Alzheimer's disease overview and clinical features

ALZHEIMER'S DISEASE

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).

Literature review

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 consequent products in causing AD are still unclear to may pharmacologist. Variants of APP from mice were re-injected after allelic regeneration and exposed to the beta secretase enzyme. The genes generated targeted separate lines of knock-in mice on the APP cut differently (Ring et al., 2007).

The authors sought to identify the primary sites of APP where the beta secretase would target possibly when truncated. With the use of the mice, it is evident that the physiology of the APP is critical in determining the nature of dementia to be experienced. The in vivo introduction of stop codons in two loci obtained from the APP's chromosome elucidated invaluable results. The mutants of the knocked in mice attenuated the same defects as seen in wild type mice (Luo et al., 2001). However, the mice that lacked the last 15 aa codons in their APP showed a significant reduction in the production of amyloid peptide. This is a clear indication that the dementia would be minimal in such circumstances because the APP would be considered inadequate for the action of the beta secretase enzyme. This study opens up the possible avenue that APP's physiological characteristics are also important even when beta secretase has been a center of attention (Ring et al., 2007; Lazarov et al., 2005).

In their study titled "The Alzheimer's disease ?-secretase enzyme, BACE1," Cole and Vassar (2007) sought to elucidate the complex nature of AD's pathogenesis. However, they acknowledged the critical role of the amyloid plaques and beta secretase enzyme in the causation of the disease. In all instances of Alzheimer's occurrence, the BACE1 enzyme acting on beta amyloid proteins has been observed. However, from their study, it is clear that mice without the BACE1 otherwise known as knock out do not suffer from the same because they lack the beta amyloid (McGowan et al. 2005). This offers an unfeasible hypothesis that dementia can be avoided by removing ones APP. However, this would result in death since APP is the significant part of the brain and only become pathogenic when acted upon by the beta secretase enzyme. The most viable option as offered in the study is the development of drugs that inhibit the BACE1. This would reduce their interaction with the APP and beta amyloid with the BACE1 with often result in dementia (Cole & Vassar, 2007).

It is important to appreciate that BACE1's physiology plays in the causation of dementia. From experiments, it is clear that mice without BACE1 were not exposed to the possible effects of beta secretase and the later occurrence of dementia. In fact, BACE1 deficient mice showed reduced rates of myelin production in their destroyed CNS compartments. The degeneration of the neurons later results in the wearing of synapses and later occurrence of Alzheimer's. It is thought that BACE1 probably maintains the synapses through the cleaving of APP. However, the over-cleaving provides substrates for the action of the beta secretase enzyme when normal functions are altered. This eventually causes dementia (Cole & Vassar, 2007).

McConlogue et al. (2007) undertook a study as they sought to show that "Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice." As shown previously, Alzheimer's disease occurs because of the plaques formed when BACE1 initiates the over-cleaving of APP. Any alteration in the amount BACE1 will eventually affect the rate of occurrence of the disease. In the study, the researchers used mice with a knockout gene as a transgenic model (Luo et al., 2001). This was done with a mutated human amyloid precursor protein (APP). It is evident that the occurrence of the plaques and further cause of dementia is only possible when BACE1 is present. Without it, the generation of amyloid beta, which would later be acted upon by the beta secretase is impossible (McConlogue et al., 2007).

In such a case, dementia would not occur. From their clinical trials, they found out that a fifty percent reduction of BACE1 enzymes resulted in reduced occurrence of dementia in young mice for up to ten percent. Total absence of dementia is seen in older mice when similar tests are done. This study is critical in any pharmacological setting, especially when drugs for combating the disease are being developed. From the study, it is evident from the study that fractional reductions of the enzymes and the amyloid beta are critical in the reduction of Alzheimer's diseases, which premise their occurrence on amyloid beta avenues (McConlogue et al., 2007).

The study by Roberds et al. (2001) largely confirms the great-unresolved dilemma of developing appropriate drugs to curb dementia. It is shown that mice without BACE1 are healthy even without the existence of beta secretase and its activity in the brain. The generation of two lines of knockout mice was critical in the success of this study (Nishitomi et al., 2006). Evidently, beta amyloid production was largely inhibited in the mice without BACE1. The authors also showed from the study that there was a significant disruption of beta secretase production in the mice with ablated BACE. Most importantly, no deleterious effects were seen in mice whose systems lacked BACE because they developed well like the normal ones (Roberds et al., 2001).

The knockout mice used in this study were obtained by replacing and deleting the axons in the BACE. Deletions targeted about four to eight exons while replacements were only done on a single exon. There was an observed non-developmental disadvantage on the alleles generated from the deleted exons in the BACE of the mice. It is evident that mice without BACE lived normal lives without showing possible occurrence of dementia. This was contrary to the wild types because the BACE offered a possible avenue for the action of the beta secretase enzyme after the APP has been broken down. It is also clear that the animals show differing behavioral characteristics depending on the presence or absence of the BACE (Lazarov et al., 2005). The study does not confirm fully whether BACE is the only beta secretase enzyme in the brain and the only causative agent of dementia (perhaps there are others). While determining the extent that BACE disruption can cause on beta secretase activity, cortical structures from mice fetuses were used. The authors showed that the activity of the enzyme in the wild type cultures (with BACE) showed a consistent production of cellular protein (Roberds et al., 2001).