The controversy swirls around Alzheimer amyloid hypothesis

May 3, 2015 | | Say something

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.

A new study examines the enormous body of research suggests that beta amyloid accumulation causes Alzheimer’s disease in the brain. The study appears in open access, peer-reviewed title Future Science Group.

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 …

the amyloid hypothesis

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 [1] .

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 . Less should mean less of Alzheimer

What do we know after 30 years

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 [3] and solanezumab, developed by Eli Lilly [4] . 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.

wrong path?

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 [11] but was also observed that different preparations give rise to different powers of the peptide Aß [12] . 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 [2] .

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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 [17] . For example, a strong association between the incidence of type 2 (T2D) diabetes and Alzheimer [18] 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 [1920] .

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 [21] . 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 [22] . 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 [23] . 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 [24] . Therefore, it could have been the same chemical cure the brain, while killing the liver.

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The future

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:

  1. late intervention ineffective
  2. Side effects drug effects on cognition masking
  3. inadequate participation secretase target for drugs.

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.



• Alzheimer’s disease (AD) is the most important population aging disease.
• So far no drugs available that can stop or even stabilize the progression of the disease.
Amyloid hypothesis

• the amyloid hypothesis describes the accumulation of β-amyloid (Aß) as the event that triggers the EA. Aß is a derivative of the larger amyloid precursor protein (APP).
• The functions of α-, β- and γ-secretase play an essential part in this model.

• ADAM10 is likely to be the α-secretase more physiologically relevant in neurons.
therapeutic potential of α-secretase

• Since the processing α-secretase APP involves cleavage within the sequence of the peptide Aß, which prevents the formation of Aß, activation of α-secretase is considered as a possible treatment for AD .
• indirect activation of the α-secretase through the associated signaling pathways may be the best approach.

• BACE1 is the enzyme β-secretase and α-secretase racing for cleavage of APP.
• BACE1 cleaves APP in the N-terminal domain Aß end -. subsequent cleavage by γ-secretase releases isoforms Aß
therapeutic potential of β-secretase

• inhibition of β-secretase block production of Aß and therefore represents a therapeutic strategy for treatment of AD.
• The last decade has witnessed intense research efforts towards inhibition of BACE1 but so far has not been successful in clinical trials.
• Concerns about the possible side effects of this approach have grown over time and greater understanding of the role of this enzyme.
• The partial inhibition of BACE1 activity could represent a viable strategy.

• γ secretase is a protein complex comprising presenilin, nicastrin, APH-1, and PEN-2. APP fragment after cleavage of β-secretase cleaves to produce Aß.
• As with β-secretase inhibition of γ-secretase is an obvious strategy to inhibit Aß.
therapeutic potential of the γ-secretase

• clinical trials of gamma secretase inhibitors to date have shown unacceptable side effects and lack of positive effects on cognition. This is probably because gamma secretase cleaves a number of important substrates besides APP.
• The hope remains around two new strategies that aim to prevent a major second γ-secretase substrate called Notch.

• it remains far from certain whether to focus on the secretase involved in the processing of APP give therapeutic success.
• high profile clinical failures have questioned the viability of the amyloid hypothesis.
• A number of clinical trials for treatment of AD may have failed due to patients’ is too advanced in the disease process in he. new trials will target patients in the early stages of the disease.
• The results of these tests can be key to the continued focus on the amyloid hypothesis as the central principle of the AD investigation.


1. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 297 (5580), 353-356 (2002).
2. Puig KL, combs CK. APP expression and function and its metabolites outside the central nervous system. Exp. Gerontol. 48 (7), 608-611 (2013).
3. Salloway S, R Sperling, North Carolina Fox et al. Two Phase 3 trials of bapineuzumab in mild to moderate Alzheimer’s disease. N. Engl. J. Med 370 (4), 322-333 (2014).
4. Doody RS, Thomas RG, Farlow M et al. Phase 3 trials of solanezumab for mild to moderate Alzheimer’s disease. N. Engl. J. Med. 370 (4), 311-321 (2014).
5. Alzheimer R. Katzman. N. Engl. J. Med. 314 (15), 964-973 (1986).
6. Terry RD, Masliah E, Salmon DP et al. physical basis of cognitive impairment in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30 (4), 572-580 (1991).
7. DeKosky ST, SW Scheff. synapse loss in biopsies of the frontal cortex in Alzheimer’s disease: correlation with cognitive gravity. Ann. Neurol. 27 (5), 457-464 (1990).
8. Dickson DW, Crystal HA, Bevona C, W Honer, Vicente I, P. Davies and pathological correlations of synaptic markers adult cognition higher. Neurobiol. Aging 16 (3), 285-298; discussion 298-304 (1995).
9. CA McLean, Cherny RA, Fraser FW et al. Soluble amyloid Abeta pool as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol. 46 (6), 860-866 (1999).
10. Wang J, Dickson DW, Trojanowski JQ, Lee VM. Levels of soluble Abeta against brain insoluble distinguish Alzheimer’s disease from normal and pathological aging. Exp. Neurol. 158 (2), 328-337 (1999).
11. Pike CJ, AJ Walencewicz, Glabe CG, Cotman CW. In vitro aging of beta-amyloid peptide causes aggregation and neurotoxicity. Brain Res. 563 (1-2), 311-314 (1991).
12. Busciglio J, Lorenzo, Yankner BA. methodological variables in the assessment of the neurotoxicity of beta amyloid. Neurobiol. Aging 13 (5), 609-612 (1992).
13. Lambert MP, AK Barlow, Chromy BA et al. diffusible ligands, nonfibrillar Abeta1-42 derivatives are potent neurotoxins central nervous system. Proc. Natl Acad. Sci. 95 (11), 6448-6453 (1998).
14. Kayed R, Head E, Thompson JL et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300 (5618), 486-489 (2003).
15. Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB. Beta-amyloid protein fibrillogenesis. Detecting a protofibrillar intermediate. J. Biol. Chem. 272 (35), 22364-22372 (1997).
16. Lesne S, Koh MT, Kotilinek L et al. A set of specific protein beta-amyloid in the brain impairs memory. Nature 440 (7082), 352-357 (2006).
17. Spinney. Alzheimer’s disease: the gene forget. Nature. 5, 510 (7503) 26-28 (2014).
18. Kim I, J Lee, Hong HJ et al. A relationship between Alzheimer’s disease and type 2 diabetes mellitus by measuring serum amyloid-beta autoantibodies. J. Alzheimer Dis. 19 (4), 1371-1376 (2010).
19. Ansari N, F. Molecular mechanism Khodagholi aspect ER stress in Alzheimer’s disease: current and future strategies approaches. Curr. Drug targets 14 (1), 114-122 (2013).
20. Viana RJ, CJ Steer, CM Rodrigues. secretion chaperone GRP94 endoplasmic reticulum amyloid-β glycoprotein induced peptide. J. Alzheimer Dis. 27 (1), 61-73 (2011).
21. Jonsson T, JK Atwal, Steinberg S et al. A mutation in APP protects against Alzheimer’s disease and cognitive impairment associated with age. Nature 488 (7409), 96-99 (2012).
22. Choi SH, Kim YH, Hebisch M et al. A three-dimensional model of human neuronal cell culture Alzheimer’s disease. Nature 515 (7526), ​​274-278 (2014).
23. Sperling RA, Aisen PS, Beckett LA et al. By defining the preclinical stages of Alzheimer’s disease: recommendations of the National Institute on Aging-Alzheimer working groups of the Association diagnostic guidelines for Alzheimer’s disease. Alzheimer Dement. 7 (3), 280-292 (2011).

This article was originally published on alzheimersweekly, Read the original article here


Posted in: Alzheimer's & Dementia, Research, Understanding Dementia

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