Its very common and accounts for 60-80 percent of the dementia cases in the united states. Alzheimer’s is caused by the buildup of a type of plaque in the brain. It interrupts the electrical signals between neurons that normally direct thoughts and memories in the brain. The result is that the person slowly becomes more and more forgetful. A certain amount of forgetfulness is normal with aging but those suffering from Alzheimer’s disease develop far more disrupted thinking patterns. People suffering from AD eventually lose the ability to recognize familiar people, even family memories. Sometimes, in late stages, their personalities change also, they become paranoid, and they become completely unable to take care of themselves. There is no cure for the disease and the medications available only treat the symptoms and show no promise in slowing the progression of this disease. Previous studies on aspirin and heart health showed a link between aspirin and Alzheimer’s disease. These studies showed that regular use of NSAIDs, including aspirin showed the users had a 20% lesser chance of developing Alzheimer’s disease.
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Doctors and scientists do not know what exactly causes this disease but they have a pretty good idea. The major issue seems to be a minuscule brain protein fragment called beta-amyloid. This beta amyloid is a small piece of a larger protein called amyloid precursor protein (APP). When APP is turned on to do its normal job, it is cut by other proteins into smaller sections that stay inside and outside cells. when this protein is cut, one of those cut pieces formed is beta-amyloid and when that forms into clumps it produces those dangerous amyloid plaques. Dr. Kalipada Pahan who is a professor of neurological sciences at Rush University, gather a team of professors and decided to use this connection between aspirin and Alzheimer’s diseases to carry out experiments that would show in depth how exactly did the aspirin help with the disease. Dr. Pahan felt that developing drugs that can reduce the amount of beta amyloid, which can in turn form amyloid plaques, is an important area of research because these plaques are one of the pathological indications of this disease. Dr.Pahan and his team developed an experiment that entailed giving aspirin to mice with a mouse version of AD. He and his team genetically modified mice so that they had symptoms that resembled AD and so that they resembled the brain pathology of Alzheimer’s patients.
They also measured the amount of beta-amyloid that built up in the brains of the mice. Dr.Pahan and his team gave aspirin to the mice by mouth for about a month then took note of how much of amyloid plaque built up in the parts of the brain affected most by Alzheimer’s disease. The study revealed that aspirin stimulates the waste-clearing lysosomes and reduces pathological plaque in mice. Lysosomes are supposed to be the waste deposit center for the cell. They are the bad protein clean up system inside all animals that consist of cells that capture and internalize bad proteins. The lysosomes are the components of these cells that break down the captured proteins. In the brain these lysosomes apparently lack the ability to properly do their jobs in patients of AD. Scientist assumed that these lysosomes were degrading the beta amyloid protein before it could turn into amyloid plaques but that’s not the case. These lysosomes that accumulate around the plaques are uncommonly embellished with beta secretase. This beta secretase is the enzyme that starts the production of the beta amyloid. These nonfunctional lysosomes cannot break down the beta amyloid so the ability to increase lysosomal clearance in the brain of AD patients has come about as a very promising strategy in slowing the progression of this disease. The experiment also revealed that aspirin intake upregulated a protein called TFEB. TFEB is transcription factor EB and it is known as a key player in lysosomal biogenesis.
A transcription factor is a protein that will bind to specific parts of the DNA as either and inducer or a repressor. Transcription factor EB exhibited activity that shows how it’s able to bond to the promoter region of autophagy genes and activate autophagosome biogenesis. The over expression of TFEB has been shown to provide positive effects in many mouse models more recently the mouse models of the most familiar genetic explanation of liver disease, the ?±1-antitrypsin deficiency. TFEB upregulation has also been proven to reduce obesity and metabolic syndrome therefore upregulation of intracellular removal by TFEB has also been proven to be beneficial in multiple mice models. Aspirin is a commonly used medication and thru multiple test it was shown to upregulate TFEB and boost lysosomal biogenesis in brain cells. The aspirin was also shown to bring about the activation of PPAR?± encourage the transcription of TFEB in a PPAR?± fashion. PPAR?± stands for peroxisome proliferator-activated receptor ?±. What PPAR?± does is when activated, it functions as a ligand-activated TF to regulate the many biological processes that occur within the body. In the 1960s scientist treated a model of rats with Clofibrate, which is now used for controlling the high cholesterol level in the blood, and the outcome of this is that it showed for the first time that the Clofibrate induced peroxisome proliferation in the rats.
A while after PPAR?± was shown to control and help regulate the expression of genes involved in regulating homeostasis, immune response, cell growth and differentiation and many other functions. In the mice model for AD, PPAR?± was proven to master regulators of metabolism which is why it is important when it comes to developing medications and treatments that can help slow the progression of Alzheimer’s in the elderly.
7 month old male and female mice were given low dose aspirin (2 mg/kg body weight/ day) for 30days. The Mice were anesthetized with ketamine-xylazine then half of the brain from each mouse was dissected so assays can be performed on them. the brains were incubated in 4% paraformaldehyde then they were incubated in 30% sucrose overnight at 4 degrees Celsius. They were then rinsed with cold ethanol then rinsed with phosphatebuffered saline 3 times. The brains were then incubated then inspected under a fluorescent microscope. To observe the DNA-binding activity of PPAR?±, it was analyzed using a non-radioactive electrophoretic mobility shift assay.
The cells were then washed with phosphatebuffered saline the placed into tubes to go into the centrifuge for 5 minutes. They then took the supernatant and placed it in lysis buffer and ran it thru the centrifuge again. After that they took the supernatant put it in a high salt buffer then placed it in the centrifuge for 15 minutes. They then placed it on a polyacrylamide gel for 2 hours then observed it under the Odyssey Infrared Imaging System. Results It was proven that aspirin was able to increase the lysosomes in the brain and this was further proven by using an Electron microscopy which showed the different stages of autophagic vesicles in aspirin-treated astrocytes. They then wanted to know if aspirin could alter TFEB. TFEB was increased after the first treatment with the aspirin. The western blot showed larger quantities of TFEB with the different doses of aspirin. The largest increase in TFEB was shown 12 hours after the aspirin treatment was done.
Majority of the TFEB activity was found in the cells surrounding the nucleus in cells compared to the control group. these results of this study showed that the aspirin activated lysosomal biogenesis by upregulating the TFEB regulator. They discovered that when PPAR?± is present, the aspirin binds to it and triggers a domino effect causing increased nerve cell interactions in the hippocampus which is a place in the brain were memories are formed. The mice were showed to have an increased ability to learn their way thru mazes after the aspirin was administered. Even though this study has shown positives effects from the use of aspirin on the brain of the genetically modified mice, aspirin should not be used as a way to treat AD because all of the side effects are not known and its not specifically proven to help with AD. For aspirin to even help with lysosomal production the receptor for PPAR?± need to be present in the patient. If it is not there in great numbers then the patient won’t benefit from the aspirin at all.
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