may also develop the disease, however, this is often the result of genetic mutations. As mentioned, two distinct types of AD exist: familial AD and sporadic AD. The two types are distinguished by their onset periods and family history. Plaque formation and neurofibrillary tangles are present in both types of the disease.
As previously stated, fAD follows an autosomal dominant pattern of inheritance and is inherited through mutations in the genes for APP, PS1, or PS2. Each of these genes encode for proteins that are involved in the production of the A? peptide.
PS1 and PS2 are proteins with numerous transmembrane domains. Higher expression of the presenilins has been noted in the cerebellum and hippocampus. The genes for PS1 and PS2 have a similar structure and are located on chromosome 14 and chromosome 1, respectively. These proteins are thought to play a role in signaling pathways, cell death, and initiating the response to unfolded proteins. They are also an important part of the ?-secretase complex that is involved in APP processing.[10]
PS1 mutations are the primary cause of fAD. Currently, more than 176 PS1 mutations have been identified in 390 families. Individuals carrying a PS1 mutation typically develop more severe forms of AD and display symptoms at an earlier age than those carrying PS2 mutations. Most PS1 mutations are missense mutations in which they cause amino acid substitutions and are located in the transmembrane domains of the affected protein.[10] PS2 mutations are a much rarer cause of fAD, and currently only 14 PS2 mutations have been identified in six families.
Amyloid precursor protein is a 695 amino acid protein that is cleaved by the ?-secretase enzyme. APP is located on chromosome 21, making individuals with trisomy 21 (Down syndrome) at higher risk for developing AD. More than 32 APP mutations have been discovered in 78 families, however the APP gene represents only a small fraction of AD.[7]
LOAD often does not show a family history and is most likely caused by risk alleles across various genes involved in A? production, aggregation, and degradation. The Apolipoprotein E (APOE) gene on chromosome 19 (specifically APOE-?4) has been demonstrated to represent a major genetic risk factor for LOAD.[1] “APOE is a lipid-binding protein and is expressed in humans as three common isoforms coded for by three alleles, APOE-?2, -?3, and -?4.”[1p61] One APOE-?4 allele increases one’s risk by two to three times while two alleles increases risk by a minimum of five times. It is important to note that not everyone who has one or two APOE-?4 genes develops Alzheimer’s disease. The disease occurs in many people who have no APOE-?4 gene, suggesting that the APOE-?4 gene affects risk but is not a cause.
Epigenetics is the phenotype expression or silence of a gene without necessarily having the genotype.[13] One way for phenotypes to be expressed or silenced is through methylation, which is a biochemical bond of a methyl group between three hydrogen atoms and one carbon atom. When there is over-methylation, it will turn the gene off whereas decreased methylation will turn the gene on. Some epigenetic marks remain for a lifetime while others are temporary, influenced by modifiable factors, such as weight, diet, or stress.[13]
Epigenetics may explain the neurological changes that occur in AD.[13] In a study of monozygotic twins at the L.J. Roberts Center for Alzheimer’s Research in Arizona, researchers found that one twin developed AD while the other twin did not. Their postmortem autopsy revealed that the Alzheimer brain had tremendous decrease of methylation of brain cells whereas the non-Alzheimer brain did not. Researchers continue to investigate whether decreased methylation caused dementia or vice versa. In another experiment, in which they conducted test tube brain experiments, they were able to confirm that epigenetics does cause the typical hallmark changes of plaques and tangles seen in AD. Future studies are needed to determine how to identify Alzheimer-related epigenetics early to help prevent or delay this disease.[13]
Alzheimer’s disease is a clinical diagnosis. Definitive diagnosis can only be made through autopsy. Imaging studies such as computed tomography, magnetic resonance imaging, single-photon emission computed tomography, and laboratory tests help to exclude other possible causes for dementia.[14] AD progresses on a spectrum of three stages: preclinical stage of no symptoms, middle stage of mild cognitive impairment (MCI), and final stage of Alzheimer’s dementia.[15] “Interviews to assess memory, behavior, mood, and functional status are best conducted with the patient alone, so that family members or companions cannot prompt the patient.”[15p2] According to the National Institutes of Health,[15] objective and subjective clinical findings found within each stage are defined as:
Getting lost
Trouble handling money and paying bills
Taking longer to complete normal daily tasks
Poor judgment
Mood and personality changes
Increased memory loss and confusion
Problems recognizing family and friends
Inability to learn new things
Difficulty carrying out tasks that involve multiple steps (such as getting dressed)
Hallucinations, delusions, and paranoia
Impulsive behavior
Inability to communicate
Weight loss
Difficulty swallowing
Groaning, moaning, or grunting
Increased sleeping
Bowel and bladder incontinence
Currently there are no standardized assessment tools for cognitive impairment.[16] The Alzheimer’s Association found that the mini-mental state exam is not feasible since there are copyright issues, requiring permission every time it is used. It did find that the memory impairment screen, general practitioner assessment of cognition, and the Mini-Cog were the best tools to use. According to Cordell et al,[16] they found that these assessment tools were:
Easy to administer
Took less than five minutes
Any medical staff could administer it
Easy to understand language
Validated for primary care or in a community setting
No copyright issues
After completing a thorough physical assessment of the patient, it is important to rule out other diseases or conditions that may contribute to those symptoms. In AD, there are multiple differential diagnoses, such as:
Traumatic or repetitive brain injury[17]
Drug or alcohol abuse[17]
Thyroid disorders[18]
Vitamin B12 deficiency[18]
Cerebrovascular disease[17]
Other types of dementia i.e. lewy body, vascular, frontotemporal, etc[17,19]
Huntington’s disease[17]
Parkinson’s disease[17]
Although this is a minute list of differentials, it is not exhaustive. Since early clinical presentations of AD are vague, primary care practitioners are typically hesitant to give the diagnosis of AD.[18] In the past, practitioners utilized “watchful waiting” when confronted with these vague symptoms. However, early diagnosis and treatment are important in symptom management. Thus, practitioners should refer patients to a neurologist or a geriatrician when they are uncertain.[18]

Cloning Plants and Animals: Arguments For and Against

Cloning is a general term for the research activity that creates a copy of some biological entity a gene, organism or cell. This term originally applied to cells of a single type, isolated and allowed to reproduce to create a population of identical cells.
For instance, sheep have been engineered to produce human insulin. If human rely on only sexual reproduction to mass produce these animals, then the risk of breeding out the desired traits is possible since sexual reproduction reshuffles the genetic deck. Other reasons why create a clone are replacing lost or deceased family pets and repopulating endangered or even extinct species.
Animal Cloning is the process by which an entire organism is reproduced from a single cell taken from the parent organism. This means the cloned animal is an exact duplicate in every way of its parent; it has the same exact DNA but they are not identical twins with the parent organism. This is because they do not develop from the same fertilized egg rather the clone comes from a mature cell taken from the parent organism, ‘mother’.
Cloning happens quite frequently in nature. Asexual reproduction in certain organisms and the development of twins from a single fertilized egg are both instances of cloning. With the advancement of biological technology, it is now possible to artificially recreate the process of Animal Cloning.
The unfertilized eggs of some animals (small invertebrates, worms, and some species of fish, lizards and frogs) can develop into full-grown adults under certain environmental conditions. This process is called parthenogenesis, and the offspring are clones of the females that laid the eggs.
Medical science, biotechnology, and other related science field keep evolving almost every day. New discoveries, inventions and medical breakthroughs are a part and parcel of the medical field. Scientist now a days seem to become more and more eager to know every single thing that occurs in a human body and to them experimenting with cloning is a major step in their research to understand human beings fully. They ultimately want to find a cure for death itself.
In 1996, the announcing of the first cloned mammal sheep named Dolly gave rise to worldwide interest and concerns about the scientific and ethical implication cloning bring about. This caused in medical scientist the long to dig deeper into the mysteries of life and to desire to grasp a better knowledge of it. The more we know about animal cloning the better we understand the miracles of DNA, genes, chromosome and eventually life itself.
Background and Importance The first cloned animal was actually a tadpole. It was created by Robert Briggs and Thomas J. King in 1952. In the 1970s, a scientist named John Gurdon successfully cloned tadpoles. He transplanted the nucleus from a specialized cell of one frog (B) into an unfertilized egg of another frog (A) in which the nucleus had been destroyed by ultraviolet light. The egg with the transplanted nucleus developed into a tadpole that was genetically identical to frog B. While Gurdon’s tadpoles did not survive to grow into adult frogs, his experiment showed that the process of specialization in animal cells was reversible, and his technique of nuclear transfer gave way for later cloning successes.
Scientists have been attempting to clone animals for a very long time. Early attempts came to nothing. The first fairly successful results in animal cloning were seen when tadpoles were cloned from frog embryonic cells. This was done by the process of nuclear transfer. The tadpoles so created did not survive to grow into mature frogs, but nevertheless it was a major breakthrough.
On July 5th 1997, Dolly was the first cloned mammal created by Scottish scientists at Roslin Institute in Edinburgh, UK. She passed away in 2003 at the age of 6. Dolly had developed a progressive chronic lung disease and arthritis so decision was made to euthanize her. Her breed of sheep normally lives from ten to twelve years. An extensive post-mortem found no evidence to suggest or even imply that being a clone contribute to her early death.
When Dolly’s creation was announced, President Bill Clinton issued a moratorium to stop all federally funded cloning projects. This was done to avert the threats of abuse of this medical breakthrough. Cloning as seen in the eyes of many anti-cloning activists is a great threat to life and peace as it can be used by organizations with criminal background. Yet cloning in many countries was still being tested and experimented on to address health issues.
The ‘mother’ sheep of Dolly had died many years before she was even created. This led to a many controversies surrounding the process of animal cloning and its capacity or power to produce a desired effect. When she died many scientific investigations were hindered but nonetheless scientist continued cloning animals.
When cloning started, the pros and cons of it were never paid close attention to by scientists all over the wold. Scientist sought to apply the results and principle of animal cloning to human. Many nations gave way to human cloning as an alternative to win over diseases. Interestingly the first cloned cat and rabbit were created in 2002 and in 2003 the first horse and rat was unveiled in France and Italy respectively
In 2008 the FDA (Food and Drug Administration) of USA informed publicly that it is safe to eat meats and dietary product of cloned animals. Since then the cattle business barons were impulse to accelerate the growth of their business with the creation of clones. Yet many American are not comfortable in consuming dairy foods sourced from cloned animals. Americans demand deeper and more conclusive studies to be done by the FDA. Even though many food crisis will be solved many humans doubt about the nutritious value of clone meats.
The European Union placed a temporary ban in October 2012 on the use of animal cloned food in Europe. This stopped the imports of food and eatable coming from cloned animals in the US and any other country. The EU Health and Consumer Commissioner John Dalli told reporters in an interview that food from cloned animals is safe, that the meat or dietary products cannot be differentiated in any way form the normal bred animals but the issue is animal welfare. In addition to this the cost parameters are high in cloned food. Let’s say if a pound of meat cost $7, the cost of a pound of cloned meat will cost $12.
From the information obtained from previous cloning failures and success three important cloning processes where developed. These three types are: (1) recombinant DNA technology or DNA cloning, (2) reproductive cloning, and (3) therapeutic cloning. In addition to generating cells for tissue and transplantation, it is hoped that by using ES cells derived from patients with known genetic defects related to ALS, Alzheimer’s disease, or Parkinson’s, researchers will be able to develop and test drug that might prove valuable in the treatment of the disease.
Cloned Species Information Genetic cloning has helped and changed the views of bio engineers towards the world. The cloning of Dolly, which was the first successful mammal to be created gave rise to many more experiments and questions which have resulted in success. As said, Dolly was not the first organism to be cloned. She became the most famous clone simply because she was the first successful clone. Bio engineers have been searching and trying to discover the mysterious of cloning since the 1950’s.
The tadpole was the first organism to ever be attempted in 1952. This created chaos since those who conducted the research themselves were puzzled as to what had occurred. In 1963, a carp was cloned by a Chinese embryologist and in 1986 the first successful mouse was cloned. In 1996 was when Dolly was created. In the 2000 the first rhesus monkey was cloned. In 2001, the first endangered species were cloned, namely Gaur and in the same year, Brazilian specialists managed to clone cattle. The first world’s cloned pet, CopyCat was cloned in 2001 and the first dog in 2005. There is evidence that larger animals have also been cloned along the time and some of them include horses in 2003, camels in 2009 and water buffalos in 2009.
Actual Process In somatic cell nuclear transfer firstly, you need to isolate the donor nucleus. A biopsy is taken to remove the cell (eg skin cell) of the organism which is desired to be cloned. The cell membrane of a somatic cell which contains the genetic makeup of a certain individual/ organism is poked using a very small needle and syringe or a short pipette which acts as a suction device to capture the nucleus and remove it from the somatic cell obtained from an adult.
Secondly, you need to obtain an unfertilized egg. Many eggs are needed since not all of them will survive the various steps of cloning. Thirdly, the eggs’ nucleus is removed. The cell is poked through using a short pipette to capture the nucleus and removed it from the cell. The zona pullucida is drilled using a pipette and so the nucleus is sucked out. This step is similar to step one. The difference is that here a reproductive cell is used, specifically a female egg cell rather than a non-reproductive cell.
Fourthly, the nucleus of the donor cell is inserted into the egg cell using the short pipette. The nucleus contains the complete genetic material of the individual from whom the cell was extracted. The egg’s genetic material now contains all traits from the donor adult. This egg is genetically identical to the donor adult.
Fifth, an impulse charge is used as a substitute for normal fertilization. This stimulates the egg and causes it to be activated on the second shock so it starts dividing and create a blastocyst, a ball of about 50-200 cells. This blastocyst is then referred to as the embryo. The embryo is then placed into the surrogate mother. The surrogate mother gives birth to clone organism, a perfect copy of its mother. A perfect example of the use of this process is the creation of Dolly, the first successful cloned sheep.
A cell from Sheep A udder was taken and placed in culture medium with low levels of nutrients. This starves the cell. It switches off its active genes. An unfertilized egg from Sheep B is taken and the nucleus is sucked out leaving only the cytoplasm which contains all the machinery need to make an embryo. The cells are placed side by side. An electric pulse makes them fuse. Cell division starts after another electric impulse. 6 days later the embryo is implanted in another ewe. The ewe gives birth to Dolly, a lamb genetically identical to the donor Sheep A. She was the only successfully cloned organism in 237 eggs that had been used to create nearly 30 embryos. Three lambs were created but only one had survived, Dolly.
The process of plant cloning is way less complicated than that of the animal cloning. An easy explanation of plant cloning is with vegetative propagation. Recently scientists are able to clone plants by taking pieces of specialized root, breaking them up into root cells and growing the cells in a nutrient-rich culture. In this culture, the specialized cells become dedifferentiated into calluses. The calluses are then stimulated by the use of appropriate plant hormones to grow into a new plant. This new plant is genetically identical to the original plant form which the root was taken from. This procedure is referred to as tissue culture propagation.
There are two types of plant cloning. They are cloning by separation or division, and cloning by cutting. In cloning by separation or division, (separation) the plant parts are merely pulled apart. The plant naturally separates the parts for the production of new plants. In division, the producer cuts the plant parts into sections and grows a new plant for each section. Specialized parts of the plants such as bulbs, corms, tubers, stolons, rhizomes and crowns are used in the cloning by separation or division method.
In cloning by cutting, a stem or root or leaf is cut from the parent tree. These cuttings are taken at certain times of the year in which the environmental conditions are suitable for the tree to ‘cure’ itself. The grower must create the proper conditions that will allow the development of roots and shoots from the plant. Proper temperature, moisture, air movement and light are needed. When you take a leaf cutting from a plant and grow it into a new plant, you are cloning the original plant because the new plant has the same genetic makeup as the donor plant. Vegetative propagation works because the end of the cutting forms a mass of non-specialized cells called a callus. With luck, the callus will grow, divide and form various specialized cells (roots, stems), eventually forming a new plant.
When a strawberry plant sends out a runner, a new plant grows where the runner takes root. That new plant is a clone. Similar process occurs in grass, potatoes and onions. Cloning allows the gardener to replicate a genetically identical plant from a parent plant. The clone will have the exact same characteristics as the mother plant, the same growth habit, disease resistance, fruit shape, flower color and yield potential.
Pros and Cons Cloning has been very useful in genetic fingerprinting, amplification of DNA and alteration of the genetic makeup of many organisms. It is used to bring about the desired traits of individuals while eliminating the negative traits. Application of cloning includes the development of human organs.
The greatest pro of cloning is organ replacement. If for any reason a vital organ of the human can be cloned, it can serve as a backup system for many human beings. Organs such as a kidney or even the heart when failure occurs can be replaced with the cloned organ. The cloning process can also be used to produce an embryo from which cells called embryonic stem (ES) cells could be extracted to use in research into potential therapies for a wide variety of diseases, generate cells and tissues for transplantation. The point is that these cells, tissues and organs will be genetically compatible with the patient, and will not be rejected.
Cloning can be useful as a substitute for natural reproduction. Infertility can be solved. The composition of genes and the effects of genetic constituents on human traits might be better understood. Genetic constituents can be altered to obtain a better analysis of genes and help combat genetic diseases such as Parkinson. Cloning can help obtain customized organisms and harness for the benefit of society. Organisms that can be used for research purposes. Such organisms include extinct and endangered flora and fauna.
Cloning extinct animals is very difficult since collecting genetic material form animals that lived thousands of years ago is virtually impossible. However, animals at the verge of extinction and be preserved. Cloning can repopulate endangered species. Scientist have been trying to bring back the Tasmanian tiger, if this is successful then the next step would be bringing back dinosaurs. Yet this will be far much harder for scientists since obtaining a sample of medical importance from a dinosaur skeleton is very difficult.
Like there are positive effects of cloning, there are also negative effects of it. The cons of cloning include: the reduction of diversity in nature, and ability to bring about all the potential uses of cloning into reality. Cloning creates identical genes thus tampering with the diversity in genes. The ability of adaptation will reduce if cloning occurs. Cloning invites malpractices such as organ trafficking. One important thing we need to put into consideration which is the cost of production of cloned organs, animals, plants etc. Moreover, human and animal rights are at stake. A con of extinct animal cloning is that cloned animals are weak and may not survive their entire expected life span. A serious question when it comes to dinosaur cloning: can we humans coexist with them? It’s something we must think of.
Ethical issues Bioengineering has brought about a revolution in which many doors in the science field have been opened yet as Newton stated “with every action there is an opposite reaction”. The greatest ethical issue is the thought of creating a man-made human being. The Catholic Church as well as other religious organization is opposed to this since in the religious belief life beings at conception and not by the intervention of scientific studies. The church also believes that the therapeutic use of cloning goes against the idea of life starting at conception and once the embryo is created it must be treated as a person rather than just a material than can be used for medical purposes. Destroying embryos and using them only for the purpose of research is not consistent with the religious view on the issue.
In 2006 the US government approved the consumption of meat from cloned animals. This decision raised significant objections associated with potential risks with cloning which could be transmitted through ingesting the animal product. New born cloned animal have a high death rate. Does this mean that they have some health issues scientists don’t want the public to know because it would stop their funding? Consumers have been wary and sceptical about such ideas, fearing that clones may carry hidden health risks that aren’t readily observable.
Conclusion Cloning can be proven useful for many important scientific advancements such as in the field of biotechnology, if all its positive ideas can be brought about. It has given scientist the opportunity to investigate and try to solve the puzzle of life itself. If cloning is to be implemented diseases, economic fluctuations and food instability can be controlled. But is it worth risking ourselves for something that can affect us? Is it worth waiting to see when it is perfect to eat or use something cloned? With the ratio given of a clone to survive from attempts is not worth it.
Even though cloning can be proven very useful in our society it brings about too many complications. Like any other action taken in life, cloning can be detrimental to our environment, ultimately to our human body. The possibility of flora and fauna diversity will cause adaption to reduce. This can cause the clones to die at an early age since they will not be accustomed to the changing environment. Possibilities are that our kids can inherit any possible unobservable disease clones bring about. Plant cloning for sure should be taken into consideration since no serious risks are taken. But we should watch out for those who use cloning as a mean of destruction.