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New Drugs to Find the Right Target to Fight Alzheimer's Disease
Next-generation drugs designed to fight Alzheimer's disease look very promising. Scientists have unveiled the mechanisms behind two classes of compound currently being tested in clinical trials. They have also identified a likely cause of early-onset hereditary forms of the disease.
The future is looking good for drugs designed to combat Alzheimer's disease. EPFL scientists have unveiled how two classes of drug compounds currently in clinical trials work to fight the disease. Their research suggests that these compounds target the disease-causing peptides with high precision and with minimal side-effects. At the same time, the scientists offer a molecular explanation for early-onset hereditary forms of Alzheimer's, which can strike as early as thirty years of age. The conclusions of their research, which has been published in the journal Nature Communications, are very encouraging regarding the future of therapeutic means that could keep Alzheimer's disease in check.
Alzheimer's disease is characterized by an aggregation of small biological molecules known as amyloid peptides. We all produce these molecules; they play an essential antioxidant role. But in people with Alzheimer's disease, these peptides aggregate in the brain into toxic plaques called "amyloid plaques" that destroy the surrounding neurons.
The process starts with a long protein, "APP," which is located across the neuron's membrane. This protein is cut into several pieces by an enzyme, much like a ribbon is cut by scissors. The initial cut generates a smaller intracellular protein that plays a useful role in the neuron. Another cut releases the rest of APP outside the cell this part is the amyloid peptide.
For reasons not yet well understood, APP protein can be cut in several different places, producing amyloid peptides that are of varying lengths. Only the longer forms of the amyloid peptide carry the risk of aggregating into plaques, and people with Alzheimer's disease produce an abnormally high number of these.
A favorite Alzheimer's target: gamma secretase
The two next-generation classes of compound that are currently in clinical trials target an enzyme that cuts APP, known as gamma secretase. Until now, our understanding of the mechanism involved has been lacking. But with this work, the EPFL researchers were able to shed some more light on it by determining how the drug compounds affect gamma secretase and its cutting activity.
In most forms of Alzheimer's, abnormally large quantities of the long amyloid peptide 42 named like that because it contains 42 amino acids are formed. The drug compounds change the location where gamma secretase cuts the APP protein, thus producing amyloid peptide 38 instead of 42, which is shorter and does not aggregate into neurotoxic plaques.
Compared to previous therapeutic efforts, this is considerable progress. In 2010, Phase III clinical trials had to be abandoned, because the compound being tested inhibited gamma-secretase's function across the board, meaning that the enzyme was also deactivated in essential cellular differentiation processes, resulting to side-effects like in gastrointestinal bleeding and skin cancer.
"Scientists have been trying to target gamma secretase to treat Alzheimer's for over a decade," explains Patrick Fraering, senior author on the study and Merck Serono Chair of Neurosciences at EPFL. "Our work suggests that next-generation molecules, by modulating rather than inhibiting the enzyme, could have few, if any, side-effects. It is tremendously encouraging."
New insights into hereditary forms of the disease
During their investigation, the scientists also identified possible causes behind some hereditary forms of Alzheimer's disease. Early-onset Alzheimer's can appear as early as thirty years of age, with a life expectancy of only a few years. In vitro experiments and numerical simulations show that in early-onset patients, mutations in the APP protein gene modify the way by which APP is cut by the gamma-secretase enzyme. This results in overproduction of amyloid peptide 42, which then aggregates into amyloid plaques.
This research illuminates much that is unknown about Alzheimer's disease. "We have obtained extraordinary knowledge about how gamma secretase can be modulated," explains co-author Dirk Beher, scientific chief officer of Asceneuron, a spin-off of Merck Serono, the biopharmaceutical division of Merck KGaA, Darmstadt, Germany. "This knowledge will be invaluable for developing even better targeted drugs to fight the disease."
Source: http://www.sciencedaily.com/releases/2013/08/130802080343.htm
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Founded by Russian entrepreneur Dmitry Itskov in February 2011 with the participation of leading Russian specialists in the field of neural interfaces, robotics, artificial organs and systems.
The main goals of the 2045 Initiative: the creation and realization of a new strategy for the development of humanity which meets global civilization challenges; the creation of optimale conditions promoting the spiritual enlightenment of humanity; and the realization of a new futuristic reality based on 5 principles: high spirituality, high culture, high ethics, high science and high technologies.
The main science mega-project of the 2045 Initiative aims to create technologies enabling the transfer of a individual’s personality to a more advanced non-biological carrier, and extending life, including to the point of immortality. We devote particular attention to enabling the fullest possible dialogue between the world’s major spiritual traditions, science and society.
A large-scale transformation of humanity, comparable to some of the major spiritual and sci-tech revolutions in history, will require a new strategy. We believe this to be necessary to overcome existing crises, which threaten our planetary habitat and the continued existence of humanity as a species. With the 2045 Initiative, we hope to realize a new strategy for humanity's development, and in so doing, create a more productive, fulfilling, and satisfying future.
The "2045" team is working towards creating an international research center where leading scientists will be engaged in research and development in the fields of anthropomorphic robotics, living systems modeling and brain and consciousness modeling with the goal of transferring one’s individual consciousness to an artificial carrier and achieving cybernetic immortality.
An annual congress "The Global Future 2045" is organized by the Initiative to give platform for discussing mankind's evolutionary strategy based on technologies of cybernetic immortality as well as the possible impact of such technologies on global society, politics and economies of the future.
Future prospects of "2045" Initiative for society
2015-2020
The emergence and widespread use of affordable android "avatars" controlled by a "brain-computer" interface. Coupled with related technologies “avatars’ will give people a number of new features: ability to work in dangerous environments, perform rescue operations, travel in extreme situations etc.
Avatar components will be used in medicine for the rehabilitation of fully or partially disabled patients giving them prosthetic limbs or recover lost senses.
2020-2025
Creation of an autonomous life-support system for the human brain linked to a robot, ‘avatar’, will save people whose body is completely worn out or irreversibly damaged. Any patient with an intact brain will be able to return to a fully functioning bodily life. Such technologies will greatly enlarge the possibility of hybrid bio-electronic devices, thus creating a new IT revolution and will make all kinds of superimpositions of electronic and biological systems possible.
2030-2035
Creation of a computer model of the brain and human consciousness with the subsequent development of means to transfer individual consciousness onto an artificial carrier. This development will profoundly change the world, it will not only give everyone the possibility of cybernetic immortality but will also create a friendly artificial intelligence, expand human capabilities and provide opportunities for ordinary people to restore or modify their own brain multiple times. The final result at this stage can be a real revolution in the understanding of human nature that will completely change the human and technical prospects for humanity.
2045
This is the time when substance-independent minds will receive new bodies with capacities far exceeding those of ordinary humans. A new era for humanity will arrive! Changes will occur in all spheres of human activity – energy generation, transportation, politics, medicine, psychology, sciences, and so on.
Today it is hard to imagine a future when bodies consisting of nanorobots will become affordable and capable of taking any form. It is also hard to imagine body holograms featuring controlled matter. One thing is clear however: humanity, for the first time in its history, will make a fully managed evolutionary transition and eventually become a new species. Moreover, prerequisites for a large-scale expansion into outer space will be created as well.
Key elements of the project in the future
• International social movement
• social network immortal.me
• charitable foundation "Global Future 2045" (Foundation 2045)
• scientific research centre "Immortality"
• business incubator
• University of "Immortality"
• annual award for contribution to the realization of the project of "Immortality”.
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