The controversy swirls around Alzheimer amyloid hypothesis ;
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In 1984, “ amyloid hypothesis “fingers beta-amyloid plaque as the culprit behind Alzheimer’s disease. 30 frustrating years later, we have not found a cure, however amyloid remains the # 1 suspect. We are barking up the wrong tree? Is research time to change course? A new study takes a look at the arguments. Read the pros and cons.
In 1984, a study by Glenner and Wong can be said to have started the “amyloid hypothesis” . It was suggested that beta-amyloid plaque in the brain made out was the trigger behind Alzheimer’s disease.
Once the target is identified, the scientists natually zoom it to try to cure Alzheimer’s disease.
Continued below video …
In overly simple terms, the brain contains a protein called the a myeloid P recursor P rotein ( APP for short). APP function is still unclear. It is expressed and clarified in considerable quantities in the neurons, heart, lung, liver and skin  .
Aß is synonymous with beta-amyloid or amyloid, in short, the suspect behind Alzheimer’s disease. Aß is a derivative of and amyloid precursor protein (APP) . Thus, the researchers calculated how to cure Alzheimer’s disease is to prevent the generation of Aß by modulating proteins called secretase. Secretase do the dirty work of harmless cut APP in the brain to kill Aß. Secretase and inhibit least get Aß . Less Aß should mean less of Alzheimer
secretase.? Today, it is still far from certain whether the orientation secretase involved in the processing of APP have the innovative therapeutic effects is urgently needed to treat Alzheimer’s disease ( AD ) . The number of high profile errors in recent years has severely affected the confidence of the big pharmaceutical companies. A number of companies have reduced their risk in this field. However, the potential benefits to the discovery of a medicament for the treatment of Alzheimer’s disease prevent a complete withdrawal of the key players
Vaccines :. Another approach has been the creation of a vaccine against Alzheimer’s. Attempts to target Aß through drugs that induce immunity have produced similar negative results leading to recent high-profile clinical failures. The two most famous were bapineuzumab, developed by Johnson & Johnson and Pfizer  and solanezumab, developed by Eli Lilly  . Both looked promising and certainly not their primary endpoints in Phase III. However, Eli Lilly has not given up solanezumab and new, but-different trials are unfolding.
The amyloid hypothesis has now been the mainstay of therapeutic research in Alzheimer’s disease for more than two decades. The series of high-profile clinical failures has inevitably called into question the viability of the hypothesis itself. A number of problems have plagued the amyloid hypothesis since its inception. First, the level of Aß load often do not correlate with clinical expression of the disease. In several studies, amyloid plaques were evident in healthy people despite no evidence of cognitive impairment [5-8] . However, other research has found a much stronger among correlation Aß levels, physical loss of synapses in the brain, and obvious cognitive impairment [9.10] .
Second, Aß is complex and comes in many “flavors”. The difficulty of isolating specific neurotoxic Aß species and characterization of its effects makes research problems. Early studies showed that toxic Aß  but was also observed that different preparations give rise to different powers of the peptide Aß  . In addition, Aß has several distinct conformations that appear to have different toxic effects on neurons. These include: oligomers formed from monomers 15-20; Aß small diffusible oligomers known as ADDLs (Aß derived diffusible ligands); and protofibrils (oligomer chains) [13-16] .
Further criticism of the evidence that supports the amyloid hypothesis revolves around the mice used in research laboratories. Today mouse-models of Alzheimer’s disease is not fully recapitulate the disease. When researchers increase Aß deposition in these mouse models, there is a lack of coincidence neuronal loss. This is believed to be mainly due to species differences in neuronal susceptibility to accumulation of Aß, lack of human tau protein in mice, and the lack of a similar human inflammatory response, also play a role critical in disease progression  .
Critics of amyloid hypothesis they have argued that it is too simplistic to focus on this approach. This zoom on amyoild by researchers may have diverted attention from other important associations in Alzheimer’s disease.
Some argue that Alzheimer’s disease can be understood rather as a failure complex caused by the aging of multiple physiological systems that interact.
If so, we can find a cause? It could well be. Some of these systems may share an underlying pathology  . For example, a strong association between the incidence of type 2 (T2D) diabetes and Alzheimer  has led to a desire for a better understanding of the common pathology of diseases involving aggregation of misfolded proteins and speculation that these diseases can share complex interactions waters below.
Similarly, there is growing recognition of the role of E ndoplasmic R eticulum ( ER ) stress and deregulation of the function ER in AD pathology. The restoration of ER stress markers appears to prevent the toxic effects of amyloid in mice  .
That the underlying physiology Alzheimer involves multiple factors would hardly be surprising in such a complex organ as the brain. It is hoped that a better understanding of systems and disease states in Alzheimer’s disease will lead to new targets to treat.
However, a greater understanding of potentially multifactorial interactions in Alzheimer’s disease has also provided additional support secretase as the best target for treatment Alzheimer’s disease. This may even still suggest softer modulator is approaching its inhibition.
In support of the importance of amyloid hypothesis high profile most important discovery in recent years has been the identification of a protective mutation in APP in an Icelandic population that significantly reduces the cleavage of APP BACE1  . This discovery is considered to provide proof of principle that the reduction of amyloidogenic APP processing has a protective effect.
Further support for the amyloid hypothesis demonstrated by the recent development of a model of human neuronal culture dimensional novel Alzheimer’s disease. He was nicknamed “ Alzheimer-In-A-Dish “. Aß generation using ß-secretase inhibitors or gamma was inhibited. Not only reduces the deposition of Aß but also attenuates the generation of phospho-tau aggregates  . Although this is only a system of a single cell, is further highlights the potential of ß-secretase inhibitors and γ-. This adds weight to the hope that the highly selective therapy with minimal side effects may still have potential to treat AD.
An important issue that has been highlighted by the failures of many AD clinical trials is the design of the trials themselves. It is generally accepted that a large number of clinical trials for treatment of AD may have failed because of the patient “too advanced in the disease process for any clinical effect of a potential therapeutic. Deposition amyloid in AD is now thought to begin many years before the onset of cognitive symptoms and the final diagnosis of dementia  . drug development both in AD is now beginning to focus on the targeting of patients in the early stages of the disease, before the obvious dementia especially in groups with familial AD. As such, the FDA has produced a guide for the design of clinical trials patients without dementia manifests. it will be interesting to see if some of the previously failed drugs have clinical efficacy when running in clinical trials of new design.
One consideration is that if healthy people should be subject to the drug discovery process, the prospect of ongoing problems with side effects could be even more serious. It is still unclear what level of may be necessary to reduce secretase to achieve a sufficient reduction in the brain Aß and whether this will bring an acceptable level of side effects. For example, the suspension of drug testing for LY2886721 due to liver toxicity which is supposed to be due to off-target effects that could be corrected by adjustments to the drug. However, worryingly, it has recently been suggested that the side effect may have occurred due to the chemical in the body that the fixed drug, which has important functions that can extend beyond the brain  . Therefore, it could have been the same chemical cure the brain, while killing the liver.
Proponents of amyloid hypothesis argue that data from clinical trials to date has not yet been adequately tested the hypothesis; it is still unclear whether the failure trial was due to a failure of the amyloid hypothesis itself, or rather, to:
The results of the current “ Early Intervention ” Essays can be key to the continued focus on the amyloid hypothesis as the central focus of Alzheimer’s research.
In addition, success in secretase -Targeting trial early intervention came at a cost of significant side effects in healthy individuals relatively well could lead to a new approach to more indirect modulatory approaches the secretase inhibition, and a further increase in efforts to determine quality biomarkers for disease development. Despite the recent failures in clinical trials is still significant hope around secretase targeting approach.
Furthermore, the highest profile clinical failures could potentially lead to the withdrawal of major pharmaceutical companies from funding anti-Aß clinical trials.
Any major success, no doubt, would be seen as a justification of the effort and resources used in the search for anti-Aß therapies in the last decade.
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