FOCAL CHANGES IN ALZHEIMER'S DISEASE AND CHOLINERGIC ..
16/11/2016 · The cholinergic hypothesis of Alzheimer’s ..
FOCAL CHANGES IN ALZHEIMER'S DISEASE AND CHOLINERGIC HYPOTHESIS.
The hallmarks of Alzheimer’s disease involve a loss of neurons, the shrinkage of large cortical neurons and synapses in the brain over a period of time. The result is an eventual degeneration in the cingulate gyrus, temporal and parietal lobes, the frontal cortex, brainstem nuclei and locus coruleus. In addition, the disease is characterized amyloid plaques and neurofibrillary tangles concentrated in vulnerable areas in the brain and are visible under a microscope. The plaques are made up fibrous proteins known as β-amyloid, diffuse plaques (poorly defined amyloids) and burnt-out plaques containing an isolated amyloid core. These plaques form clumps in the cortex and are hypothesized to result in a cascade of events leading to cell dysfunction and necrosis. (Yaari, 2007) Even with increasing evidence to suggest this, it is not a view supported by all. (Hardy, 1991). Neurofibrillary tangles are associated with tau, a microtubule protein that has become hyperphosphorylated and clustered together with others of its kind. Though these plaques and tangles are not only seen Alzheimer’s sufferers, those who do suffer from the disease exhibit a much larger prevalence of them than one who does not suffer from it. (Bouras, 1994).
To summarize, Alzheimer's Disease is a very common case of dementia that has significant implications the future health and well being of elderly patients. Currently, the most accepted hypothesis by scientists is the Beta-amyloid hypothesis which describes possible processing faults involved with the Amyloid Precursor Protein (APP) causing degradation of brain tissue. In most cases, epidemiology shows that age is a main factor for Alzheimer's disease to appear. Characterized by a loss of cognitive function, this debilitating disease unfortunately has no forms of prevention other than eating foods that boost cognitive functions and brain activity. In terms of future research, a novel treatment that has recently been discovered is the use of immunization to stop the development of the disease. Through techniques of active or passive immunization, the administration of antibodies causes alterations and improvement in the beta-amyloid plaques. With such a high onset rate at relatively high ages, future scientific research will be essential to continue to find new preventative measures and more effective treatments.
A New Hypothesis About Alzheimer's Disease -- …
The Tau Hypothesis suggests that the formation of Neurofibrillary tangles (NFTs) –that is characteristic of Alzheimer’s Disease– is due to the hyperphosphorylation of Tau proteins. Tau proteins normally play a role of structural support as they are responsible for microtubule stabilization. However, Tau Hyphosphorylation results in clumping of other Tau proteins which eventually develop into NFTs in Alzheimer’s Disease. Research has shown that Tau Hyperphosphorylation has led to neuronal cell death through microtubule dysfunction which disrupts the structural integrity of the cell. As a result, this has been associated with the cognitive decline that is seen in Alzheimer’s Disease (Maccioni et al., 2010).
Although Alzheimer's Disease (AD) has a number of non-modifiable genetic risk factors, there are also potentially modifiable risk factors such as hypertension, hyperlipidemia and environmental exposures that can be improved with improved with proper care and preventative measures (Patterson et al., 2008). Beginning with genetic factors, there are three gene mutations that almost always result in the occurrence of Alzheimer's Disease. These include a mutation in either the amyloid precursor protein gene, presenilin-1 gene or presenilin-2 gene (Patterson et al., 2008). In terms of non-genetic factors, studies have shown a correlation between systolic blood pressure and an increased risk of dementia. After the study group with high systolic blood pressure received antihypertensive treatment, the incidence of dementia was reduced by 50% from 7.7 to 3.8 cases per 1000 patients in the treatment group (Patterson et al., 2008). A second non-genetic risk factor for Alzheimer's is the increased risk of the disease with hyperlipidemia. Speculative studies have suggested that increased levels of total serum cholesterol levels have been linked to increased risk of Alzheimer's (Patterson et al., 2008). However, there are many studies that have downplayed the role of increased cholesterol in Alzheimer's patients. For instance, there is no correlation between cholesterol and beta-amyloid peptide production (Ledesma et al., 2005). Despite the many factors leading the Alzheimer's, the consumption of several medications have been known to reduce the risk of the disease. These primarily include non-steroidal anti-inflammatory drugs (NSAIDs) and vitamin supplements (Patterson et al., 2008). Follow-up studies revealed that although the consumption of NSAIDs does not directly reduce the risk of Alzheimer's, patients who took an NSAID such as Naproxen were protected from the onset of AD by 67% compared to the placebo (Imbimbo, 2010). More specifically, it has been hypothesized that the consumption of NSAIDs might only be beneficial in the early stages of AD, during the initial Beta-Amyloid deposition process (Imbimbo, 2010).
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Figure 4:This figure shows a simplification of the cascade of events that occur in Alzheimer's disease as predicted by the Amyloid Hypothesis. (Karran, 2011).
The biochemistry or course of actions that results in Alzheimer’s disease is not yet definite. Many hypotheses have been established over the years in order to explain the phenomenon. Of all of the existing theories, three have gained ample recognition and support in comparison to the rest. Before examining the theories below, it is important to note that there is no causational link clearly identified in the literature. The three most popular hypotheses include: Amyloid Hypothesis, Cholinergic hypothesis and Tau hypothesis.
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One of the older theories, the cholinergic hypothesis states that Alzheimer’s associated brain tissue degradation is a result of the deficiency in the neurotransmitter acetylcholine. Research now shows that there isn’t a causational relationship acetylcholine levels and the onset of Alzheimer’s disease. It is shown, however, that lower levels of acetylcholine are present in patients with the disease and this may be due to brain tissue damage. In the recent past, the neurotransmitter has been proposed to be a potential causal agent in the formation of aggregates and neuroinflammation. (Shen, 2004)
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Karran, E., Mercken, M., & Strooper, B. D. (2011). The amyloid cascade hypothesis for Alzheimer's disease: An appraisal for the development of therapeutics. Nature Reviews Drug Discovery Nat Rev Drug Discov,10(9), 698-712.
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Maccioni, R. B., Farías, G., Morales, I., & Navarrete, L. (2010). The revitalized tau hypothesis on Alzheimer's disease. Archives of medical research, 41(3), 226-231.
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