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Introduction
Alzheimer’s disease is a progressive neurodegenerative disease that leads to memory deficits and eventually fatality. Around the world, one person is diagnosed with Alzheimers every 2 seconds currently affecting around 40 million people worldwide but by 2050 it will be 150 million people. For people older than 85 their chance of having Alzheimers is almost 1 in 2. Today of the top ten causes of death worldwide Alzheimers is the only one we cannot prevent, cure, or even properly slow down. Though the number of people with Alzheimers disease is increasing each year because of extended life expectancy universally, present treatment can only slightly relieve the symptoms of Alzheimers disease. There is no established treatment to cure or avert the disease, perhaps owing to a lack of understanding concerning the molecular mechanisms of disease pathogenesis. Recent studies have acknowledged the amyloid hypothesis, in which the neuropathogenesis of AD is thought to be activated by the accumulation of the toxic amyloid beta protein in the central nervous system. The knowledge that may be critical to unscrambling the unknown pathogenic pathway of Alzheimers disease has remained exposed. This essay focuses on the neurotoxic form of amyloid protein in the brain of people diagnosed with AD and also reviews current advances in the analysis of these accumulation mechanisms alongside the knowledge impact on therapeutic strategies for this disease.
Alzheimer’s disease is a progressive neurodegenerative disease discovered by a German physician called Dr. Alois Alzheimer in 1906. This disease can happen in anybody at any stage in life; Although, it is most frequent among the aging and is rarer in the youthful population. However, Alzheimer’s disease develops differently for each individual, it generally gives similar symptoms; in the premature phases, the most common deficiency is a recollection of recent proceedings or short-term recall mutilation. As the disease develops, Alzheimer’s disease patients progressively lose their aptitude to contemplate and reason distinctly, make decisions, solve complications, interact with people, and self-care. In addition, there are symptoms such as mood swings, irritability, confusion and aggression, vicissitudes in character and behavior, difficulties with attentiveness and spatial coordination, difficulty with language, and long-standing recollection loss, all of which can distress a person’s everyday life. Alzheimer’s disease can reach the stage of the death of the suffering patient in the ultimate stages by causing, brain death, malnutrition, and organ failure due to the number of nerve cells that have decreased. Today, Alzheimer’s disease affects more than 26.6 million globally, and its pervasiveness is escalating radically every year. By 2050, the quantity of Alzheimer’s disease patients is estimated to quadruple to more than 106 million worldwide, and it is projected that 1 in 85 people will be diagnosed with the disease. Following numerous decades of research, Alzheimer’s disease is considered a complex disease that outcomes from both environmental and genetic factors, such as the family history of Alzheimer’s disease age, and gender. Conversely, the definite stimulant of Alzheimer’s disease is still unknown. Moreover, Alzheimer’s disease is not yet fully understood, however, its histopathological features in the brain are well understood. So far, there have been a large number of studies that have conjectured disease mechanisms for Alzheimer’s disease, of which most of which back the amyloid hypothesis. It is believed that the neuropathogenesis of this disease may be activated by the accumulation of toxic amyloid in the central nervous system (CNS). Therefore, a richer awareness of how these toxic proteins accumulate in the brain of Alzheimer’s disease patients is crucial for the development of more effective therapeutic and precautionary approaches. Possible mechanisms linked to overproduction or impaired clearance of these amyloids that may lead to their abnormal deposition in the brain as well as some possible molecular targets for Alzheimer’s disease treatment will be the focus of this review.
Amyloidosis
Amyloidosis is a mass group of proteins in which a specific protein called amyloid is accumulated within several tissues and organs. Recent research has suggested that this is due to the build-up of a protein in the brain called amyloid beta protein. Amyloid beta protein is a sticky protein that has the tendency to clump together and is produced from a large precursor protein. The amyloid precursor protein clumps together the amyloid beta protein and these clumped proteins interact with the surface of our nerve cells and then cause problems that we see in people who have Alzheimer’s disease. If we can understand how amyloid is produced, how it clumped together, and how it is interacting with the nerve cells, then there is potential to disrupt the processes and produce a potential treatment for Alzheimer’s disease. Trying to understand the process that is going on in the brain causing Alzheimers disease is not fully understood. If we can understand any weaknesses of Alzheimers we could exploit them as therapeutic methods for the future development of drugs.
In amyloidosis, amyloid refers to starch like and it goes back to an observation made by the German scientist Rudolph Virchow who saw mysterious deposits in the tissue that stained blue with iodine just like plant starch. Amyloids are proteins that take on an abnormal shape which makes them stick together and settle in tissues amyloidosis is the name given to the disease that develops from the tissue damage that results from the tissue deposits. Normally our cells produce thousands of proteins every moment and these proteins need to fold into a particular shape to carry out their specific function. If the protein is synthesized incorrectly, normally it is seen as foreign and destroyed by proteases. In amyloidosis there are a few different ways in which protein folding can occur, one way is when normal proteins are produced in large amounts and a small fraction of them fold incorrectly. Secondly, abnormal proteins with incorrect amino acid sequences are produced and they fold incorrectly. The misfolded proteins with amyloids start to build up. Sometimes there are simply too many of them for the proteases to handle and other times the way that they are folded makes them tough to break down. When the amyloid proteins get excreted outside the cell they tend to clump together forming a rigid insoluble structure called the beta-sheet. These beta-sheets then deposit in the extracellular space of the tissues and cause damage. So amyloidosis is a process where there are extra protein deposits, and there are many different proteins and diseases that follow this same underlying process. In general, amyloidosis can be systematic, meaning that those proteins occur in multiple organ systems or it can be localized meaning that they occur in one organ. There are two types of systematic Alzheimers, one of the types is AL amyloidosis. The A refers to Amyloidosis and the L refers to the immunoglobin light chain as the protein that gets misfolded and deposited and deposited. In plasma cell disorder, like multiple myeloma plasma cells, the bone marrow produces more light chains than heavy chains and these excess light chains leak out into the blood. Since there are so many light chains some misfold into AL proteins, and build up in various tissues.
Many years before a person becomes forgetful they will build up plaque in the brain composed of this amyloid protein, they are round neurotic plaques also known as senile and amyloid plaques which can only be seen microscopically. Shortly after the build-up of amyloid protein, tangles will build up in the brain with the Tau protein. The Plaques and tangles together mount up over decades and lead to short-circuiting of nerve cells, leading to a failure of the systems in the brain for one nerve to transfer communication to the next. In 1992 Brival Hospital studied that the Amyloid beta protein is made within everyone throughout life. Everyone does not get Alzheimer’s disease because there are genetic risk factors and environmental factors that help people handle the amyloid protein more poorly than other which lead to these people obtaining Alzheimer’s disease. There are two types of amyloidosis, systematic, where amyloid is accumulated throughout the body and localized amyloidosis where amyloid is accumulated in specific areas of a single tissue.
Systematic Amyloidosis
In AA amyloidosis previously known as secondary amyloidosis the misfolded protein comes from serum amyloid A. Under normal circumstances, serum amyloid A is a properly folded protein thats an acute phase reactant meaning that it is secreted into the bloodstream by the liver whenever theres inflammation. But when inflammation goes on for too long, like in rheumatoid arthritis, inflammatory bowel disease, and various cancers, or hereditary immune disorder like Familial Mediterranean fever, there is a lot of serum amyloid A in the blood, and a small proportion of the serum spontaneously fold incorrectly into AA amyloids, which end up accumulating within tissues creating Amyloidosis.
In systemic amyloidosis, amyloids deposit in various organs. In the Kidneys, amyloid deposits can damage the podocytes which are the cells that line the glomerulus. When the podocytes are damaged, proteins like albumin spill into the Urine which result in proteinuria, typically if there are greater than 3.5 grams a day hypoglycemia occurs. Over time with less protein in the blood, the oncotic pressure falls and that drives water out of the blood vessels and into the tissues this process is called Edema. Albumin and other proteins normally inhibit the synthesis of lipids, or fat so losing them leads to hyperlipidemia.
In the heart, amyloid deposits can make the heart walls stiff and non-compliant and this can lead to restrictive cardiomyopathy which is when the ventricle is unable to stretch out and fill up with blood. Over time this can lead to congestive heart failure. Amyloid deposits can also interfere with the electrical conduction system of the heart causing arrhythmias, and an irregular heartbeat. In the intestine amyloid deposits can damage the tips of the villi. When the Villi are damaged nutrients are not absorbed and end up in the stool. Amyloid deposits can also build up in the liver, spleen, or tongue, making them enlarge. Amyloid deposits can injure peripheral nerve fibers like the one carrying sensory or motor signals, or autonomic nerves that control things like digestion and blood pressure.
Localized amyloidosis
AL amyloidosis can too act as a localized disease, where amyloid deposition is restricted to a single organ. The area of the body disturbed varies upon the biochemical nature of the amyloid fibril protein and, constant with this, Kourelis demonstrated that IGVL gene usage is different between localized and systemic forms of the disease. Localized AL amyloidosis may initially be noticed based on its location. Standard sites related to localized AL amyloidosis include skin, brain, urinary tract, bladder, larynx, conjunctiva, and the tracheobronchial tree in the non-existence of systemic visceral dysfunction. For patients with localized AL amyloidosis that need life-long monitoring are necessary, whilst these patients have been revealed to have a normal life expectancy.
Potential treatments
The treatments for Alzheimers disease are limited. Two drugs in the one class called cholinesterase inhibitors have been around for a long time and their mechanism is that we know in people with AD start to lose a neurotransmitter called Acetylcholine. There is an enzyme that breaks Acetylcholine and this is the cholinesterase inhibitor. They give Cholinesterase inhibitors to make the enzyme less able to break down the Acetylcholine that is in the brain. Early in AD when there are still enough brain cells around to make this chemical it makes sense that this treatment would work. Later in the disease, there are not many brain cells left that are making acetylcholine so we do not know whether to give it or not toward the later stages of AD makes. Too much of a difference. The other class o drugs there is the generic name Memantine commonly known as Namenda. Memantine protects damaged brain cells from further injury from glutamine which is a normal chemical within the brain. Glutamine will attack the injured brain cells in AD and make them die faster so the Memantine will protect the brain cells a little bit longer. Neither acetylcholine nor Memantine is cured, most of the studies with these drugs indicate that they slow down the progression of AD. Some studies look t small changes in memory or function and whilst it does help a little, the drugs are not too effective. When treating a disease that has no known cure there is a tremendous placebo effect that can go along with these drugs because it looks as if they are causing a positive effect.
At the Tsai laboratory at MIT, a team established that the gamma rhythm amplitude at the 40 Hertz range was reduced in mice with AD called 5XFAD mice. More specifically, the gamma rhythm was significantly decreased in a brain region crucial for learning and memory, called the hippocampus. The diminished gamma rhythm in 5XFAD mice occurred with the accumulation of amyloid beta, which eventually becomes toxic and resulted in neuronal death and memory loss within the mice. Researchers in the lab used optogenetics to artificially correct the gamma rhythm in the hippocampus of 5XFAD AD mice. By stimulating neurons in the 40 Hertz range at the optimal gamma rhythm amplitude, they showed that amyloid beta levels were cut nearly in half. They discovered that the 40-hertz optogenetic stimulation to correct the gamma rhythm in Ad mice activated genes in the brain cells called microglia. Microglia are part of the brain’s immune system and function in part to ingest or clear away microorganisms that might cause disease. Optogenetic stimulation at the 40-hertz range activated microglia to promote the clearance of amyloid beta to create an effective treatment in humans with AD, it’s ideal to invent a non-invasive technique. The team created a sensory paradigm that uses flickering light to restore the gamma rhythm and reduce the levels of amyloid beta.
The use of natural elements from plants for medication is can help due to their low cost, availability, and safer. Nonetheless, the efficacy and safety of each natural or plant product must be established before human usage. Many herbs have been described to exhibit a neuroprotective effect in Alzheimers disease. Herbal medications have the mechanisms essential to Amyloid beta accumulation, which is now thought to be a principal instrumental pathway in Alzheimers disease pathogenesis, which could be the most efficient approach to averting the disease. For example, cerebral blood plants may be beneficial, the ethanolic. part of the Morinda citrifolia fruit, containing its chloroform and ethyl acetate segments, was recently stated to considerably improve cerebral blood flow in a mouse model, signifying that Morinda citrifolia may prevent Amyloid beta buildup. Increased oxidative stress and AChE undertakings, which are common problems in AD, were also diminished by the ethanolic part of Morina citrifolia, which upkeeps its prospective belief to prevent AD. Changing the guideline of the appearance of genes involved in amyloid genesis may be an additional mechanism of neuronal defense by plants.
Conclusion
To conclude, Alzheimer’s disease is a progressive neurodegenerative disease that leads to memory impairment and eventually fatality. Though, there is presently no established medication to stop or cure the development of the disease. This essay fixated on the amyloid hypothesis, which believes that the neuropathogenesis of Alzheimer’s disease is activated by the build-up of toxic Amyloid beta in the Central Nervous System. I underlined the significance of the current treatment used to try and tackle Alzheimers. In addition to this, I wrote about the possible use of medicinal plants as an alternative to current treatments.
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