Alzheimer’s drug turns back clock in cellular powerhouse - J147

Alzheimer’s drug turns back clock in cellular powerhouse

The experimental drug J147, a synthetic, modified version of the curcumin molecule found in the spice turmeric, is almost ready for human trials. The lab of Dave Schubert developed J147 while looking for plant compounds that reverse cellular and molecular aging in the brain. Since then, the team has shown J147 reverses memory deficits, drives the production of new brain cells and slows or reverses Alzheimer’s disease progression in mice. Now Schubert, first author Josh Goldberg and their colleagues have figured out how J147 works: in a study published in Aging Cell on January 9, 2018, they reported that the drug binds to an enzyme called ATP synthase, which is found in our cells’ power-generating organelles (mitochondria). The team showed that, by manipulating ATP synthase activity, they could protect brain cells from multiple toxicities associated with aging. Unraveling J147’s mechanism of action is a critical step towards clinical trials in humans.

https://www.salk.edu/news-release/can-hear-now-ensuring-good-cellular-connections-brain/

Researchers identify the molecular target of J147, which is nearing clinical trials to treat Alzheimer's disease
January 9, 2018, Salk Institute

The experimental drug J147 is something of a modern elixir of life; it's been shown to treat Alzheimer's disease and reverse aging in mice and is almost ready for clinical trials in humans. Now, Salk scientists have solved the puzzle of what, exactly, J147 does. In a paper published January 7, 2018, in the journal Aging Cell, they report that the drug binds to a protein found in mitochondria, the energy-generating powerhouses of cells. In turn, they showed, it makes aging cells, mice and flies appear more youthful.

"This really glues together everything we know about J147 in terms of the link between aging and Alzheimer's," says Dave Schubert, head of Salk's Cellular Neurobiology Laboratory and the senior author on the new paper. "Finding the target of J147 was also absolutely critical in terms of moving forward with clinical trials."

Schubert's group developed J147 in 2011, after screening for compounds from plants with an ability to reverse the cellular and molecular signs of aging in the brain. J147 is a modified version of a molecule found in the curry spice curcumin. In the years since, the researchers have shown that the compound reverses memory deficits, potentiates the production of new brain cells, and slows or reverses Alzheimer's progression in mice. However, they didn't know how J147 worked at the molecular level.

In the new work, led by Schubert and Salk Research Associate Josh Goldberg, the team used several approaches to home in on what J147 is doing. They identified the molecular target of J147 as a mitochondrial protein called ATP synthase that helps generate ATP—the cell's energy currency—within mitochondria. They showed that by manipulating its activity, they could protect neuronal cells from multiple toxicities associated with the aging brain. Moreover, ATP synthase has already been shown to control aging in C. elegans worms and flies.

"We know that age is the single greatest contributing factor to Alzheimer's, so it is not surprising that we found a drug target that's also been implicated in aging," says Goldberg, the paper's first author.

(More at link: https://medicalxpress.com/news/2018-01-molecular-j147-nearing-clinical-trials.html  )

Glypican-4 is a protein that in humans is encoded by the GPC4 gene.[5][6]

Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The GPC4 gene is adjacent to the 3' end of GPC3 and may also play a role in Simpson-Golabi-Behmel syndrome.[6]

https://en.wikipedia.org/wiki/Glypican_4

K-glypican: a novel GPI-anchored heparan sulfate proteoglycan that is highly expressed in developing brain and kidney

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2120559/

OCT 07, 2015 09:00 AM PDT
Advancing neuroscience: functional insights from in vitro microelectrode arrays
SPONSORED BY: Axion BioSystems

Abstract:
DATE: October 7th, 2015
TIME: 9am Pacific time, 12pm Eastern time

The neuroscience field is rapidly evolving as both a burgeoning area for basic research (Parkinson’s, Alzheimer’s, Amyotrophic Lateral Sclerosis (ALS) to name just a few) and as a focus area for commercial therapeutics.  However, research and drug discovery in this field is often hindered by the low-throughput of many of the established techniques.  In addition, many of the common assays used require advanced expertise and are quite costly.

Enter the microelectrode array (MEA) and the Maestro platform from Axion BioSystems:  a simple approach to measuring complex, functional neural responses at the throughput level you need.  Together with integrated control software, the Maestro makes acquisition and analysis of neural networks accessible, straightforward, and scalable up to 96 wells.

After a brief introduction to MEA technology, we will showcase two examples of successful implementation of the Maestro platform into neuroscience research and discovery programs:


   John Graef, PhD from Bristol-Meyers Squibb will present on pain modeling using Dorsal Root Ganglia

   Carol Marchetto, PhD from the Salk Institute will speak about using the Maestro to explore network-level signaling in an in vitro autism model

https://www.labroots.com/webinar/advancing-neuroscience-functional-insights-vitro-microelectrode

https://www.youtube.com/watch?v=9yjQLfNEccA

Diseases In A Dish: Modeling Mental Disorders
Using skin cells from patients with mental disorders, scientists are creating brain cells that are now providing extraordinary insights into afflictions like schizophrenia and Parkinson’s disease.



FOR MANY POORLY UNDERSTOOD MENTAL DISORDERS, such as schizophrenia or autism, scientists often wish they could turn back the clock to uncover what has gone wrong in the brains of these patients, and how to right it before much brain damage ensues. But now, thanks to recent developments in the lab, that wish is coming true.

Researchers are using genetic engineering and growth factors to reprogram the skin cells of patients with schizophrenia, autism, and other neurological disorders and grow them into brain cells in the laboratory. There, under their careful watch, investigators can detect inherent defects in how neurons develop or function, or see what environmental toxins or other factors prod them to misbehave in the petri dish. With these “diseases in a dish” they can also test the effectiveness of drugs that can right missteps in development, or counter the harm of environmental insults.

“It’s quite amazing that we can recapitulate a psychiatric disease in a petri dish,” says neuroscientist Fred (Rusty) Gage, a professor of genetics at the Salk Institute for Biological Studies and member of the executive committee of the Kavli Institute for Brain and Mind (KIBM) at the University of California, San Diego. “This allows us to identify subtle changes in the functioning of neuronal circuits that we never had access to before.”

Below is an edited transcript of a conversation with Gage and Anirvan Ghosh, a neurobiologist at the University of California, San Diego and also an executive committee member of KIBM. Both researchers are on the cutting edge of disease-in-a-dish modeling of neurological disorders. Gage and Ghosh discuss how human skin cells induced to return to an immature state (“induced pluripotent stem cells” or IPS cells) are revolutionizing our understanding and treatment of mental and neurodegenerative disorders, such as Parkinson’s disease, as well as leading to new models of drug development for all diseases.



THE KAVLI FOUNDATION (TKF): Dr. Gage, in your model you found that neurons look pretty similar between schizophrenic patients and normal controls, and it is just the connections between them (synapses) that are different, right?


Surprising Findings for Schizophrenia

Labs in Dishes and on Chips

A New Dynamic with Pharmaceutical Companies

Creating a Deep Baseline of Knowledge
.

FRED "RUSTY" GAGE: Yes. That doesn’t mean on closer inspection, and with better tools, more profound or subtle changes won’t be found. I wouldn’t be surprised if some more specific defects are revealed by a more sophisticated tool.

TKF: You then applied schizophrenia drugs to these not-fully-mature cultured neurons derived from schizophrenic patients and found that some of these drugs reversed the abnormalities in synapse formation you saw. How closely did you model what you would actually be seeing in a patient, given patients take these drugs once their neurons are mature and differentiated?

GAGE: We have to admit to ourselves this is a model of what might be going on in the brain and not think of it as a one-to-one relationship. It’s too soon to ask if this is how it happens in a patient; instead we are asking how do these drugs affect neurons.

TKF: So what are some of the surprises this modeling has revealed so far?

GAGE: One surprise is that neurons appear to undergo structural changes when they are given neuropsychiatric drugs. This is unexpected, as since the 1970’s companies have developed neuropsychiatric drugs on the premise that you modulate mood by regulating the amount of chemical signals available in the brain. These chemical signals are called neurotransmitters, and consequently the drugs have focused on modulating neurotransmitters such as dopamine and serotonin.

"As we accumulate models for these diseases – bipolar disease, schizophrenia, depression, autism – we are going to be able to explore if there are really differences between them that exist on a cellular or gene expression level." — Fred Gage

But one of the take home messages I got from my study is it’s not just the moment-to-moment regulation of dopamine that may be affecting the symptoms of schizophrenia, but the structural organization of how these synapses interact with each other. In other words, changing the regulation of dopamine or some other compound appears to have the additional effect of causing structural modifications that also affect how neurons interact.

TKF: This might explain why many of these drugs require a long period of time before a patient experiences a benefit.

GAGE: Exactly. If depression is merely due to a modulation of transmitter content and its receptor affinity, why wouldn’t these anti-depressants have their effects immediately? Normally it takes weeks. One of the emerging ideas is that part of the reason it takes longer is these drugs have other effects than what we’ve anticipated. Our findings support that possibility. Looking ahead, the next generation of drugs may not target dopamine or serotonin concentrations but instead the structure and function of synapses.

Confocal images of neurons derived from patients with Schizophrenia. SCZD hiPSC neurons express βIII-tubulin (red) and the dendritic marker MAP2AB (green). DAPI (blue). 400xmagnification. Credit: Kristen Brennand, UCSDConfocal images of neurons derived from patients with Schizophrenia. SCZD hiPSC neurons express βIII-tubulin (red) and the dendritic marker MAP2AB (green). DAPI (blue). 400X magnification. (Credit: Kristen Brennand, UCSD)

TKF: Dr. Ghosh, what other surprises has this modeling revealed?

ANIRVAN GHOSH: I think it’s remarkable what Rusty uncovered about schizophrenia. This is a pretty broad disorder and one we've suspected may have many different genetic causes. Yet they found there were shared cellular traits (phenotype) between the patients. This is a very exciting result because it raises the possibility of being able to find the phenotype—physical hallmarks--that might be shared for most, if not all, individuals with the disease.

TKF: What technological advances are needed to explore this further?

GAGE: One limitation is we haven’t differentiated the cells into specific cell types—neuronal subtypes. Right now we’re just laying these neurons down and allowing them to form connections as they might. Looking ahead, it’s going to be important for us to differentiate the cells. For example, to differentiate and model the cortical neurons, which are responsible for thinking tasks, or the hippocampal neurons, which are responsible for memory tasks. I can one day see us using microfluidic chambers to achieve this. They will allow us to compartmentalize microscopically specific subtypes of neurons in certain locations, and then regulate how they connect to each other. That way you can simulate in a more accurate manner how these subtypes connect with each other in the brain. The future of this is really exciting because the dish is going to get much more complicated.
"I think it’s remarkable what Rusty uncovered about schizophrenia. This is a pretty broad disorder and one we suspected may have many different genetic causes. ... [This] raises the possibility of being able to find the phenotype – physical hallmarks – that might be shared for most, if not all, individuals with the disease." — Anirvan Ghosh

TKF: So you’ll be able to combine the "disease in a dish" with a "lab on a chip"?

GAGE: Yes, the bioengineering part of this is becoming very exciting and interesting, and a lot of us will be relying heavily on that. It will enable three-dimensional cultures so you can have dopamine neurons projecting through a gradient into the types of neurons affected by Parkinson’s disease, for example. This way you can set up a whole neuronal network or circuitry that hopefully will be akin to what you see in the brain. We’re also trying to figure out what role inflammation plays in Parkinson’s disease. So for our model of this disease, which we are currently developing, we have to generate a variety of other brain cell types besides neurons that are thought to foster immune responses in the brain.

TKF: And you can compare mental disorders literally side-by-side; or rather, dish-by-dish.

GAGE: That’s the idea. As we accumulate models for these diseases — bipolar disease, schizophrenia, depression, autism — we are going to be able to explore if there are really differences between them that exist on a cellular or gene expression level.

(More at link:
http://www.kavlifoundation.org/science-spotlights/neuroscience-diseases-dish-modeling-mental-disorders
)

Diet and Neurogenesis
By mhedlin 01 Jul, 2011 Diet and HD

Myth(edited)A novel track of research has unearthed new meaning to the old adage “you are what you eat”. Research suggests that our diet plays a role in neurogenesis, the process by which we produce new neurons. Therefore, a diet rich in “brain food” may promote neurogenesis and thereby might repair some of the damage brought on by Huntington’s disease (HD).

Scientists think DR brings about these beneficial effects by conditioning cells to be better at protecting themselves. DR is a mild stress that puts cells on the defensive, and causes them to start expressing protective genes and stockpiling useful proteins. Therefore, cells stressed by DR are better able to cope with further stressors. For more information on DR, click here.

One stressor that occurs in many neurodegenerative conditions, like Alzheimer’s, Parkinson’s, and HD, and can be ameliorated by DR, is oxidative stress. In HD, oxidative damage occurs when injured neurons release free radicals, which go on to damage neurons around them (Mattson et al., 2004). For more information on oxidative damage, click here. Therefore, DR may help patients with neurodegenerative diseases by causing neurons to fortify themselves, which could prepare them for the stress caused by HD.

Scientists also believe that DR can help patients with neurodegenerative conditions by promoting neurogenesis. DR increases adult neurogenesis in young adult rats, and reduces age-related declines in neurogenesis in older mice (Levenson and Rich, 2007). Furthermore, DR stimulates neurogenesis in the hippocampus, a brain region important for memory. DR also causes an increase in levels of BDNF, a protein shown to help newly born neurons survive (Mattson et al., 2004). For more information on BDNF, click here. Researchers have found that DR can improve the symptoms of HD and several other neurodegenerative conditions in mice. When rats were injected with a chemical that causes brain damage, the rats kept on a restricted diet were more resistant to the chemical’s neurodegenerative effects, and showed fewer learning and memory problems (Mattson et al., 2004). When HD mice were kept on a restricted diet, they showed less striatal neuron death, it took longer for movement problems to arise, and the mice lived longer (Mattson et al, 2004). So DR may protect against neurodegenerative conditions by stimulating neurogenesis and causing neurons to fortify themselves.

DR, however, is a drastic strategy: it takes tremendous willpower to limit calories to 70% of the normal diet. Furthermore, DR is difficult to implement properly; there is a risk of starvation if the diet is unbalanced, which can have wide-ranging consequences. Luckily, similar effects to DR have been found in mice by simply increasing the amount of time between meals (Stangl and Thuret, 2009).

Some scientists have attempted to harness the beneficial effects of DR through resveratrol, a chemical found in red wine. Resveratrol mimics many of the effects of DR, and is thought to work through the same biological pathways (Greenwood and Parasuraman, 2010). For more information, click here.

https://web.stanford.edu/group/hopes/cgi-bin/hopes_test/diet-and-neurogenesis/#neurogenesis-and-hd

Do Adult Brains Make New Neurons? A Contentious New Study Says No

It’s the latest chapter in a century-long debate about whether neurogenesis continues throughout humans’ lives.
Ed Yong
Mar 7, 2018
Mouse neurons
Mouse neuronsReuters

In 1928, Santiago Ramón y Cajal, the father of modern neuroscience, proclaimed that the brains of adult humans never make new neurons. “Once development was ended,” he wrote, “the founts of growth and regeneration ... dried up irrevocably. In the adult centers the nerve paths are something fixed, ended and immutable. Everything must die, nothing may be regenerated.”

Ninety years later, it’s still unclear if his statement is true.

For decades, scientists believed that neurogenesis—the creation of new neurons—whirs along nicely in the brains of embryos and infants, but grinds to a halt by adulthood. But from the 1980s onward, this dogma started to falter. Researchers showed that neurogenesis does occur in the brains of various adult animals, and eventually found signs of newly formed neurons in the adult human brain. Hundreds of these cells are supposedly added every day to the hippocampus—a comma-shaped structure involved in learning and memory. The concept of adult neurogenesis is now so widely accepted that you can find diets and exercise regimens that purportedly boost it. Predictably, there’s even a TED talk about it.

The trouble is: This stream of fresh neurons might not actually exist.

In a new study, and one of the biggest yet, a team led by Arturo Alvarez-Buylla at the University of California at San Francisco completely failed to find any trace of young neurons in dozens of hippocampus samples, collected from adult humans. “If neurogenesis continues in adult humans, it’s extremely rare,” says Alvarez-Buylla. “It’s not as robust as what people have said, where you could go running and pump up the number of neurons.”

Needless to say, that’s a highly contentious claim. “There is a long history of concluding that adult neurogenesis doesn’t exist in a given species based on difficulty in identifying new neurons,” says Heather Cameron from the National Institutes of Mental Health. “This happened in rats and then in nonhuman primates, both of which are now universally acknowledged as showing adult hippocampal neurogenesis.”

Fernando Nottebohm from Rockefeller University sees things differently. He was one of the first scientists to conclusively show that adult neurogenesis occurs, by studying the brains of canaries. Alvarez-Buylla was one of his students, and Nottebohm speaks effusively about his former protégé—and his latest study. “It’s first class,” he says.

After Alvarez-Buylla left Nottebohm’s team and started his own, he showed that rodents continually add new neurons to the olfactory bulb—a region devoted to smell. But in humans, this river of olfactory neurons is finite: It’s there in infants, but dries up in adults. The same is true for the frontal lobe—the front-most part of the brain that governs our most important mental abilities. Floods of fresh neurons migrate there during early childhood, but they stop as we mature.

(More at link:
https://www.theatlantic.com/science/archive/2018/03/do-adult-brains-make-new-neurons-a-contentious-new-study-says-no/555026/
)

https://www.scientificamerican.com/article/new-neurons-make-room-for-new-memories/

New Neurons Make Room for New Memories

How does the brain form new memories without ever filling up? Scientists turn to the youngest neurons for answers

By William Skaggs

For many years scientists believed that you were born with all the neurons you would ever get. The evidence for this dogma seemed strong: neuroanatomists in the early 20th century had identified immature neurons under the microscope but only of fetuses... never after birth.