Single Drug Treatment for Alzheimer's, MS, TBI, and More

In a study published in the Journal of Neuroscience, a collaborative team of researchers led by Linda J. Van Eldik, director of the University of Kentucky Sanders-Brown Center on Aging, and D. Martin Watterson of the Northwestern University Feinberg School of Medicine, present results showing that a new central nervous system drug compound can reduce Alzheimer’s pathology in a mouse model of the disease.

The drug, called MW-151, is a selective suppressor of brain inflammation and overproduction of pro-inflammatory molecules from glial cells. The drug can be taken by mouth and readily enters the brain. The new study tested the hypothesis that intervention with drugs like MW-151 could be effective as a preventive measure, when administered at an early stage before Alzheimer's pathology appears, as well as after disease symptoms have begun to appear. _Source

The UK / Northwestern team has developed two drugs in this new class -- MW 151 and MW 189. This new class of drugs protects the brain by limiting production of and preventing the accumulation of pro-inflammatory cytokines in the brain. Inflammation in the brain can be particularly destructive in a wide range of infections, diseases, traumatic injuries, vascular insufficiencies, and more.

When too many of the cytokines are produced, the synapses of the brain begin to misfire. Eventually the entire organization of the brain falls into disarray, like a computer failing. The neurons lose their connections with each other and can eventually die. The resulting damage in the cortex and hippocampus can compromise memory and decision-making.

"In Alzheimer's disease, many people now view the progression from mild cognitive impairment to full-blown Alzheimer's as an indication of malfunctioning synapses, the pathways that allow neurons to talk to each other," said Watterson, the John G. Searle Professor of Molecular Biology and Biochemistry. "And high levels of proinflammatory cytokines can contribute to synaptic malfunction."

Because this harmful inflammatory mechanism also appears to be a major player in other neurodegenerative disorders in addition to Alzheimer's, the class of drugs represented by MW151 might hold bright potential as co-therapies for Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, M.S. and the longer term complications of brain injury, Watterson said. _MedXpress

It is likely that this new class of drugs with its very broad spectrum of affects will find application in a wide range of conditions -- some not yet anticipated.

Regardless of neuro-inflammation’s exact role, a prevailing hypothesis is that targeting of pro-inflammatory cytokine overproduction in the brain might be a useful therapeutic strategy to add to the armamentarium of emerging interventions. The primary brain cell target for such a disease modifying strategy would be glia, cells in the brain that produce pro-inflammatory cytokines and other innate immunity responses to injury or disease progression. Glial cells normally cooperate with the nerve cells to keep the brain operating smoothly. When an injury or change in the brain occurs, the glial cells mount a beneficial inflammation response to fight off the insult and restore the brain to its proper functioning. This beneficial process sometimes gets out of balance and the inflammation becomes too strong or does not shut off on schedule. _SurfKy

Fine Tuning Brain Ensembles with Glial Overseers

Glia cells, named for the Greek word for "glue," hold the brain's neurons together and protect the cells that determine our thoughts and behaviors, but scientists have long puzzled over their prominence in the activities of the brain dedicated to learning and memory. Now Tel Aviv University researchers say that glia cells are central to the brain's plasticity — how the brain adapts, learns, and stores information.

...Almost all neurodegenerative diseases are glia-related pathologies, Prof. Ben-Jacob notes. In epileptic seizures, for example, the neurons' activity at one brain location propagates and overtakes the normal activity at other locations. This can happen when the glia cells fail to properly regulate synaptic transmission. Alternatively, when brain activity is low, glia cells boost transmissions of information, keeping the connections between neurons "alive." _aftau.org

To understand the brain, one must conceptualise multiple levels of activity occurring simultaneously. The level where glial cells influence neurons and synaptic output is a relatively low to mid-level, but a crucial one. Neuroscience has barely begun to understand this basic interaction between cell types, and is forced -- as in this study -- to use neurocomputational models in an attempt to expand the comprehension of this complex give and take.

The brain is constituted of two main types of cells: neurons and glia. Neurons fire off signals that dictate how we think and behave, using synapses to pass along the message from one neuron to another, explains De Pittà. Scientists theorize that memory and learning are dictated by synaptic activity because they are "plastic," with the ability to adapt to different stimuli.

But Ben-Jacob and colleagues suspected that glia cells were even more central to how the brain works. Glia cells are abundant in the brain's hippocampus and the cortex, the two parts of the brain that have the most control over the brain's ability to process information, learn and memorize. In fact, for every neuron cell, there are two to five glia cells. Taking into account previous experimental data, the researchers were able to build a model that could resolve the puzzle.

The brain is like a social network, says Prof. Ben-Jacob. Messages may originate with the neurons, which use the synapses as their delivery system, but the glia serve as an overall moderator, regulating which messages are sent on and when. These cells can either prompt the transfer of information, or slow activity if the synapses are becoming overactive. This makes the glia cells the guardians of our learning and memory processes, he notes, orchestrating the transmission of information for optimal brain function. _aftau.org

PLoS CompBioLooking at how synaptic connections change during learning and memory is a little bit like trying to understand what goes on inside an office building by studying a set of architectural blueprints and reviewing the utility bills. It provides a bare beginning, but it's a start.

Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neuronal activity. Because it admittedly underlies learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. Short-term presynaptic plasticity refers to changes occurring over short time scales (milliseconds to seconds) that are mediated by frequency-dependent modifications of the amount of neurotransmitter released by presynaptic stimulation. Recent experiments have reported that glial cells, especially hippocampal astrocytes, can modulate short-term plasticity, but the mechanism of such modulation is poorly understood. Here, we explore a plausible form of modulation of short-term plasticity by astrocytes using a biophysically realistic computational model. Our analysis indicates that astrocytes could simultaneously affect synaptic release in two ways. First, they either decrease or increase the overall synaptic release of neurotransmitter. Second, for stimuli that are delivered as pairs within short intervals, they systematically increase or decrease the synaptic response to the second one. Hence, our model suggests that astrocytes could transiently trigger switches between paired-pulse depression and facilitation. This property explains several challenging experimental observations and has a deep impact on our understanding of synaptic information transfer. _PLoSCompBio

PLoS Comp BioBy understanding how synaptic frequencies can be modulated by changes in the glial::neuronal interaction, scientists can begin to bridge upward to the next higher levels of cognition -- local and distant neuronal ensembles. No one said it would be easy.

Neuroscientists are forced to work with a variety of animal models, human brain imaging techniques, cell culture approaches, and computational models, in order to enlarge their understanding of the foundations of an incredibly complex, multi-layered, and time-dependent phenomenon -- consciousness. And at that, we are talking about the consciousness of lower animals.

PLoS article in full

Bonus link: Wim de Neys at U. Toulouse is attempting to clarify some of the insights that come from the work of Nobel Prize winner Daniel Kahneman. de Neys seems to want to place human intuition on a higher level than the one on which Kahneman's work suggests it belongs. Certainly humans are dependent upon their intuitions for most of the things they do and virtually all the choices they make. In the opinion of Al Fin cognitivists, such psychological research still suffers from the lack of a firm neuroscientific foundation.

A Brain Within a Brain: Growing a Parallel Brain In Place

The brain consists of two major cell types: neurons, which transmit information, and glial cells, which support and protect neurons. Interestingly, evidence suggests that some glial cells, including astroglia, can be directly converted into neurons by specific proteins, a transformation that may aid in the functional repair of damaged brain tissue. However, in order for the repaired brain areas to function properly, it is important that astroglia be directed into appropriate neuronal subclasses. In this study, we show that non-neurogenic astroglia from the cerebral cortex can be reprogrammed in vitro using just a single transcription factor to yield fully functional excitatory or inhibitory neurons. We achieved this result through forced expression of the same transcription factors that instruct the genesis of these distinct neuronal subtypes during embryonic forebrain development. Moreover we demonstrate that reactive astroglia isolated from the adult cortex after local injury can be reprogrammed into synapse-forming excitatory or inhibitory neurons following a similar strategy. Our findings provide evidence that endogenous glial cells may prove a promising strategy for replacing neurons that have degenerated due to trauma or disease. _PLOS

Scientists from the Helmholtz Center and Ludwig-Maximilians University in Munich, have used a virus to reprogram brain helper cells -- astroglia -- into actual neurons. They were able to convert astroglia from early post-natal and adult mouse brains into either excitatory or inhibitory neurons, depending upon the transcription factors which were introduced.

The study adds to growing evidence that certain cell types can be transformed directly into other cell types without first being converted into stem cells. Researchers have previously transformed skin cells into neurons, and one type of pancreatic cell into another. Marius Wernig, a coauthor of the skin cell study and a stem cell biologist at Stanford University, says there's a growing awareness that it may not be necessary to erase a cell's existing identity before giving it a new one.

...this latest study "means that these astroglial cells could be converted in the brain" without the need for a transplant. Berninger says that one of the next challenges is to determine whether these reprogrammed neurons can survive and function in a living brain.

Fortunately, the brain seems to have a ready source of astroglia. When the brain is injured, these cells proliferate, similar to the way the skin repairs itself after a wound. The researchers found they could also derive neurons from injury-induced astroglia taken from the brains of adult mice. _TechnologyReview

More:

we first aimed at a more potent neuronal reprogramming by inducing higher and more persistent expression of neurogenic fate determinants in astroglial cells. This allowed us not only to obtain fully functional neurons that also establish synapses from astroglial cells in vitro but also to demonstrate that distinct neurogenic transcription factors, such as on the one hand Neurog2 and on the other Dlx2 alone or in combination with Mash1, can indeed instruct the selective generation of different neuronal subtypes, such as glutamatergic and GABAergic neurons, respectively. Moreover, we found that the reprogramming efficiency of postnatal cortical astroglia towards GABAergic neurons by Dlx2 could be enhanced by first expanding the astroglial cells under neurosphere conditions prior to forced expression of Dlx2. Given that following brain injury reactive astroglia from the adult cerebral cortex de-differentiate, resume proliferation, and can give rise to self-renewing neurospheres in vitro [16], we finally show that neuronal reprogramming and subtype specification are not restricted to postnatal stages but can also be achieved from adult cortical astroglia responding to injury. _PLOS

The findings are a striking reminder that nature offers us many more possibilities than we can presently conceive of. But perhaps we will grow in our conceptual capacity, over time.

The possibility of regenerating brain tissue in situ -- without the need for inserting new cells from elsewhere -- offers new hope for brain trauma, infection, infarct, atrophy, and senility. But it also offers a distinctly new possibility which most observors are not quite ready to think about -- much less discuss.

I am referring to the possibility of growing entirely new neural networks in situ, from astroglia. The possibility that humans can induce their own brains to create entirely new brain centers and pathways, using more advanced forms of such techniques, should not be overlooked.

There is currently a race between biological methods of repairing and enhancing human organs, and technological methods of compensating for organ damage or loss -- the cyborg approach. A cyborg may utilise nano-technological enhancement, and thus manifest no outward sign of distinction from standard normal humans. The same would be true for most biological enhancements or remediation.

This lack of overt differences between ordinary persons and enhanced persons is quite important to most military uses of enhanced individuals, and to virtually all covert uses by government and other organisations.

But these tools of transformation are not likely to remain limited to deep pocketed groups and individuals. Garage biohackers are not as uncommon as you might think, and are performing a similar service for bio-hacking as the garage techno-hackers performed for microcomputers in the early days. And it is also extremely likely that persons involved in expensive and large scale research into bio-transformation technologies will set off on their own as they discover the ability to profit from their technical knowledge and skills.

Cross posted to Al Fin Longevity

More on this topic later.

Astrocytes: The Power Behind the Neuronal Throne?

Scientists are learning more about an interesting brain cell known as an astrocyte. Astrocytes are glial cells, or support cells of the brain. But is it possible that astrocytes were never told that they are mere support cells?

Scientists at Yale, most notably Ann H. Cornell-Bell and Steven Finkbeiner, have shown that calcium waves can spread from the point of stimulation of one astrocyte to all other astrocytes in an area hundreds of times the size of the original astrocyte. Furthermore, calcium waves can also cause neurons to fire. And calcium waves in the cortex are leading scientists to infer that this style of communication may be conducive to the processing of certain thoughts. If that isn't convincing, it was recently shown that a molecule that stimulates the same receptors as THC can ignite astrocyte calcium release. _SciAm

Those are the words of neuroscientist Andrew Koob, author of the book "The Root of Thought," which suggests that astrocytes may be an important key to human consciousness. Glia are the most numerous cells in the brain, and are crucial to the survival of neurons. But until recently, no one believed that astroglia may be active participants in human consciousness itself.

The means by which astrocytes may alter and control human consciousness is thought to be "the calcium wave."

Interestingly, astrocytes are excitable cells like neurons. They base their communication on spontaneous or evoked cytosolic Ca2+ variations, instead of membrane electrical transients. Their remarkable morphology supports intercellular signaling as they form interconnected networks of cells coupled by gap-junctions, where each unit occupies a virtually non-overlapping domain of the inter-neuronal space. Surprisingly, astrocytes communicate also to neurons and synapses. In fact, they extend membrane processes to simultaneously contact hundreds of neuronal dendrites, thousands of synapses and even blood vessels. Indeed, astrocytes control the vasculature tone and they are likely to sense neuronal energy-demand and gate its consumption. Their physiology is thus bidirectionally linked to neuronal and synaptic activity, as they are capable of selectively respond to it on a millisecond time scale, by releasing specific neuroactive molecules (Ni et al., 2007). Notable are the discoveries of the -interaction with synaptic physiology and plasticity that led to -revisiting -information transfer between neurons, with the proposed concept of a “tri-partite synapse” (Perea and Araque, 2002). _frontiers

Actually, science has just begun to understand astrocytes. Beneath the level of the "calcium wave" is the "calcium oscillation". Calcium oscillations occur within individual astrocytes spontaneously within the hippocampus -- the seat of human long-term memory formation. Connections between calcium oscillations, calcium waves, neuronal oscillations, and various neuronal correlates of consciousness, will take time to locate and solidify. Stay tuned, and don't forget to drink your high calcium beverage of choice.

Alzheimer's Disease and Microglia Triggered Inflammation

A recent posting at Developing Intelligence blog discussed the vital role of glial cells in the activity of neurons, including the effect of inflammation triggered by glia. Now U Penn Medical School researchers have shown that microglial activation leads to formation of neural tangles of tau protein. These tangles cause more inflammation and so on . . .

Researchers at the University of Pennsylvania School of Medicine have shown that impaired function and loss of synapses in the hippocampus of a mouse form of Alzheimer’s disease (AD) is related to the activation of immune cells called microglia, which cause inflammation. These events precede the formation of tangles – twisted fibers of tau protein that build up inside nerve cells – a hallmark of advanced AD. The researchers report their findings in the February 1 issue of Neuron.

“Abolishing the inflammation caused by the accumulation of the tau protein might be a new therapy for treating neurodegenerative disorders,” says senior author Virginia Lee, PhD, Director of the Center for Neurodegenerative Disease Research. “This work points the way to a new class of drugs for these diseases.”

In addition, the immunosuppressant FK506 diminishes neuron loss and extends the life span of the transgenic Alzheimer’s mice. Normally only 20 percent of these mice survive by one year. With FK506, 60 percent of the mice were alive by one year.

Source.

Glial cells perform housekeeping functions for neurons, but in some situations can trigger inflammation that leads to neuron death. Learning how to intervene in such situations before irreversible damage is done to neurons may postpone the loss of mental function in senescent individuals.

Another Anti-Alzheimer's Compound

This bio.com newsfeature points to research done at Northwestern University.

As described in the Jan. 11 issue of the Journal of Neuroscience, the compound, called MW01-5-188WH, selectively inhibits production of pro-inflammatory proteins called cytokines by glia, important cells of the central nervous system that normally help the body mount a response, but are overactivated in certain neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, stroke and traumatic brain injury.

The compound was designed and synthesized in the laboratory of D. Martin Watterson at Northwestern University Feinberg School of Medicine, using a synthetic chemistry platform developed in his lab by researchers at the Northwestern University Center for Drug Discovery and Chemical Biology (CDDCB) for the rapid discovery of new potential therapeutic compounds.

Watterson is co-director of the CDDCB, the J.G. Searle Professor of Molecular Biology and Biochemistry and professor of molecular pharmacology and biological chemistry at the Feinberg School.

There is a delicate balance of pro-inflammatory and anti-inflammatory hormones, including cytokines, in the neuron's environment. Rational drug design methods allow the targeted development of chemical compounds designed for very specific purposes. These compounds are not necessarily safe and effective because they were "rationally designed." They must still go through a thorough vetting process by national drug regulatory agencies. But even if these pinpoint specific compounds fail the tests for regulatory approval, they are often still useful scientific probes for studying biological systems. Development of these rapid discovery tools is one of many new mechanisms propelling biological science rapidly ahead.