The Pathophysiological Treatments of Alzheimer's Disease - Literature review Example

The Pathophysiological Treatments of Alzheimer's Disease Abstract Even in modern times, the treatment of Alzheimer’s disease (AD) is dependent upon the symptomatic effects of cholinesterase inhibitors as well as the use of the NMDA-receptor antagonists. Researchers have sought to examine new methods that will modify the disease and inhibit some of the core symptoms and enzymes in action amongst AD patients. Some of the present drugs are either undergoing stage two or three trials, showing the level of motivation as researchers work on ways of inhibiting amyloid beta proteins that seemingly play a huge role in the progression of dementia. Tau treatment has featured greatly as a means of treating the disease across the divide. New methods like stem cell treatment and gene therapy methodologies are also under research. Their effect – presently and in the future – on AD will also be mentioned. To examine the role of the research, this study aims at reviewing the pathophysiology of AD and examines the relevant literature on AD. It aims at creating a review that identifies the main candidate drugs and enzymes noted to play a huge role in the treatment of AD patients. It will touch on the relevant enzymes such as amyloid hypothesis, which play a huge role in underlining the importance of preclinical treatment for AD patients. Therapeutic modifications necessary for the treatment of AD will also be reviewed. Key words Alzheimer’s disease, antidementia drug, beta-amyloid, cognitive impairment, Tau treatment Introduction As it is well known, Alzheimer’s disease (AD) is the number one cause of dementia in the world. Being one of the neurodegenerative diseases, there is a need to look for ways of dealing with it. It is important to examine its pathophysiology because AD affects so many people in the world today. To tackle the issue on pathophysiology, the article will look at models and mechanisms that have been operating in the general treatment of AD across the world. Beta-myloids are the peptides of amino acids crucially involved in the amyloid plaques in brains of patients suffering from AD. Tau treatment involves the use of microtubule-bound protein in the treatment of AD patients. Cognitive impairment will be discussed because it is the intermediate stage that occurs as normal aging declines, based on cognitive measures. Anti-dementia drugs are important because they play a critical role in lessening the aggression of AD. This will then give way to a discussion on the therapeutic targets for AD modifications. Development will only occur from proper understanding of the present treatments and the impact they have on the degeneration of brain tissues. Many researchers suggest that biological and structural changes start occurring during the preclinical phase that begins before the clinical symptoms emerge. Continued research places the diagnosis of AD in various categories that have evolved from a clinical-pathological entity to a clinical-biological entity. Pathophysiology The core findings of the neuropathology of the disease have led to the discovery of certain changes in the extracellular amyloidal plaques, neuronal death, synaptic deterioration, and intracellular NFTs (Thies and Bleiler, 2011: 208). Upon the examination of tissues, it is easy to see the granulovacuolar degeneration in the patient’s hippocampus and the amyloidal deposition within the blood vessels. Research also revealed that the increased interference of synaptic activity by the amyloidal plaque initiates a series of downstream effects that lead to further increase in intraneuronal dysfunction, and this leads to the death of cells (Hardy, 2009: 1129). Pathological Mechanisms in AD One of the most common pathological models of AD is the amyloid hypothesis, and has come to be accepted by various researchers. The model posits that the overproduction of amyloid beta peptides and its consequent accumulation in the plaques lead to the formation of neuritic plaques that signal an early and central event in the pathophysiology of AD (Meraz-Ríos et al., 2010: 1356). On the other hand, the downstream phenomenon is regarded as the cytoskeleton changes arising from the intracellular aggregation to microtubule associated protein known as tau. This then forms the neurofibrillary tangles. The amyloid hypothesis is the most prevalent theory based on the available successes in its utilization in the treatment of AD. Some researchers sub-classify the amyloid plaques based on their composition (Kalaria et al., 2008: 815; Meraz-Ríos et al., 2010: 1357; Hardy, 2009: 1131). All these amyloid plaques contain β-amyloid protein (Aβ). This amino acid peptide forms after a proteolytic cleavage of APP (amyloid precursor protein) by the use of α-secretase (non-amyloidogenic), gamma (γ) and beta (β) secretases (amyloidogenic). The products commonly attained from the cleavage are Aβ1-40 and Aβ1-42 (Tripathi et al., 2012: 231). The amount of each is dependent on the activity of the major APP cleaving enzymes in progress. In AD, amyloid plays an essential role while the proteins coded as APP, PS1, PS2, SorL1 and ApoE play a huge role in the trafficking and/or processing of the amyloid generated (Mathuranath et al., 2010: 293). It is critical to note that several studies have disputed the claims that amyloids are the main cause of AD. This is owing to the fact that the amyloid plaque can be found in normal adults. In addition, it is not linked to the degree of impairment in individuals with AD dementia. Further, it is associated with cognitive improvement in some of the AD rat models used in the labs (Wiessner et al., 2011: 9325). Aβ oligomers are known to exert neurotoxic effects, while the Aβ1-42 is known to be more prone to the formation of insoluble aggregates hence more toxics in comparison to Aβ1-40. The production and clearance of toxics equilibrium seems to be affected largely by the homeostatic changes of the ageing process, with the interaction of environmental and genetic factors (Landen et al., 2013:15). Neurofibrillary tangles (NFTs) arise from the paired helical filaments (PHFs) which constitute a majority of the intracellular aggregates. These helical filaments arise from the collapse of the neuronal cytoskeleton. BFTs are an important pathological hallmark simply because of the impact they have on the disease. The structure and function of the microtubules became impaired owing to the abnormal hyperphosphorylation of the tau protein. This prohibits its ability to stabilize the alpha and beta-tubulin monomers. The tau aggregates into oligomers that form PHFs, leading to the formation of the NFTs. This process involves several protein kinases such as glycogen synthase kinase-3 beta (GSK3 β), extracellular signal-related kinase-2 (ERK2) and the cyclin-dependent kinase-5 (CDK5) (Burstein et al., 2013:10; Barakos et al., 2011:75). The GSK3β is one of the most significant Tau kinases in the neurons and, consequently, most overactive in AD. Drugs that can successfully preclude the activities of GSK3β make it easy to preclude the hyperphosphorylation of the tau protein, and the consequent dehyperphosphorylation of any of the hyperphosphorylated epitopes, and this is because of the action in the protein phosphatases (Hamada and Kiso, 2013:720). Several studies have shown that the inhibition of GSK3β is responsible for the down-regulation of the amyloidogenic cleavage of the APP compound, which shows there is a chance to cross-talk the two pathological cascades in AD and achieve desirable results. Some studies also show that the Aβ oligomers are nontoxic unless Tau is present (Chang et al., 2011:780; Landen et al., 2013:17; Mathuranath et al., 2010:294). Therapeutic targets for AD modifications Researchers note that the increased recognition of secondary and core pathophysiological mechanisms in AD will be influential in the identification of molecular targets in the development of the specific drugs. The world has realised the impact that AD has in the society and more than 200 compounds are in stage two or three of trials trying to create some pharmaceutical compounds imperative for the management of the disease (Bard et al., 2012:38-40). The compounds are in various divisions, with the most common and vital ones being the anti-amyloid drugs and the drugs targeting other pathological pathways (Carlson et al., 2011:397). The anti-amyloid drugs are further divided into other categories such as those drugs aiming at blocking or precluding the aggregation or overproduction of Aβ, while others are in favour of clearing the Aβ protein from the brain (Salomone, et al., 2012:510; Bard et al., 2012:40). Other drugs are grouped in accordance with their predominant mechanisms. Fine examples include neurotransmitter and cell-signalling agents, neuroprotective agents, glial cell modulators, and Tau-based therapies. The study of gene and stem cell therapy is also gearing up (Bard et al., 2012:40). It is noted that in most AD cases, the pathophysiological mechanisms in use are effective in the changing of soluble Aβ peptides into fibrillary oligomers and subsequent insoluble fibrils. These then accumulate within the exterior portion of the neural tissue and within the intima of the brain. The accumulation also affects the systemic vessels. Extracellular occurrence of Aβ oligomers and the presence of the fibrillary lead to a synaptic dysfunction that affects the dendritic spines and axons (Castillo-Carranza, Guerrero-Muñoz and Kayed, 2014:24). This eventually leads to neuronal loss in AD. The studies, however, are slowly demystifying AD, and providing clear answers to some of the present symptoms (Carlson et al., 2011:399). As noted by several other authors, emergence of some of the problems associated with AD begins before the clinical symptoms set out, and this is true for the intracerebral amyloidosis (Uenaka et al., 2012:25). Once the utilisation of the cerebrospinal fluid becomes active, it is easier to determine the pathological process in an AD patient at the prodromal or preclinical stages. This is done by analysing the cerebrospinal fluid and the use of molecular neuroimaging biomarkers (Carlson et al., 2011:400; Uenaka et al., 2012:26; Nordberg, 2011:6). Other therapies are still in use. The anti-amyloid therapy is a common strategy comprising of pharmaceutical compounds distinct in their actions against AD. These drugs should facilitate the clearance of the Aβ proteins, inhibit the continued production of Aβ, or prevent the aggregation of Aβ. Several pharmaceuticals have developed drugs that aim at tackling the amyloid cascade with the aim of reducing the Aβ burden amongst mild to moderate dementia AD patients (Uenaka et al., 2012:27). Studies show that these interventions work best when applied in the earlier AD stages. The noted impact is felt amongst those in the stage of incipient dementia or those in the stage prior to the conversion from MCI to dementia. If the disease can be diagnosed earlier, these drugs will even be more effective (Ballard, et al., 2011:1020). The use of new technology needs to be investigated further. The video-monitoring technologies and other tele-health technologies seem to provide new methods that can aid in the assistance of daily activities for AD patients. These technologies will be advantageous to the patients as they relate well to their environment (Hamada and Kiso, 2013:718). The demerits lie in the inaccessibility of these new technologies until they are easily attainable and cheaper for the vast majority. As such, this should be the next point of concern as researchers look for new avenues of increasing productivity amongst patients with AD. Gene therapy could be a new way of looking for new solutions to the disease. Stem cell treatments could also be reviewed to see if they are viable in the treatment of AD. These methods could have different impacts on facilitating the creation of a well-regulated treatment regimen for patient (Castillo-Carranza, Guerrero-Muñoz, and Kayed, 2014:25-26). It is critical to keep in mind that the active and passive immunisation targets lead to the reduction of intercerebral Aβ burden through the eliciting of the humoral response of the body against the Aβ peptide. This helps in the facilitation of the peptides’ clearance using the immune-mediated mechanisms (Sivilia et al., 2013:45). Findings presented by preclinical studies from transgenic mice show that active and passive immunisations were essential in clearance of the Aβ peptide, leading to improvements in cognition and behaviour (Castillo-Carranza, Guerrero-Muñoz, and Kayed, 2014:22; Hamada and Kiso, 2013:721). Other methods of treatment are also possible and common, though they border mainly on the treatment of key symptoms within AD. These may include treating depression which is one of the common sources of worsening mental losses (Ballard, et al., 2011:1020). Antidepressant drugs can be effective in this case. Neuropletics are also excellent in dealing with the delusions and psychotic symptoms common amongst patients with AD. The only side effects of these drugs are those related to individual reactions, and are good in lessening the impact of the disease amongst patients (Ballard, et al., 2011: 1022). Conclusion Pathophysiology allows for future studies that will enhance the proper understanding of the disease as a whole. A proper understanding of the β-amyloid protein is essential as the amino acid peptide forms after a proteolytic cleavage of APP (amyloid precursor protein) by the use of α-secretase (non-amyloidogenic), gamma (γ) and beta (β) secretases (amyloidogenic). The amyloid hypothesis gives a better understanding of AD, and is essential in the development of the treatment required by AD patients. 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