by Jared Gedney
for Biochemistry II
May 29, 1996
An MRI (magnetic resonance image) spectrum of an Alzheimer's patient's brain shows neurofibrillary tangles and enlarged ventricles. These changes indicate damage to the mechanism that screens out excessive stimuli and allows for precise focus, impairing the ability to tolerate multiple stimuli and stress. Another characteristic of Alzheimer's disease is the development of senile plaque in the brain. In the clusters of senile plaque they have found traces of aluminum metal, cathepsin E ("a protease...potentially capable of cleaving [the amyloid precursor protein] (APP) at the (-secretase site"(4)), and (-amyloid. Another interesting protein that is detected in the senile plaque, is the human version of synelfin (a protein produced in the brains of baby zebra finches, believed to aid in the memorization process of songs(10)).
There is no known cure for Alzheimer's disease. We know that Alzheimer's disease is the result of the gradual destruction of brain cells. The cause of this destruction, is not fully understood, there are however some speculations as to the causes of Alzheimer's disease. These include chromosomal mutations, a decrease in the energy supplying mitochondria, apolipoprotein E, and (-amyloid. It is not clear if some of these are the cause of Alzheimer's disease or if they are byproducts of the disease(2).
There are two basic types of Alzheimer's disease; the more common form, known as late-onset, strikes people, who are usually over the age of 65. This form of Alzheimer's is thought to be due to both genetic and environmental causes. The other form called autosomal dominant, early-onset or familial Alzheimer's, strikes people who are under the age of 65, and is strictly due to genetic abnormalities(4). This second form accounts for less than 10 percent of all Alzheimer's cases. Yet in these cases most of the major break through in discovering the chromosomal mutations that contribute to Alzheimer's disease are being discovered.
Of the familial cases of Alzheimer's disease, the most prominent is that of the Volga Germans, who comprise about 80% of all familial Alzheimer's cases. Upon the invitation of Empress Catherine the Great, thousands of Germans emigrated to Russia to farm the plains near the Volga River in the 1760's. When World War I erupted, many of the Volga Germans fled from Russia to the United States. This group of Germans has been studied in great detail for Alzheimer's because of the number of both early-onset and late-onset Alzheimer's cases that have been prevalent in their families for multiple generations(4).
Recently scientists at the University of Toronto cloned a flawed gene that is responsible for a form of the early-onset Alzheimer's disease. This genetic defect, is in the long arm of chromosome 14 (14q24.3), and has been labeled S182. It is believed that this gene produces a membrane protein which builds external or internal structures in cells. This chromosomal mutation, however was not responsible for Alzheimer's disease in the Volga German's. After studying the chromosomal mutation of this particular familial Alzheimer's disease were able to quickly determine the chromosomal mutation that was responsible for the Volga German's form of Alzheimer's disease. The striking similarities between the two genes which provided clues to the second mutation are as follows. The two genes sequences reveal that their protein products contain about 450 amino acids. Also both proteins weave through the cell membrane crossing it seven times. The protein sequences are 67 percent identical, with the membrane segments showing the greatest similarities, being 84 percent identical. This second mutation was discovered by researchers in Massachusetts General Hospital in Boston and was a gene on chromosome 1 (1q31-42). This mutation is believed to account for most of the remaining familial Alzheimer's cases. This gene is named STM2 (for the second seven-transmembrane gene associated with Alzheimer's disease). It has been shown to be a point mutation, resulting in the substitution of an isoleucine for an asparagine at codon 141 (N141I), in affected individuals. In the STM2 protein, the transmembrane helices are capped at the COOH-terminal end by a lysine residue. This lysine is found either at the very end or within a few residues of the end of the transmembrane domains. The N141I mutation consists of the substitution of a hydrophilic asparagine residue to a hydrophobic isoleucine residue at a position directly adjacent to the first predicted transmembrane domain. These mutations, could adversely affect the anchoring of these proteins, or their insertion into cell membranes(3).
It is believed that this new protein could potentially function in the cytoplasmic partitioning of proteins. Mutations in STM2 could change intracellular protein flow of APP and eventually lead to altered APP processing and an increased production of (-amyloid. This theory is supported by the abnormally high quantities of (-amyloid that is produced as a result of the chromosomal mutation(2). Many researchers believe that it is the abnormally high production of (-amyloid and subsequent build up of it in the brain that causes Alzheimer's disease. Some effects of an increase in (-amyloid are modifications to ion channel behavior, alterations in the transport of choline, disruptions in phosphatidylinositol metabolism, and reduction of synaptic field potentials in organotypic cultures. A synaptic field potential refers to the potential across the synaptic cleft, from one neuron to the next. This all occurs before overt neuronal death. Also notable, (-amyloid can cause apoptotic neuronal death in vitro and in vivo. Scientists are now looking for ways to inhibit the production of (-amyloid or at least decrease the rate of production(7).
Another suggested cause of Alzheimer's disease, although controversial, is that of having mutation in mitochondrial ATP (Adenosine Triphosphate) within our cells. As a result of accumulated mitochondrial DNA mutations within the cell, mitochondrial energy production declines. Normally this would not be a problem, because ATP production starts out so high that the decrease rarely goes below that needed to maintain the cell. But if the person started life with a lower than average energy production or some environmental factor decreased the amount of ATP production then cell death could occur. This is especially critical in the brain because it's energy demand is so high. In support of this hypothesis Dr. Douglas C. Wallace of Emory University School of Medicine in Atlanta found that there was a specific mutation in mitochondrial DNA that was found in more than 5 percent of Alzheimer's patients, and was found in less that 1 percent of a random group consisting of people without Alzheimer's. A later study supported Wallace's findings, reporting the same mutation in 8.3 percent of Alzheimer's patients and in only 0.34 percent of age matched controls. This data on mitochondria suggests that mitochondrial defects may predetermine people to neurodegenerative diseases later in life. Studies in animal models, supports the importance of mitochondria in neurological brain disorders. When mitochondria were intentionally destroyed or inhibited in rats or mice, they develop the behavioral and physical characteristics that are associated with Alzheimer's(6).
With the discoveries of the mutations on chromosomes 1 and 14 that account for most of the familial cases of Alzheimer's disease, and the possible connection between mitochondrial ATP production and Alzheimer's disease, there is a renewed enthusiasm for finding a cure to the more common form of this dreadful disease. Scientists are already searching for a way to decrease or reverse the rate of (-amyloid production hoping to slow or prevent the apoptotic neuronal death associated with (-amyloid. These clues along with the advancements, in the technology, used to determine gene sequences and functions, scientists will soon know, the functions of the proteins resulting from the chromosomal mutations. When scientists determine exactly what the proteins functions are they will have a clearer understanding of how to treat the disease. It is at this time when the largest steps towards the cure for Alzheimer's disease will be made.
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