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Examining the potential use of beta secretase enzymes in the treatment of Alzheimer's Disease
Examining the potential use of beta secretase enzymes in the treatment of Alzheimer's Disease
Efforts to develop a drug for Alzheimer's disease, which mostly affect people in older age, have not been successful. Instead, most of the treatments offered often target the behavioral symptoms of the affected individual, but not the cause of the disease. The occurrence of the disease has largely been related to amyloid plaques in the brains of the affected individuals. The plaques are composed of amyloid-beta peptides with beta secretase as the enzyme facilitating the generation of amyloid beta. The successful development of a drug for the management of this disease often targets the BACE1, which lowers amyloid beta production and eventual prevention and a possible treatment of Alzheimer's disease. This study provides an account of various clinical trials on mice with the use of beta secretase enzymes desire to offer successful treatment of AD (Nishitomi et al., 2006).
In the study titled "The ?-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease," Vassar and Kandalepas (2010) showed that familial Alzheimer's disease is caused by mutation in the amyloid precursor proteins and prepenisilin genes. It is further evident from their clinical trial that amyloid beta has a role in the causation of the AD. The role of the study sought to evaluate the possible approach of reducing the production of amyloid peptide, which would eventually result in the elimination of possible occurrence of the disease. The presence of beta and gamma secretase enzymes ensure that the amyloid beta produced is broken down in the brain through the process of endoproteolysis. Amyloid peptide is the pathogenic form of the useful peptide in the brain, and the inhibition of the beta secretase enzyme will limit the occurrence of AD (Vassar & Kandalepas, 2010; Dominguez et al., 2005).
The successful trial of the mice by Vassar and Kandalepas (2010) was successful with the basic knowledge of the existence of BACE1 enzyme. The experiment showed that BACE1 was a beta secretase through the generation of BACE1-/- mice. In fact, the breeding of the mice in APP transgenic ones resulted in amyloid pathology and amyloid peptide production. It is also evident from the study that total inhibition of BACE1 is associated with adverse side effects on mice and may not be practical in human beings (Nishitomi et al., 2006). Therefore, moderate inhibition of the same would be the better option adopted, especially when limiting the number of toxins exposed to the CNS. The mild inhibition of the BACE1 reduces the possible occurrence of Alzheimer's because the amyloid peptide production is reduced. The researchers also suggested the need for drug makers and physicians to appreciate the role played by BACE1 inhibitor when minimizing the toxicity of the brain. Further studies in the BACE1 and understanding and the role it plays in causing AD will be critical in the development of appropriate therapies related to the disease (Vassar & Kandalepas, 2010: McGowan et al. 2005).
Lu, et al. (2012) undertook a study on mice cells with the aim of identifying the role of various inhibitors on BACE1 and the causation of Alzheimer's disease. The inhibitor used was the L655,240 transferred to the beta secretase (BACE1) with the use of fluorescence energy. The neurodegenerative nature of the disease is evident from the study undertaken; various physicians have opted to utilize diverse inhibitors thought to alleviate the effects of the disease. Some of the commonly used inhibitor drugs that have been shown to limit the occurrence of the disease include acetylcholinesterase inhibitors antihypertensive drugs, (AChEIs), and N-methyl-D-aspartate (NMDA) antagonists. This is the basis of the clinical trials undertaken by Lu et al., which targeted the BACE1. It is important to appreciate the role of the beta amyloid peptide in initiating the occurrence of AD. The peptide 40 and 42 are largely blamed (Lu, et al., 2012).
Although the trials were not carried on mice, but their cells and E. coli, it is postulated that the results would be the same. The existence of inhibitors on the active sites of BACE1 is critical in managing the occurrence of the disease. This is possible and important in the limiting the deposition if amyloid peptides plaques in once brain and further occurrence of dementia and its effects. Even with the inhibitors, the role of APP and gamma secretase couple with that of beta secretase is important. The clinical use of BACE1 has, however, not been feasible, although the results from the experiment were promising in the management of AD (Lu, et al., 2012).
Hu et al. (2010) undertook a study titled "Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves" with the aim of showing that BACE1 is a good target that physicians must utilize in case they want to alleviate the occurrence and effects of dementia. However, critical concerns must always focus on the victim's nervous system, especially in the maintenance of the myelin sheath and its production. The authors have shown that the beta secretase enzyme targets the weak myelinated sites of the CNS in the brain (Lazarov et al., 2005). The trials were carried out on mice without the BACE1 where the beta secretase enzyme usually targets when causing dementia. It is evident that mice, which had been genetically altered to lack the ability to have their sciatic nerves remyelinate, were prone and largely exposed to contracting Alzheimer's disease. The authors showed that exposed unmyelinated nerves were easy targets for the BACE1 (Hu et al., 2010).
With the use of the wild type and BACE1-null mice, the authors showed that the sciatic nerves were largely affected: the axons and myelin sheaths underwent significant degeneration with the presence of beta secretase. Observations from the destroyed myelin sheath in both categories of mice showed distinct re-growth distances. However, the wild type mice showed a normal process of remyelination and were not prone to a possible occurrence of dementia (Nishitomi et al., 2006). However, the BACE1-null showed a slow rate of re-myelination and was prone to the disease. The experiment supported their study that the deletion of BACE1 was responsible for the delay and reduction of myelin production and reproduction after destruction (Hu et al., 2010; Luo et al., 2001).
It is further evident that BACE1 manages the production of the myelin sheath and its thickness after it has been destroyed in adults. This affects the role of beta secretase enzyme in the causation of Alzheimer's disease. The authors have advised that therapeutic approaches must focus on reducing BACE1. It cleaves on APP although it affects the process of myelination and re-myelination after destruction (McGowan et al. 2005). The trials also created an avenue of identifying possible inhibitors. Such are useful because BACE1 can cleave APP in a selective manner with the aim of managing dementia and occurrence in adults. The pharmacological focus of inhibiting BACE1 is important in managing AD is important as shown in the study (Hu et al., 2010).
Hong-Qi, Zhi-Kun, and Sheng-Di (2012) undertook a study titled "Current advances in the treatment of Alzheimer's disease: focused on considerations targeting A? And tau" with the aim of identifying possible treatments that can be undertaken to treat patients with Alzheimer's disease. The use of beta secretase inhibitors has proven to be useful in the management of dementia as suggested by various studies related to BACE-knockout mice. It is important to note that beta secretase is the beta site APP enzyme also known as BACE1 (Lazarov et al., 2005). From the study, it is evident that mice without the BACE produce low amounts of amyloid peptide from APP compared to the wild types. This would otherwise be a prime target for the beta secretase enzyme, but the existence of the BACE inhibitor showed significant reduction of the amyloid peptide 40 and 42 in the brain (Hong-Qi, Zhi-Kun, & Sheng-DI, 2012). The use of KMI-429 inhibitor in the experiment gave further insights on the possible adoption of the same concept in pharmacology. The drugs produced must always be inhibitory in nature with their prime targets being the enzyme targets. This will eventually alleviate the possible occurrence of dementia in any individual using drugs with such inhibitors. This often prevents the cleavage of APP by the beta secretase enzyme, which eventually reduces the amyloid peptides that cause dementia. The study shows that regulation of BACE1 is critical in this process and any viability of the drugs developed (Hong-Qi, Zhi-Kun, & Sheng-Di, 2012).
Ring et al. (2007) undertook a study seeking to show that "The secreted ?-amyloid precursor protein ectodomain APPs? is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-
deficient mice." The success of the study is premised on the idea that Alzheimer's results from the production of beta amyloid peptide in the victim's brain when beta secretase enzyme acting on APP. The authors appreciated the fact that the characteristics of the APP and its…[continue]
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