Genetic Interaction Between Lsd1 And Hyperphosphorylated Tau

Alzheimer 's disease (AD) was discovered by a German doctor Alois Alzheimer in 1906 when he found amyloid plaques and neurofibrillary tangles in the autopsy of a woman who died of an unknown mental disease. The extracellular amyloid plaque deposits, composed of insoluble amyloid-Beta peptide were hypothesized to be the main etiological factor. “The most important abnormality is an excess of Amyloid-beta peptides brought about through either overproduction or failure in degradation.” (Uzun, Kozumplik, & Folnegović-Smalc, 2011) Later, it was discovered that intracellular neurofibrillary tangles composed of hyper-phosphorylated, helically-paired tau

Alzheimer’s disease known to be a neurological disorder of the central nervous system is an irreversible disorder in which brain cells deteriorate resulting to loss of our cognitive functions, primarily memory, movement coordination, reasoning and judgment, and pattern recognition. In its advanced stage, all memory and mental functioning could be lost (Healthcommunities.com, 2016). This disease is known to be caused by parts of the brain shrinking (atrophy), which destroys the structure and function of particular areas of the brain (Nhs.uk, 2016). Although the exact cause to this process is not known, research suggest that in the brains of patients with Alzheimer 's disease, scientists have found amyloid plaques (abnormal deposits of protein), neurofibrillary tangles containing tau and acetylcholine a chemical imbalances (Nhs.uk, 2016).

1.1 Dementia is an umbrella term for a range of diseases that affect memory, behaviour and motor skills. The causes vary depending on the disease but largely the presence of “plaques” and “tangles” on the neurons of the brain is found in people with Alzheimer’s. Plaques are protein that the body no longer breaks down and allows to build up; these get between the neurons and disrupt the message transmission. Tangles destroy a vital cell transport system made of proteins. The transport system is organised in orderly parallel strands like rail tracks. In healthy areas a protein call “tau” helps the tracks stay straight but in areas where tangles

The cause of Alzheimer’s is still mostly unknown except for one to five percent where genetic mutations have been identified as the cause. However there are many competing hypotheses that try to

The damage then alters the permeability of the axon membrane resulting in a large inflow of calcium, and the release of apoptotic cell death mediators that may be responsible for the phosphorylation, shortening, misfolding and aggregation of tau proteins (2011). Thus, the neurodegeneration that begins in the cortical sulci and initially surrounding only small blood vessels, spreads to larger portions of the brain. This tau-toxic factor associated systemic degeneration in regions of the brain that regulate emotion, memory, and other cognitive functions, leads to the physical and neuropsychological sequelae of CTE (McKee, et al., 2010).

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most widespread age-related neurodegenerative diseases. Both diseases impact a considerable number of people, where AD occurs in around 10 percent of the population greater than the age of 65 while PD occurs in roughly 1 percent of the population above the age of 65. AD is considered to be the most widespread cause of dementia, characterised by the progressive memory and cognitive deficits which impair ones day to day activities. The pathological hallmark of AD comprises of extracellular accumulation of senile plaques consisting of mainly amyloid-beta (Aβ) peptides, along with neurofibrillary tangles which are composed of the phosphorylated tau protein, located in the hippocampus and cortex. Conversely, PD is considered to be the most widespread movement disorder that is characterised by symptoms such as rigidity slow movements, resting tremor and other instabilities. The extreme loss of dopaminergic neurones in the substantia nigra is what defines PD, as the loss of this nerve cell can be linked to Lewy bodies containing aggregates of a soluble protein called α-synuclein.

Alzheimer’s disease is named after Dr. Alois Alzheimer who first discovered deviations from normal tissues of healthy individuals in the brain tissue of a lady in 1906. The woman, who showed symptoms of erratic behavior, loss of memory, and problems with communication, died of a then unfamiliar mental disorder. This led Dr. Alzheimer to investigate the cause of her unusual death. He assessed the brain of the woman and found that there were many anomalous masses (amyloid plaques) and intertwined bundles of fiber (neurofibrillary tangles). Scientists today have pinpointed the qualities of Alzheimer’s to be a) tangles in the brain (neurofibrillary tangles), b) plaque in the brain (amyloid plaques), and c) loss of connections among nerve cells.

Alzheimer’s disease or AD is an incurable disorder of the brain that results in loss of normal brain structure and function. In an AD brain, normal brain tissue is slowly replaced by structures called plaques and neurofibrillary tangles. The plaques represent a naturally occurring sticky protein called beta amyloid and in an Alzheimer’s brain, sufferer’s tend to accumulate too much of this protein. Neurofibrillary tangles represent collapsed tau proteins which, in a normal brain along with microtubules, form a skeleton that maintains the shape of the nerve cells. In Alzheimer’s disease, the tau proteins break loose from their normal location and form tangles. Without the support of these molecules, nerve cells collapse and die. As normal

In order to effectively treat and reduce the symptoms of Alzheimer’s, we still need to learn more about b-amyloid buildup and tau protein associated neurofibrillary tangles in the brain, which are characteristic of the disease. Similarly, we need to find if these are linked to APOE4 as those who inherit APOE4 have a greater chance of developing Alzheimer’s disease because is does not break down proteins (Molenda-Figueira, 2015).

There are more than 5 million people in the U.S. with Alzheimer’s and it causes 500,000 deaths a year in the U.S. alone. This disease is growing quickly, by the year 2050 it is expected that there will be 16 million people diagnosed with it in the U.S. and 100 million worldwide. The goal is to overcome this disease by the year 2025, which is possible, but very challenging. A neurologist at Harvard Medical School, by the name of Rudolph Tanzi said, “We will be able to identify those most at risk based on their genetics, do imaging tests to determine the onset and then institute therapies that nip it in the bud”(Marsa). This is great news because it will help the doctors get a jumpstart on those who are at risk of getting the disease. Memory loss is the main issue of Alzheimer’s which is caused by tangles in the brain. Without the tangles there is no disease, the tangles are what cause it. Alzheimer’s also causes shrinkage to the brain. Moving ahead with a cure, researcher need to figure out how the protective mutant gene works, making a treatment to copy what it does

Alzheimer’s disease or also known as Alzheimer’s is the neurodegenerative most common type of dementia that usually commences in older people; this is a very complex brain disorder that interferes with the affected individual’s life as soon as it initiates its mission of destroying the brain, it progresses slowly and gets worse over time from mild forgetfulness to brain impairment. Furthermore, scientist do not fully understand what causes this irreversible disease that has no cure or prevention and it may be inherited. Alzheimer’s disease seems to be caused by unusual plaques (beta-amyloid) and tangles in the brain, damaging important areas of memory and learning (Hanyu et al., 2010), together with, dementia is defined as a loss of mental

Awareness is necessary in understanding this disease. As humans continue to live longer, the risk for many illness and deficiencies begin to present them. Alzheimer’s and dementia is one of the many problems that plague the aging population. Understanding brain aging and reducing risk for neurological disease with age requires searching for mechanisms and treatment options beyond the age-related changes in neuronal

The causes of Alzheimer’s are not yet fully understood; however, its effect on the brain can be understood. Alzheimer’s disease - insidious, attacking and terrifying - stalks and then murders brain cells. A brain afflicted with Alzheimer’s disease has a decreased count in cells and connections among cells. The more brain cells die, the smaller the brain of a person with Alzheimer’s gets. When doctors examine a brain with Alzheimer’s tissue, they see two types of deformities that are known to be trademarks of the disease. The first trademark is known as plaque, which is a cluster of a beta-amyloid protein that may damage and kill brain cells in a number of ways, including blocking with cell-to-cell communication. Whereas the final cause of brain-cell death in Alzheimer’s remains a mystery, the groups of beta-amyloids that cover the brain cells are a sure sign of the disease. The second trademark of Alzheimer’s is the tangle. Brain cells are reliant on internal support and a transport system to bring nutrients and other essentials to their distant regions. This system needs a protein called tau. In Alzheimer’s, strings of tau protein roll into abnormal tangles inside brain cells, concluding in failure of the cell's transport system. This breakdown of the system is powerfully involved in the decline and death of brain

The two main biomarkers of AD are beta-amyloid (Aβ) and tau and are highly debated in regards to their function in AD pathophysiology. The production of beta-amyloid plaques may be due to improper functioning of the proteasome preventing the breakdown of Aβ. Support for this theory comes from research indicating that the 20S proteasome is responsible for Aβ degradation and that alterations to the kinetics of the proteasome increased Aβ levels (Zhao & Yang, 2010). These accumulated levels of Aβ plaques leads to lower levels of soluble Aβ, which is needed for memory formation. This may occur through activation of nicotinic acetylcholine (ACh) receptors and AChE levels are drastically reduced in AD patients. (Garcia-Osta & Alberini, 2009). The microtubule stabilizing protein tau may become hyper-phosphorylated in AD due to the presence of high levels of Aβ. Hoshi et al (1996) showed that Aβ exposure to rat hippocampal neurons in vitro produced increased levels of the tau kinase GSK-3 (glycogen synthase kinase 3) which in turn hyper-phosphorylated tau leading to cellular death. (Hoshi et al., 1996) The neurotoxicity of tau may not be produced solely because of GSK-3, but may be due to

One of the primary events that are implicated in these diseases is the amassing of distinct protein-based macroscopic deposits in the brain, leading to neuronal apoptosis [7]. Alpha synuclein was found to be the major component of lewy body, which is the hallmark of degenerating neurons in Parkinson’s disease (PD) [8]; whereas Alzheimer’s disease (AD) is marked by the existence of intracellular lesions of tau which forms neuro fibrillary tangles (NFT) and extra cellular lesions called plaque, consisting β-amyloid (Aβ) peptide as a major component [9]. In ALS, cytoplasmic lesions of SOD1 protein have been found in transgenic mice over expressing mutant SOD1, leading to the development of an array of neurodegenerative changes consisting of vacuolization and swelling of mitochondria as well as axonal degeneration [10]. These deposits are a classic disease signature; although the main protein component is dissimilar in each disease, they have parallel morphological, structural, and staining