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).
Further results confirmed the earlier doubled fact that BACE is the only beta secretase in the brain cells and is largely to blame for the occurrence of AD. The study confirms other observations made in other experiments that the amyloid beta production is diminished when BACE1 activity is inhibited. In large pharmacological settings, drugs can be developed with inhibitors targeting the functionality of the BACE1. This will prevent the continued accumulation of the plaques responsible for causing dementia. It is not feasible to knock out BACE in humans as is done in mice. The neurotoxic nature of AD plaques is characteristically enhanced by the amyloid beta interaction with the beta secretase enzymes. It is important for phamacotherapists to focus their efforts in developing drugs that inhibit the BACE1 active sites and their interaction with APP. Dementia victims can use this current remedy when further feasibility studies identifying the appropriate drugs with lasting and dependable solutions are being developed (Luo et al., 2001; Dominguez et al., 2005).
Alzheimer's disease continues to plaque the society. Anyone beyond the age of sixty-five can contract this disease, which is often characterized by intellectual and memory loss. Alzheimer's was previously considered as a normal part of the aging process: the notion was later discounted because it does not occur uniformly or to all the old people. Since the disease has no current cure, various clinical trials have been done in mice with the aim of establishing possible remedies to the victims. Many of the treatments available in the market today only target on limiting the symptoms of the disease. However, death is inevitable in the end. As this study reviewed various studies relating to the clinical trials that have been undertaken in mice with greater focus on the role of beta secretase enzyme (Nishitomi et al., 2006).
Beta amyloids, which are also known as amyloid plagues, are products of BACE1 enzyme's action on APP. They often form within the brain neurons, which lead to the memory loss, depreciation of intelligence, and eventual death. From the clinical trials carried out on mice, it is evident that the development of drugs acting as inhibitors of the BACE1 / beta secretase enzyme reduces the occurrence of dementia symptoms. Some of the drugs that have been developed as inhibitors of the enzyme include CTS-21166 by CoMenthis, ACI-91 from AC Immune and LY2886721 from Lilly all available to be taken orally. The concept used in making the drugs imitates principle used in the experiments identified in this study. Further experiments and the eventual development of drugs acting as BACE1 inhibitors will lead to…