BiologyPaper


				Jessica Wallace BSCI 10110 Spring 2002
		The Quest for a Cure


On April 10, 2001 Ceregene Inc. announced that the first Alzheimer�s patient had been treated in a gene therapy study. The phase 1 study, led by Mark Tuszynski, involved the surgical implantation of cells extracted from the patient�s skin that produce nerve growth factor. Nerve growth factor (NGF) is a naturally occurring protein that maintains the survival of nerve cells within the brain. The cells were surgically injected into the nucleus basalis of Meynert, the area of the brain most affected by Alzheimer�s disease (AD). The question of this study is can the NGF prevent death of some nerve cells affected by AD and can it enhance the function of certain remaining brain cells? When the experiment was performed on monkeys, the loss of cholinergic neurons due to normal aging was reversed and restoration of normal activity levels of axons was achieved. Updates of Tuszynski�s human study should be available some time this year (Anonymous, 2001).
Currently, nearly 4 million Americans suffer from Alzheimer�s disease, and as many as 22 million individuals worldwide are predicted to be affected within the next 25 to 50 years (George-Hyslop, 2000; Christensen, 2001; Spake, 2001). According to Peter H. St. George-Hyslop (2000), 15 percent of people up to the age of 65 will develop some form of dementia. By the age of 85, nearly 35 percent will fall victim to this form of disease (Harder, 2002). There is no accurate diagnosis of such a degenerative disease until the patient�s brain can be analyzed during autopsy to confirm the presence of amyloid plaques and tangles within the brain (Martindale, 2002).

	Neurofibrillary tangles consist of a protein called tau. Tau binds to a protein, tubulin, which forms microtubules that are very important to cells. In patients affected by Alzheimer�s, amyloid plaques form between nerve cells in the hippocampus and cerebral cortex of the brain. These plaques - made up of beta-amyloid precursor proteins (�APP) from which beta-amyloid stems - can be seen very early in the development of the disease, oftentimes before any outward symptoms arise. The beta-amyloid plaques are accompanied by reactive inflammatory cells known as microglia which react as part of the brain�s immune system and quite possibly attempt to rid the brain of plaques or damaged neurons (George-Hyslop, 2000).

	Studies suggest that the beta-amyloid peptide, located on chromosome 21, disrupts calcium regulation; ultimately leading to cell death. Not only does beta-amyloid interfere in calcium regulation, but it also damages the mitochondria within the cells, causing them to release free radicals that cause extensive damage to lipids, proteins, and even DNA. In addition, the peptide leads to the release of cellular compounds that may attract immune cells, facilitating an inflammatory response that also leads to much damage (George-Hyslop, 2000).
To this day, the genetic factors involved in Alzheimer�s is unknown, however three genes have been identified that are associated with and are perhaps causes of the disease. The beta-amyloid precursor protein gene, presenilin 1 and presenilin 2, and the apolipoprotein E gene have been identified as probable roots to Alzheimer�s thus far (Duijn, 1998). Most recently, nine chromosomes have also been discovered, the most important being APOE4, located on number 19 chromosome, that many believe to be the biggest link discovered that bestows the greatest risk for both early-onset and late-onset Alzheimer�s (Duijn, 1998; George-Hyslop, 200; Harder, 2002; McKinney, 2002). Furthermore, presenilin 1 and presenilin 2 located on chromosome 14 account for the aggressive form of early-onset Alzheimer�s. Although genetic mutations may also be causes leading to the disease, they only account for 5 percent of all instances (George-Hyslop, 2000).
Studies have shown that those with the APOE4 gene that have suffered a brain injury had more impaired memory than those patients that had other forms of the APOE gene (McKinney, 2002). It is believed that APOE influences recovery after brain injury by affecting repairing processes in the brain. This finding is helping Dr. Fiona C. Crawford to better understand what is triggered after a brain injury and further studies may enable researchers to develop drugs that would be able to activate the processes that repair damaged tissues or even block the processes that contribute to damage. Those neurons that contain APOE4 do not recover as well after injury because they are believed to not be as efficient as the other forms of APOE in transporting cholesterol to repair the damaged neurons. This study is the starting point to comprehending exactly what the role of APOE4 is in the brain (McKinney, 2002). In respect to Alzheimer�s, those patients with the E4 gene have more beta-amyloid build-up than those with E2 and E3. Those with both �APP mutation and the E4 gene develop Alzheimer�s earlier than those that have �APP and either E2 or E3 (George-Hyslop, 2001).
In recent studies, Rudolph E. Tanzi, a neurologist at Massachuesetts General Hospital in Boston, screened the entire genomes of nearly 2000 people of which 1439 developed Alzheimer�s after the age of 50. Tanzi located single-nucleotide polymorphisms (SNPs) that contained links to the patterns of the incidence of Alzheimer�s. According to his studies, APOE4 increases the risk of Alzheimer�s disease. He also found associations between the disease and regions of chromosomes 1, 4, 9, and 10. From other potential chromosomes involved, chromosomes 6, 11, 14, and 21 were noted because they may contain genetic factors that influence the risk of developing Alzheimer�s. This research performed by Tanzi will have quite an impact on current Alzheimer�s research, helping to pinpoint precise locations within the genome that are associated with the disease. Tanzi will continue his studies, concentrating on chromosomes 9 and 10. Also, Tanzi will further study the IDE gene on chromosome 10 that produces an enzyme that aids in the ridding of beta-amyloid from the brain (Harder, 2002).
In February of 2001, 15 patients fell ill to brain inflammation due to a trial study of a possible Alzheimer�s vaccine. Since then, researchers have been a bit apprehensive about administering a vaccine to patients stricken with the disease for fear of furthering degeneration of the brain (Martindale, 2002). Mice that were given the vaccine, however, had produced antibodies that not only prevented the accumulation of beta-amyloid plaques, but also helped to clear them up (Christensen, 2001; Martindale, 2002). As theory goes, the antibody forms a complex with the beta-amyloid, triggering the microglia to destroy the plaques. At the end of this year, Cynthia A. Lemere will introduce the beta-amyloid vaccine for use in clinical trials (Martindale, 2002).
Some researchers detest the beta-amyloid theory, proposing that other factors, such as tau tangles are just as important. John Blass of Cornell University noted that nearly 20 percent of those diagnosed with Alzheimer�s have no signs of beta-amyloid plaques at autopsy. In relation, 50 percent of individuals that contained a rather high amount of beta-amyloid plaques at autopsy showed no symptoms of mental illness before their death. Studies have also shown that free radical damage occurs before the formation of plaques, keying that plaque formation is not the trigger for AD. Mark Smith of Case Western Reserve University suggests that perhaps beta-amyloid actually acts as a defense mechanism in the brain, leaving behind destruction in its path. In further studies, a protein known as Pin-1 has been tested in regard to its relationship with tau. Pin-1 binds to the amyloid precursor protein and tau. Test tube studies have shown that Pin-1 allows phosphorylated tau proteins to continue their normal functions. This finding could lead to a treatment for Alzheimer�s (Christensen, 2001).
Although chances increase for those inflicted with the faulty genes, genetics is not the sole cause of this disease. Poor early-childhood education, serious head injury, and even exposure to aluminum in drinking water has been linked to put those at a higher risk for developing Alzheimer�s (George-Hyslop, 2000). Other environmental factors include alcohol, smoking, vascular disease, and depression. However, it must be made clear that these are not the underlying causes of the disease (Duijn, 1998). Lifestyle habits may also contribute to the onset of Alzheimer�s. According to Amanda Spake (2001), mental work and challenging leisure activities equal brain strength. Intellectual stimulation of the brain creates reserves of healthy nerve cells, thus one would become more resistant to AD. Robert Friedland, of Case Western Reserve University, states that nerve cell activity leads to fewer plaques. Statistically, Alzheimer�s is more rare in those with a higher education and career attainment. Cardiovascular health and exercise also contribute to nerve cell stimulation (Spake, 2001).
	Lifestyle habits may also contribute to the onset of Alzheimer�s. According to Amanda Spake (2001), mental work and challenging leisure activities equal brain strength. Intellectual stimulation of the brain creates reserves of healthy nerve cells, thus one would become more resistant to AD. Robert Friedland, of Case Western Reserve University, states that nerve cell activity leads to fewer plaques. Statistically, Alzheimer�s is more rare in those with a higher education and career attainment. Cardiovascular health and exercise also contribute to nerve cell stimulation (Spake, 2001).
	The key to putting a halt to, or perhaps developing a cure for Alzheimer�s disease is to first understand the underlying cause or causes of this degenerative disease. Yet, this brings forth a rather large obstacle when we as humans have yet to comprehend how our brain works and how we are capable of performing the many tasks that we carry out on a day-to-day basis, let alone understand how we have been able to invent such complex contraptions such as computers, microwaves, or laser technology. The development of some sort of therapy, vaccine, or treatment of Alzheimer�s is going to be especially important in the upcoming years due to the aging population of the �Baby-Boomers�. Although there has been no cure yet discovered, researchers have definitely paved the way to better understanding the causes, to lead us to a method of prevention.
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