Alzheimer's Degenerative Disease

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

In neurofibrillary tangles, axons become twisted to form paired, helical filaments (PHFs) (Scheibel 1996). The PHFs are predominantly composed of the protein tau, a microtubule-associated protein (Forsyth and Ritzline 1998). Normal tau protein promotes axonal integrity and transport by playing an important role in the assembly of microtubules throughout the nervous system. The gene responsible for tau synthesis is subject to alternative splicing and as a result, six isoforms of tau are found in the human brain (Buee et.al. 2000). These isoforms vary in their state of phosphorylation, altering the proteins’ binding affinity for microtubules. As observed in the neurofibrillary tangles of AD, pathological tau is hyperphosphorylated. Research suggests that this abnormal phosphorylation state is attributable to an imbalance in the regulation of tau kinases and phosphatases: either over-activity of kinase in the brain tissue or inactivity of the corresponding phosphatases (Drewes et.al. 1992). Hyperphosphorylation of tau initiates destabilization of microtubules, irregular axonal transmission, and ultimately, neuronal death (Figure 1). While some degree of tangling is a normative sign of aging, large concentrations of neurofibrillary tangles are well correlated with dementia and Alzheimer’s disease (Munoz 2000).

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

Alzheimer’s disease is a common problem in today’s society and within the older population this disease makes up the largest form of dementia. Although it is a problem in mainly older people, this disease can still occur in the younger population also. People in their 30s-50s can be diagnosed with this disease, even though it is not as common as people in their 60s-90s. The number of people with Alzheimer’s in the U.S. is close to five million and is expected to double within the next 30 years. With our modern medicine and advancements one would think a cure would be available, however, getting to the cause of the disease is a major factor. The cause of Alzheimer’s disease is one that is very debatable and questionable and most likely is a result of multiple factors rather than one. The main issue with finding the cause is because this disease affects the brain and can

Alzheimer's seems to be a degenerative disease that affects everyone no matter the ethnic group one associates themselves with. Alzheimer's is a form of dementia, which is the general medical term for memory loss and the diminishing of intellectual abilities that eventually affects one's daily life. An ethnic group that is experiencing a growing rate of Alzheimer's is Japanese Americans. Several longitudinal studies of Japanese Americans have found rates of Alzheimer's Disease comparable to those found with older non-Latino white populations in the United States (Lee, Melichar, Musselman, & Yoo, 2015). Although studies have shown that rates are comparable for Japanese Americans versus the American majority, studies are consistently showing

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 the six leading cause of death in America with its major cause still unknown. Scientist understand that even before early onset symptoms appear there are communication errors between the neurons of the brain. As the disease progresses, family members often notice that their loved ones are more forgetful then normal. The disease progressively worsens until one is unable to recognized loved ones, has difficulty speaking, walking, and even swallowing. The brain of one with advanced Alzheimer’s is actually radically different from that have a healthy brain.

Background: Dementia, loss of intellectual abilities that is severe enough to interfere with social or occupational functioning, is a major socioeconomic problem. Two of the most common causes of dementia are AD (comprising 50-70% of all cases) and FTD, which makes up to 50% of dementias before age 60. Though there have been major efforts to therapeutically treat these diseases, these dementias at present are not curable. AD is characterized by early memory deficits, followed by gradual erosions of other cognitive functions. In AD, healthy brain tissue degenerates, causing a steady decline in memory and mental abilities such as abstract thinking, disorientation, loss of judgment, difficulty in performing familiar tasks, and personality changes. Several studies have suggested the importance of microtubule dependent axonal transport in dementia and that impairments in axonal transport will negatively affect the health of neurons (reviewed in Liu et al., 2012). Molecular motors such as kinesins and dynein’s transport proteins, RNAs and organelles along microtubules. Kinesin transports towards distal processes from the cell body and dynein transport from the distal processes towards cell body of neurons. Two elegant studies demonstrated that a reduction in tau protein level, a microtubule associated protein, is sufficient to improve memory loss in mouse models of neurodegenerative diseases. In the

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by β-amyloid plaque formation caused by aggregation of β-amyloid42 within the brain leading to a progressive decline in cognitive function and memory loss (2). Hyperphosphorylated tau protein is occasionally found in brains of AD patients with advanced pathology however, it is not necessarily an indicator of AD but considered a sign of disease severity (2, 4, Kosik et al, 1986). AD is separated into two subcategories following the simple sporadic and familial disease classifications, early-onset AD (EOAD) which develops in individuals between 30 and 60+ years of age and late-onset AD (LOAD) which develops in individuals 60 years of age or older (2). Familial AD may

There are two important physiological abnormalities that define the disease: amyloid plaques and tau tangles. Abnormal protein deposits throughout the brain form amyloid plaques and tau tangles. Amyloid is a normally harmless protein that appears throughout the body. Cleavage of the amyloid precursor protein by β-secretase and γ-secretase leads to the formation of beta-amyloid, a toxic version of the protein, which leads to the death of neurons. While the mode of action of beta amyloid is still not definitively known, a 2012 study by the University of Michigan supports the idea that it damages neuronal membranes (Moore). According to this theory, the plaques poke tiny holes in the membrane, allowing calcium to flow into the neuron uncontrollably, leading to the eventual death of the neuron. Another theory is that the beta amyloid breaks down to form free radicals that attack the neurons. The degenerated neurons and the amyloid protein combine to form sticky clumps, known as amyloid plaques, that the body is incapable of breaking down naturally. As a result, these plaques build up throughout the brain, leading to the loss of connections between neurons. According to research, plaque formation first occurs in the hippocampus, which plays a vital role in memory formation. Overtime, additional brain structures are affected, and significant brain tissue shrinkage

Alzheimer 's disease is a severe illness that affects the brain and leads to gradual memory loss, reduced intellectual ability and deterioration function of thinking. Alzheimer 's disease (AD), the most common type of dementia, is a progressive neurological disorder that increasingly robs individuals of cognitive, behavioral, and functional skills (Demakis, 2007). The reason for the appearance this disease is a collection of disorders in the brain due to which its cells are dying partially. In the case of the early stage of Alzheimer disease when the disease is not carried out the appropriate treatment mental functions are destroyed completely. The disease is diagnosed mainly in elderly people. The symptoms of Alzheimer 's disease, were first isolated by German psychiatrist Alois Alzheimer, is one of the most common forms of dementia. “As is well known, Alzheimer first described the disease that would eventually be named for him at a meeting of the South West German Psychiatrists in Tubingen in 1906. It was a brief report of the case of a 51year old woman who developed progressive dementia, accompanied by focal signs, hallucinations and delusions. On post-mortem, her brain was found to contain numerous senile plaques and a newly observed pathological structure – densely twisted bundles of neurofibrils, or neurofibrillary tangles, which were made visible to microscopic observation through a newly developed silver-staining technique.” (Perry, G. et. all, 2006). Typically, the

The research into Alzheimer's Disease has come a long way since 1906 when it is was discovered by Alois Alzheimer. He detected microscopic brain tissue changes called senile and neuritic plaques in deceased patients. These are chemical deposits consisting of protein molecules called Amyloid Precursor Protein(APP) that are fundamental components of a normal brain. However in the brain of an Alzheimer patient, an enzyme cuts the APP apart and leaves fragments in the brain tissue. These combined with degenerating nerve cells cause the plaques or lesions. These lesions are found in many sections of the brain including the hippocampus which regulates emotion and memory, the basal forebrain, and especially the basal nucleus of Meynert and the cortex, where the memory function is located.(2) Another sign of a diseased brain are neurofibrillary tangles, which are malformations within nerve cells.

Alzheimer’s disease is the most common form of dementia and is characterized by the degeneration and death of brain cells that causes a loss of mental function. Although neuronal loss is not considered a normal part of aging, age is a significant risk factor for Alzheimer’s disease (AD) (Lindsay et al., 2002). Hallmarks of AD include tau tangles and Amyloid-β plaques, whose interaction is thought to lead to neuronal death (Ittner & Götz, 2011). At present, there is no singular cause identified for AD, and further study is required before a cure can be developed. One proposed link to AD is a mutation in Microtubule Associated Protein Tau (MAPT), coded by the MAPT gene located on chromosome 17 (Lee, Goedert, & Trojanowski, 2001). Tau protein is normally soluble and functions to stabilize microtubules within axons. However, mutations in MAPT can cause Neurofibrillary Tangles (NFTs) comprised of hyper-phosphorylated tau protein to collect within neurons and spread throughout the brain (Clavaguera et al., 2009). These tau tangles are detergent-insoluble and impair axonal transport to an extent (Zhang et al., 2012). Transgenic mice expressing mutant human P301S tau protein exhibit synaptic dysfunction followed by hippocampal and cortical neuronal loss (Yoshiyama et al.,

Furthermore, these fragments were only present in regions that are implicated with AD-related cognitive deficits, the hippocampus and the neocortex (Brecht et al., 2004). Shi et al. (2017)’s article follows through these results in that accumulation of phosphorylated tau was also found in an age dependent manner in AD-vulnerable regions, particularly the hippocampus (Figure 1b). Phosphorylated tau also accumulated in an ApoE isoform and age dependent manner, such that neurons overexpressing ApoE4 showed increasingly higher levels of phosphorylated tau as the mice get older but not in ApoE3 overexpressing mice (Figure 1A) (Brecht et al., 2004).

The pathophysiology surrounding neurofibrillary tangles and hyperphosphorylated tau is poorly understood, but there are 2 theories as to how this works: