Alzheimer new experiments

Source: https://blogs.scientificamerican.com/talking-back/a-new-tack-to-stave-off-alzheimer-s-years-before-the-first-symptom/

Vocabulary:
the moment at which something unpleasant begins:
goes awry
intended to address other manifestations
cellular mechanisms
accelerates many
mice genetically engineered

Text: A New Tack to Stave Off Alzheimer's Years before the First Symptom
Researchers try to prevent onset(=the moment at which something unpleasant begins) of the disease by correcting a brain cell process that goes awry

The new mantra for researchers fighting Alzheimer’s disease is “go early,” before memory loss or other pathology appears. The rationale for this approach holds that by the time dementia sets in the disease may already be destroying brain cells, placing severe limits on treatment options.

Some large clinical trials are now testing drugs intended to clear up the brain’s cellular detritus—the aggregations of amyloid and tau proteins that may ultimately destroy brain cells. So far this approach has had decidedly mixed results.
Some researchers are choosing a different direction. They have begun to ask what happens in the brain before the plaques and tangles of amyloid and tau appear—and to look at interventions that might work at this incipient disease stage.

The Alzheimer’s Drug Discovery Foundation has focused in recent years on funding new agents that do not target amyloid but are intended to address (=abordar) other manifestations of the disease, such as inflammation and the energy metabolism of neurons.
At a foundation meeting last month in Jersey City, N.J., neuroscientist Grace Stutzmann of the Chicago Medical School at Rosalind Franklin University of Medicine and Science presented her work on restoring a basic cellular process—called calcium signaling—that goes off track in

Alzheimer’s. Scientific American asked her recently about her work.
[An edited transcript of the conversation follows.]
Scientific American: Can you explain in a simple manner for our readers what calcium signaling is in the brain and what can go wrong in Alzheimer's?

While many people are aware of calcium as a component of strong bones, calcium is also a very important feature of cellular function. Calcium ions within brain cells play fundamental roles in activating genes to make proteins in energy metabolism, in signaling inside cells and even in cell death. Perhaps most relevant to Alzheimer’s disease though is its central role in neuronal transmission and communication between synapses (junctions between neurons). These are the cellular mechanisms by which memories are formed and maintained. In Alzheimer’s disease, too much calcium is being released within the neuron, and this initiates or accelerates many of the pathological processes seen in Alzheimer’s disease (AD), especially the events that lead to memory loss.

Is stopping the process of aberrant calcium signaling a good place to intervene? Is that because of the particular stage at which calcium becomes a problem in the course of the disease?

The dysregulated calcium signaling is thought to occur early in the disease process, which suggests it is part of the “cause” rather than a later-stage “effect.” Mechanistically, this supports targeting calcium abnormalities as a good therapeutic strategy. Importantly, we feel that our laboratory has identified the particular channel underlying the excess calcium release (the ryanodine receptor), which provides a specific target when trying to prevent the calcium dysregulation.

Can you explain specifically what you’ve done?
We first confirmed the role of the specific calcium channel in AD by examining its effects in several experimental models of AD, and we also confirmed abnormalities in human brains from AD patients. We then moved back to the models (including mice genetically engineered to exhibit AD pathology) and tested existing drugs known to inhibit the calcium channel, which generated incredibly encouraging results. Not only did one of these drugs reverse the excess amounts of calcium but it also altered many of the other aspects of AD, such as the accumulation of amyloid and tau, loss of synapses, and impaired synaptic plasticity. These findings set the stage for the development of our own compounds that are designed for better targeting of the receptors and gaining better access to the brain. We soon partnered with a medicinal chemistry group to help design and synthesize a series of new compounds to test in these models systems of AD.

How will you test people without symptoms to know whether they're at risk?
Ah, there is the rub. Numerous groups, ours included, are looking for biomarkers to indicate amount of risk or likelihood of developing AD. And there is also brain imaging of plaques (and more recently tau pathology) that many are using as an indicator of AD risk. But since there is little correlation between plaques and cognitive function, many of us are questioning this as a diagnostic or biomarker tool. So for now it's very hard to accurately assess risk in most people. Realistically, we are hoping to catch early-stage symptoms including the behavioral and memory disruptions, and then prevent further cognitive impairment.

Tell us about the company you've started and the drug you're developing.
Once we realized we had a valid and novel strategy to treat AD, a library of new compounds and powerful biological screening assays to test our compounds, we got to work trying to identify which of these compounds could prove to be effective in treating AD. To our great joy, the first generation of compounds produced several successful “hits,” which restored intracellular calcium signaling to its normal state in the AD models, and also reduced several of the related pathological features of AD.
Soon after, we partnered with SmartHealth, a North Chicago-based health care activator (an incubator for biotech startups), to create NeuroLucent to accelerate the process of developing, testing and optimizing our new compounds to hopefully move them into the clinic. Glenn Gottfried, an adviser with SmartHealth, is serving as president. I also brought in a medicinal chemist, Dr. John Buolamwini, and a molecular biologist, Dr. Robert Marr, both colleagues with me at Rosalind Franklin University.  We’re still a new startup, but we are in the process of raising funds and establishing partnerships to scale up and advance the complex process of moving a compound from the lab to the FDA.

Haven't there been previous attempts to try to correct calcium signaling? How is yours different?
That is correct. This is not the first calcium-channel strategy attempted for the treatment of AD. However, the previous approaches were targeting entirely different types of calcium channels, found on the outer membrane of the cell, that do not seem to be linked to AD pathology in any clear way. For example, there is a class of calcium channels on the surface of the cells that is activated by excitatory activity that opens the cell channel. Drugs that inhibit these calcium channels have been very effective for several conditions, such as high blood pressure, but did not improve cognition or reduce the symptoms of AD. We have also been studying these channels in our experimental models of AD, and they have always functioned normally. Since this series of calcium channels doesn’t seem to be defective or causative in AD, I can understand why these previous attempts weren’t successful in the clinic.

A major difference in our approach is that the calcium channel we are targeting is found inside the cell, and controls calcium signaling from the endoplasmic reticulum (ER), a cell component with a very high calcium concentration. In AD, the channel on the ER membrane releases too much calcium from its internal stores, and this triggers a host of pathological cascades. We are attempting to normalize the calcium signaling through ER channels and target this one specific source. This is mechanistically much different than the previous attempts. Plus, we know in experimental AD models and in human AD patients that this calcium source is functioning abnormally. Several research labs have demonstrated this across many different models. If it were only our lab obtaining these findings, I wouldn’t feel comfortable trusting our results in isolation.

Is it important to consider your approach given the poor track record with other Alzheimer's drugs?
I do feel very strongly about this, and it doesn’t have to be “my” approach per se—but anymechanistically valid approach that is distinct from the series of recent failed clinical trials. The majority of the compounds that disappointed were targeting a particular protein aggregate, beta-amyloid plaques. And, while the presence of plaques is integral to the diagnosis of AD, it is unclear what their role is in the disease process and how the accumulation of beta-amyloid actually links to memory loss. Actually, several of these drugs worked very well in that they were able to reduce the beta amyloid in the brain; however, they were not able to show any improvement in cognitive function.
In parallel, we know there is little relationship between the amount of amyloid in one’s brain and your memory function.  In fact, those “super-agers”—your 95-year-old great-great-aunt who finishes the crossword puzzle in 20 minutes, is president of the bridge club and has a better golf handicap than you—may have just as many amyloid plaques in her brain as AD patients. In the big picture, I think we need to take a few giant steps backwards and work on understanding the early mechanisms of AD as it relates to memory loss. That will then enable us to build therapeutic strategies based on these data. We feel enormous potential exists in addressing an early and central signaling pathway that affects amyloid production, tau pathology, neuroinflammation and memory loss, among other AD features, but there may be other targets besides calcium dysregulation that would be effective. I think the research community needs to increase our efforts in finding the common denominator driving the multifaceted disease processes in AD. Our lab is continuing to explore what is causing AD and now is using human neurons to validate our approach. But as a field, we research scientists need to better understand what it is we are fighting in order to formulate the best approach.

Japones recebe o premio nobel de medicina

Source: http://www.nytimes.com/2016/10/04/science/yoshinori-ohsumi-nobel-prize-medicine.html?rref=collection%2Fsectioncollection%2Fscience&action=click&contentCollection=science&region=rank&module=package&version=highlights&contentPlacement=1&pgtype=sectionfront&_r=0

Vocabulary:
Ohsumi used baker’s yeast
floundered at first trying
garbage dump
autophagy goes awry
diseases and aging
to the Japanese broadcaster

Yoshinori Ohsumi of Japan Wins Nobel Prize in Medicine
Yoshinori Ohsumi, a Japanese cell biologist, was awarded the Nobel Prize in Physiology or Medicine on Monday for his discoveries on how cells recycle their content, a process known as autophagy.
Yoshinori Ohsumi do Japão ganha premio nobel em medicina
Yoshinori Ohsumi, um japones biólogo celular, foi premiado com o premio nobel em psicologia ou medicina na Segunda-feira para as descobertas dele em como as celulas reciclam o conteudo delas, um processo conhecido como autofagia.

Autophagy, derived from Greek, means “self-eating.”
“This concept emerged during the 1960s, when researchers first observed that the cell could destroy its own contents by enclosing it in membranes, forming sacklike vesicles that were transported to a recycling compartment, called the lysosome, for degradation,” the Nobel Assembly at Karolinska Institutet in Stockholm said in announcing the prize.
Autofagia, derivado do grego, significa auto-comer
Esse conceito emergiu durante os anos 1960, quando pesquisadores observaram primeiro que a celula poderia destruir o conteudo de si mesmo colocando-se em membranas, formando vesículas que foram transportadas para um comportamento reciclavel, chamado lisossomo, por degradação, a assembleia nobel em Karoilnksa instituto em stockhold disse em anuncio do premio.

In a series of experiments in the early 1990s, Dr. Ohsumi used baker’s yeast to identify genes essential for autophagy, and he went on to examine the underlying mechanisms of the process.
“Ohsumi’s discoveries led to a new paradigm in our understanding of how the cell recycles its content,” the Nobel Assembly said. “His discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes, such as in the adaptation to starvation or response to infection.”
Em uma serie de experimentos no começo de 1990s, Dr Ohsumi usou fermento para identificar genes essenciais para autofagia, e ele foi examinar os mecanismos mais destacaveis do processo. As descobertas do ohsumi levaram a um novo paradigma no nosso entendimento de como as celulas reciclam os seus conteudos, a assembleia nobel disse: "As descobertas dele abriram um novo caminh opara entendre a importancia fundamental da autofagia em muitos processos fisiologicos, como na adptação da fome ou resposta para infecção.

Mutations in autophagy genes can cause disease, the assembly said, and disruptions in the process have been linked to Parkinson’s disease, Type 2 diabetes and cancer.
Biography
Like many scientists, Dr. Ohsumi, who was born in 1945 in Fukuoka, Japan, and received a Ph.D. from the University of Tokyo in 1974, floundered at first trying to find his way. He started out in chemistry but decided it was too established a field with few opportunities.
Mutações em genes autofagicos podem causar doença, a assembleia disse, e rupturas no processo foram ligados a doença de parkson, diabete tipo 2 e cancer.
Biografia
Como muitos cientistas, Ohsumi, que nasceu em 1945 em Fukuoka, Japão, e recebeu PhD da universidade de tokyo em 1974, fracassou na primeira tentativa em encontrar o seu caminho. Ele começou em quimica, mas decidiu que era um campo muito estavel com poucas oportunidades.

So he switched to molecular biology. But his Ph.D. thesis was unimpressive, and he could not find a job. His adviser suggested a postdoctoral position at Rockefeller University in New York, where he was to study in vitro fertilization in mice.
“I grew very frustrated,” he told the Journal of Cell Biology. He switched to studying yeast.
He became an associate professor and established his research lab in 1988.
Entao ele trocou para biologia molecular. Mas a sua teste em PhD era inexpressiva, e ele nao pôde achar um trabalho. O seu tutor sugeriu um cargo de pos doutorado na universidade de Rockefeller em nova york, onde ele estudava fertilização de vitro em ratos.

There, at age 43, he made the discoveries that the Nobel Assembly recognized on Monday. Dr. Ohsumi later moved to the National Institute for Basic Biology, in Okazaki, and since 2009, he has been a professor at the Tokyo Institute of Technology.
When he received the Canada Gairdner International Award last year, which is given for outstanding discoveries or contributions to medical science, he described himself to The Globe and Mail newspaper as “just a basic researcher in yeast.”
Ali, aos 43 anos, ele fez descobertas que a Assembleia nobel reconheceu na segunda-feira Dr. Ohsumi depois foi par ao Instituto nacional de biologia basica, em Ozakaki, e desde 2009, ele foi um professor no instituto de tokio de tecnologia. Quando ele recebeu o premio Canada Gairdner no ultimo ano, que foi dado pelas descobertas incriveis ou contribuições para a ciencia médica, ele se descreveu para o globo e jornal como sendo uma pesquisa basica em fermento.

He acknowledged, however, that the process was seen as fundamental to human cell survival. “I believe its relevance to many diseases will be discovered in the near future,” he told the newspaper.
Why did he win?
Ele foi reconhecido, porém, que o processo estava sendo visto como fundamental para a sobrevivencia da celula humanaa. "Eu acredito que é relevante que muitas doenças serão descobertas em um futuro proximo", ele disse ao jornal.
Por que ele ganhou?

Cells need to degrade proteins in development and in their normal lifetimes as well as during diseases like cancer, infection and starvation. Biologists knew there was a sack in the cell that seemed like a garbage dump, but few had bothered to ask much more about it. Dr. Ohsumi discovered how cells control degradation of their own proteins, what genes are involved, and what happens when autophagy goes awry.
Celulas precisam degradar proteinas em desenvolvimento e nas vidas normais delas também como duração de doenças como cancer, infecção e fome. Biólogos sabiam que ali tinha um saco na celula que paarecia como um depósito de lixo, mas alguns tinham sido incomodados por perguntar muito sobre isso. Ohsumi descobriu como a degradação do controle de celulars das proteinas deles, quais genes estao involvidos, o que acontece quando autofagia da errado.

Why is his work important?
Disruptions in autophagy are thought to underlie many conditions, including cancer, infections, neurological diseases and aging. And since autophagy is a fundamental and crucial function in cells, it can be important to understand how it is controlled and what its consequences are.
Por que o trabalho dele é importante?
Rupturas em autofagia sao tidas como sendo a base de mutias condições, inculindo cancer, infecções, doenças neurologicas e envelhecimento. E desde que a autofagia é uma função fundamental e crucial nas celulas, pode ser importante par aentender como ela é controlado e as suas consequencias.

Reactions
“All I can say is, it’s such an honor,” Dr. Ohsumi told reporters at the Tokyo Institute of Technology, according to the Japanese broadcaster NHK. “I’d like to tell young people that not all can be successful in science, but it’s important to rise to the challenge.”
Reações
Tudo o que eu posso falar é, que é uma honha, Dr Ohsumi disse aos reoprters no instituto de tecnologia de tokio, segundo a emissora japonesa NHK. Eu gostaria de dizer as pessoas jovens que ninguém pode ser bem sucedido na ciencia, mas é importante aumentar o desafio.