Alzheimer's
From Science Online
Contents |
A Quick Blast to the Past
Alzheimer's disease was first discovered in 1907 by scientist, Alois Alzheimer. The diagnosis began when Alzheimer was notified that a fifty-year old woman had been suffering from severe cognitive malfunctions that dealt with memory, speech, and interaction. After the woman had died, Alzheimer conducted an autopsy on her brain by using the silver stain technique which allowed Alzheimer to identify neurons. During the process, Alzheimer noticed strange formations which today are called senile plaques. Alzheimer's unusual finding within the woman's brain were later diagnosed as Alzheimer's disease. Even with this discovery, Alzheimer's was not a common term used during the early 20th century and did not become fully noticed until the science world exploded in the 1970s.
Introduction:Symptoms,Statistical Evidence,and General Information
The national extremity of Alzheimer's disease effects the lives of about five million Americans today. Inheriting the disease creates a tremendous burden on your lifestyle which forces you to involuntarily adjust. Patients with Alzheimer's experience the once simple, but now arduous tasks of communicating, learning, contemplating, and reasoning. Scientists have developed a clear cut warning list to help families discern full-blown Alzheimer's disease from normal age-related memory alterations. Some of the symptoms of Alzheimer's disease include frequently forgetting recently obtained information, strain to handle everyday tasks, forgetting simple words and the patient's mother-tongue itself, befuddled to time and place, the diminishment of judgment and erratic behavior, changes in personality, and the loss of will to survive. If the rate of augmentation for the disease continues, by two-thousand and fifty, thirteen point two million Americas will have Alzheimer's disease. Not only does Alzheimer's disease alter a patient's quality of life, but it also puts a major strain on the economy. Both the national direct and indirect price for the treatment of Alzheimer's disease is around one-hundred billion dollars per year. By two-thousand and fifteen, this amount will exceed to about one-hundred and eighty-nine billions dollars per year. Even though the biochemical understanding of Alzheimer's disease is still relatively lacking, recent studies have shown the world that full understanding is impending and that ameliorated treatments to stop its progression are reachable.
The Countless Myths of Alzheimer's Disease
The reality of the causes and effects of Alzheimer's is understood by few. Myths or "wives tales" relating to Alzheimer's disease are currently the mainstream thought in American society. The most popular myth is that loss of memory is simply a natural occurrence in the aging process. Today, researchers know that memory loss is a symptom of serious illness. The majority of Americans feel that as they grow older their memory become less in tuned, but this belief is still a researcher's challenge in the science world. Another well known rumor is that Alzheimer's disease is not deadly. Truth of the matter is, Alzheimer's will kill its hostage because it destroys the brain's cells, alters your memory, causes belligerent behaviors and the body's inability to function properly. Also, the elderly are not the only age group who can obtain Alzheimer's because out of the estimated five million Americans with Alzheimer's, already five-hundred thousand people under sixty-five have Alzheimer's or similar types of dementia. During the 1960s and 1970s, aluminum became a highly recognized risk in Alzheimer's. Recent studies have noted that they cannot find any concrete evidence that aluminum may be a risk factor and tend to focus on more immediate issues. As well as aluminum, at one time aspartame was believed to cause Alzheimer's disease. However in 1996, the FDA approved the artificial sweetener for use in all foods and beverages. Even after this expert approval, most American were still cautious about aspartame's health effects. Again, in May 2006, the FDA could not find any research that would lead to the conclusion that aspartame was harmful. The most wishful myth on Alzheimer's in America is that there are current treatments available to inhibit the escalation of Alzheimer's disease. The actual reality is that there is no cure or delay effect for Alzheimer's, although FDA certified machines can temporarily ease the pain symptoms for only six to twelve months.
Alzheimer's A4 Beta Protein Precursor
This is an image of the x-ray crystal structure of the protease inhibitor domain of Alzheimer’s Amyloid A4 Beta-Protein Precursor or APP.The image is showing 1AAP; chains A and B. There are in all 56 residues in its domain length, 2 alpha helices, and 4 beta sheets.
Biochemistry
Neurons are electrically stimulated cells located in the nervous system that communicate information and are the cells that comprise the brain. The amyloid beta hypothesis tries to account for the loss of these neurons in the brain. Neuronal loss is caused by the accumulation of fibrils and plaques. Amyloid fibrils form around the exterior of neurons in dense regions called senile plaques or neuritic plaques. Small blood vessels throughout the brain contain amyloid fibrils in their walls, which is called angiopathy. Within these plaques and fibrils of patients who have Alzheimer‘s Disease, researchers have found misfolded amyloid beta proteins. The misfolding of proteins causes the protein to be misshaped and the shape of the protein directly correlates with the protein’s ability to function properly. In healthy patients, amyloid beta proteins are either degraded or expelled from the brain whereas Alzheimer’s patients display the congregation of amyloid beta proteins which form hard plaques that are unable to be broken down by the body. Amyloid beta is a short peptide that originates from the amyloid precursor protein (APP) as a fragment that has been cut off. There are currently three known hypotheses on Alzheimer’s Disease, but the one that is most supported and recognized as the primary agent of Alzheimer’s is the amyloid hypothesis. Alzheimer’s effects the brain and inhibits the proper function of neurons.
Amyloid beta proteins are modified by abnormal metabolites which are caused by the inflammation of the brain. In some cases, these stimuli can occur years before any symptoms of Alzheimer’s Disease first appear. Metabolites accelerate the aggregation of amyloid beta proteins through a two-step mechanism. In the first step, metabolites use the Schiff base formation to modify amyloid beta proteins and there function. The Schiff base formation takes place when an amine reacts with either an aldehyde or ketone to transform into a carbinolamine. A carbinolamine is produced when a hydroxyl group and an amine are joined to an identical carbon atom. The second step occurs when fibrillar congregate in dense regions and acts as a catalyst towards the production of Alzheimer’s Disease. These metabolite mechanisms offer an answer for why amyloid beta condensation could form in the first place.
As discussed earlier, inflammation creates mutated metabolites that cause amyloid beta proteins to misfold through the Schiff base two-step process. These misshaped amyloid beta proteins are unable to function accordingly and accumulate into plaques and fibrils while normally, amyloid beta proteins would quickly be eliminated or broken down. This process causes the implications of neuronal loss throughout the brain, which inevitably leads to onset of Alzheimer’s Disease and its fatal symptoms.
Amyloid Beta Protein's Significance
Why do amyloid beta proteins aggregate? Is it due to its unique shape or structure? Why do metabolites modify amyloid beta proteins in certain brains, but not all? Why do some people who have brain damage form metabolites and obtain Alzheimer's while others do not? These questions are some of the many that biochemists are trying to solve today. Thousands of questions are still unanswered, but certain unprecedented scientific experiments have shown possible new break-throughs.
The Department of Chemistry at Princeton University has revealed to society a newly developing answer to why the amyloid beta protein tends to aggregate as published in "Mutations Enhance the Aggregation Propensity of the Alzheimer's Amyloid Beta Peptide." They have investigated the sequence of events that leads to aggregation by studying the relationship between amino acid substitution and protein misfolding that may lead to an increase or decrease in aggregation. Countless mutations have been found through scientific studies, but mutations that augment the threat of aggregation have been revealed. Chemists of Princeton University decided that it would be best to create a fake genetic screen that would isolate noteworthy mutations that proliferate aggregation tendency. This screen would not be of much use if it did not solely rely on the indication of amyloid beta's green fluorescent protein (GNP) mixture in Escherichia coli.
Escherichia coli is a well known bacteria that can be found in the lower intestines of warm-blooded mammals. Even though it is only found in mammal intestines, it has the ability to survive outside of the body for short durations so it is an ideal scientific testing organism.
Green fluorescent protein's power to fold and fluoresce is inversely related with the gathering of the amyloid beta primary structure. Utilization of this newly developed screen allowed the isolation of twenty misfolded versions of amyloid beta along side amino acid mutations at seventeen locations in the forty-two-remain primary structure of amyloid beta. Studies of man made peptides corresponding to primary structures identified by the screen show the augmentated aggregation tendency of the mutants. These mutations were identified by using an indifferent screen that provides no assumptions on the sequence determinants of aggregation. Nevertheless, all sixteen of the aggregating mutants have mutations that decrease charge and/or boost hydrophobicity. This innovative experiment provides intriguing results that support the idea that sequence hydrophobicity is a large factor in amyloid beta aggregation.
The National Institution Against Aging has recently informed America that a new, innovative hypothesis has emerged within scientific laboratories across the United States. The hypothesis begins with the amyloid beta precursor protein (APP)and the fact that at some specific time it is cleaved into several fragments.
For a while, scientists believed that one or two specific enzymes were the cause of the cleavage of APP, but had difficulty actually identifying them. Today, due to the wonders of modern technology, experts have found three cleaving enzymes. These enzymes are alpha-secretase, beta-secretase, and gamma-secretase. A huge understanding is now known that depending on where and which enzyme cleaves APP, APP can follow one of the two routes that result in different consequences.
In the first pathway, the alpha-secretase cuts the APP protein within the part that has the ability to become beta-amyloid. Once APP has been cleaved at this specific location, it results in the release into the area outside the neuron of a section called sAPPa. sAPPa is known to have very beneficial attributes that facilitate neuronal grown and survival. The remaining APP peptide that is still located within the neuron's membrane, is then cut by beta-secretase at the very end of the amyloid-beta primary structure. The small fragments resulting in this cleavage are released outside of the neuron, while the larger fragments remain tethered within the neuron and enters the nucleus. Through this detailed passage, no amyloid-beta proteins are produced.
In the second pathway, alpha-secretase cuts the APP molecule at one end that has the most ability to become amyloid-beta, while simultaneously releasing the fragment sAPPa. Next, gamma-secretase cleaves the other part of the fragment at the end of the beta-amyloid primary structure. Now that the APP molecule has been cleaved at both ends, a beta-amyloid peptide is then launched into the space outside of the neuron. This formation and releasing of the amyloid-beta peptide causes the route to be dangerous because these peptides start to stick or aggregate to one another.These clumps are referred to as amyloid-beta derived ligands (ADDLs). ADDLs are small, soluble ligands, but as aggregation increases, the clumps become more and more insoluble. This insolubility forms fibrils and protofibrils and ultimately form into plaques. Although plaques have been a well known characteristic of Alzheimer's disease, scientists now believe that oligomers (condensed amyloid-beta peptides) are the most risky culprit.
Prevention/Treatment
Unfortunately, there is no current cure for Alzheimer's disease, but there are available treatments that can help aide both cognitive and erratic behavioral symptoms.These two categories are the only aspects within Alzheimer's that can be treated. Changes in memory,speech,judgement, and ability to accomplish everyday simple tasks all relate to cognitive symptoms of Alzheimer's disease while how patients feel emotionally and act relate to behavioral symptoms. The FDA has certified cholinesterase inhibitors to stop the diminshment of acetylcholin. Acetylcholine is a chemical messenger significant in dealing with the memory of the brain. This medicine aides communication within nerve cells by setting acetylcholine levels high. Most patients who consume cholinesterase inhibitors notice 6-12 months of delay in cognitive Alzheimer’s disease symptoms. Examples of cholinesterase inhibitors are Donepezil , Rivastigmine, and Galantamine. Among these, Donepezil is used to delay the most severe types of Alzheimer’s disease.
Another approved drug, Memantine, helps ease Alzheimer's symptoms by regulating the process of glutamate.
Glutamate is similar to acetylcholine in that it too is a chemical involved in how the brain understands and remembers certain ideas. Certified in 2003, Memantine is the only treatment of its type that has been approved to aide Alzheimer’s symptoms. Most medicines have severe side effects and Donepezil and Memantine are no different. With Donepezil , patients will feel nauseous,have a low appetite, and experience countless bowel movements. Similarly, headaches, constipation, and dizziness all exist from the contraception of Memantine. Many families have learned that behavioral symptoms such as verbal/physical outbursts, emotional distress, restlessness, hallucinations, and delusions are the most difficult symptoms of Alzheimer’s. Non-drug applications should be used before diving into treatment drugs. Simple ways that families could potentially solve behavioral problems are monitoring comfort levels, straying away from arguments, constructing a serene environment, creating frequent rest periods, and above all, simplicity, simplicity, simplicity. If all else seems to fail, turning to medications should be an validated option, but researched with care. For instance, anti-depressants should only be taken if the patient is lowly or tense. Anxiolytics should not be taken unless the Alzheimer’s patients is feeling restless and anxious. Finally, it is very important to note that antipsychotic medicines should solely be used for frequent hallucinations and delusions. Overall, talking with your doctor and asking many questions should be the first-step taken in this long, arduous process.
There are also many other alternative treatments that are mostly 'all natural' oriented. The exotic plant, Ginkgo Biloba supposedly has several compounds that can lead to positive characteristics on cells inside our bodies. Most importantly, it is theorized that Ginkgo Biloba contains both antioxidant and anti-inflammatory characteristics that support cell membranes and regulate neurotransmitter purposes. It is a very common and well-known alternative treatment for neurological disorders and has been used in Chinese medicines for centuries and is emerging among European nations. According to the Journal of the American Medical Association, experts noticed amelioration in the cognitive symptoms of Alzheimer's. These interesting results are considered preliminary due to the participation of only two-hundred people. Because of this study, a massive federally supported research center is investigating wheter Ginkgo Biloba aides in the delaying of Alzheimer's disese.
Vitamin E is sometimes prescribed by doctors to help delay the loss of ability to finish daily tasks in Alzheimer's disease. Experts believe that vitamin E works because it is an antioxidant that supposedly protects nerve cells from deteriorating. It it very important to realize that no one should take vitamin E for Alzheimer's disease unless it was prescribed by a physician. Dosages in funded studies have been rather high and vitamin E has been known to negatively interact with other medicines.
Looking into the Future
According to the Alzheimer's Society, the next ten years in Alzheimer's research looks positive. Clinial trials will be tested for medicines that stop enzymes from cleaving amyloid-beta from APP, drugs that inhibit the amyloid-beta protein from aggregating, treatments that help diminish amyloid-beta proteins before they have a chance to clump together,"neuroprotective drugs" that help nerve cells survive, new vaccines that will destroy tangles and so on. Even though some might reason that these ideas are idealistic rather than realistic, Dr. Peterson, an Alzheimer's researcher has noted, "We have moved a great distance forward in understanding what might be the key, or, in the least, an important aspect of this disease. And we are at the threshold of developing therapies that we hope will eventually impact Alzheimer's disease." This impact that Dr. Peterson is referring to will by no means be a cure, but will hopefully be an innovative treament that diminishes the patient's and family's burden of living with Alzheimer's.
