Liver, Not Brain, May Be Origin of Alzheimer’s Plaques

Liver, Not Brain, May Be Origin of Alzheimer’s Plaques

  10:02:00 AM    Science Lover

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Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter scientists' ideas about Alzheimer's disease -- pointing to the liver instead of the brain as the source of the "amyloid" that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer's prevention and treatment.

New research suggests that the liver instead of the brain 
may be the source of the "amyloid" that deposits as brain 
plaques associated with Alzheimer's disease. 
(Credit: iStockphoto/David Marchal)

 

The study was published online March 3 in The Journal of Neuroscience Research.

In the study, the scientists used a mouse model for Alzheimer's disease to identify genes that influence the amount of amyloid that accumulates in the brain. They found three genes that protected mice from brain amyloid accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain. One of the genes encodes presenilin -- a cell membrane protein believed to contribute to the development of human Alzheimer's.

"This unexpected finding holds promise for the development of new therapies to fight Alzheimer's," said Scripps Research Professor Greg Sutcliffe, who led the study. "This could greatly simplify the challenge of developing therapies and prevention."

An estimated 5.1 million Americans have Alzheimer's disease, including nearly half of people age 85 and older. By 2050, the number of people age 65 and over with this disease will range from 11 million to 16 million unless science finds a way to prevent or effectively treat it. In addition to the human misery caused by the disease, there is the unfathomable cost. A new report from the Alzheimer's Association shows that in the absence of disease-modifying treatments, the cumulative costs of care for people with Alzheimer's from 2010 to 2050 will exceed $20 trillion.

A Genetic Search-and-Find Mission

In trying to help solve the Alzheimer's puzzle, in the past few years Sutcliffe and his collaborators have focused their research on naturally occurring, inherited differences in neurological disease susceptibility among different mouse strains, creating extensive databases cataloging gene activity in different tissues, as measured by mRNA accumulation. These data offer up maps of trait expression that can be superimposed on maps of disease modifier genes.

As is the case with nearly all scientific discovery, Sutcliffe's research builds on previous findings. Several years ago, researchers at Case Western Reserve mapped three genes that modify the accumulation of pathological beta amyloid in the brains of a transgenic mouse model of Alzheimer's disease to large chromosomal regions, each containing hundreds of genes. The Case Western scientists used crosses between the B6 and D2 strains of mice, studying more than 500 progeny.

Using the results from this study, Sutcliffe turned his databases of gene expression to the mouse model of Alzheimer's, looking for differences in gene expression that correlated with differences in disease susceptibility between the B6 and D2 strains. This intensive work involved writing computer programs that identified each genetic difference that distinguished the B6 and D2 genomes, then running mathematical correlation analysis (known as regression analysis) of each difference. Correlations were made between the genotype differences (B6 or D2) and the amount of mRNA product made from each of the more than 25,000 genes in a particular tissue in the 40 recombinant inbred mouse strains. These correlations were repeated 10 times to cover 10 tissues, the liver being one of them.

"A key aspect of this work was learning how to ask questions of massive data sets to glean information about the identities of heritable modifier genes," Sutcliffe said. "This was novel and, in a sense, groundbreaking work: we were inventing a new way to identify modifier genes, putting all of these steps together and automating the process. We realized we could learn about how a transgene's pathogenic effect was being modified without studying the transgenic mice ourselves."

Looking for a Few Good Candidates

Sutcliffe's gene hunt offered up good matches, candidates, for each of the three disease modifier genes discovered by the Case Western scientists, and one of these candidates -- the mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset Alzheimer's disease -- was of special interest to his team.

"The product of that gene, called Presenilin2, is part of an enzyme complex involved in the generation of pathogenic beta amyloid," Sutcliffe explained. "Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer's-like pathology."

This finding suggested that significant concentrations of beta amyloid might originate in the liver, circulate in the blood, and enter the brain. If true, blocking production of beta amyloid in the liver should protect the brain.

To test this hypothesis, Sutcliffe's team set up an in vivo experiment using wild-type mice since they would most closely replicate the natural beta amyloid-producing environment. "We reasoned that if brain amyloid was being born in the liver and transported to the brain by the blood, then that should be the case in all mice," Sutcliffe said, "and one would predict in humans, too."

The mice were administered imatinib (trade name Gleevec, an FDA-approved cancer drug), a relatively new drug currently approved for treatment of chronic myelogenous leukemia and gastrointestinal tumors. The drug potently reduces the production of beta amyloid in neuroblastoma cells transfected by amyloid precursor protein (APP) and also in cell-free extracts prepared from the transfected cells. Importantly, Gleevec has poor penetration of the blood-brain barrier in both mice and humans.

"This characteristic of the drug is precisely why we chose to use it," Sutcliffe explained. "Because it doesn't penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease."

The mice were injected with Gleevec twice a day for seven days; then plasma and brain tissue were collected, and the amount of beta amyloid in the blood and brain was measured. The findings: the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate. Thus, an appreciable portion of brain amyloid must originate outside of the brain, and imatinib represents a candidate for preventing and treating Alzheimer's.

As for the future of this research, Sutcliffe says he hopes to find a partner and investors to move the work into clinical trials and new drug development.

In addition to Sutcliffe, the authors of the study, titled "Peripheral reduction of β-amyloid is sufficient to reduce brain Aβ: implications for Alzheimer's disease," include Peter Hedlund and Elizabeth Thomas of Scripps Research, and Floyd Bloom and Brian Hilbush of ModGene, LLC, which funded the project.

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Genetic "Light Switches" Control Muscle Movement The technique will improve research on neuromuscular disorders and could one day help paralyzed patients.

Genetic "Light Switches" Control Muscle Movement The technique will improve research on neuromuscular disorders and could one day help paralyzed patients.

  9:57:00 AM    Science Lover

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Using light-sensitive proteins from a single-celled alga and a tiny LED "cuff" placed on a nerve, researchers have triggered the leg muscles of mice to contract in response to millisecond pulses of light.

Light movement: This image shows a cross-section of a mouse sciatic nerve genetically engineered to produce a light-sensitive protein (shown in green). Stanford researchers used this protein to trigger muscle movements in the animal’s leg.
Credit: Nature

The study, published in the journal Nature Medicine, marks the first use of the nascent technology known as optogenetics to control muscle movements. Developed by study coauthor Karl Deisseroth, an associate professor of bioengineering and of psychiatry and behavioral science at Stanford University, optogenetics makes it possible to stimulate neurons with light by inserting the gene for a protein called channelrhodopsin-2, from a green alga. When a modified neuron is exposed to blue light, the protein initiates electrical activity inside the cell that then spreads from neuron to neuron. By controlling which neurons make the protein, as well as which cells are exposed to light, scientists can control neural activity in living animals with unprecedented precision. The paper's other senior author, Scott Delp, a professor of bioengineering, mechanical engineering, and orthopedic surgery at Stanford, says that the optical control method provides "fantastic advantages over electrical stimulation" for his study of muscles and the biomechanics of human movement.

Members of Deisseroth's lab had engineered mice to produce channelrhodopsin-2 in both the central and the peripheral nervous systems. Michael Llewellyn, a former graduate student in Delp's lab, developed a tiny, implantable LED cuff to apply light to the nerve evenly. He placed the cuff on the sciatic nerves of anesthetized mice and triggered millisecond pulses of light. This caused the leg muscles of the mice to contract. When Llewellyn compared the muscle contractions stimulated by light to those generated using a similar electrical cuff, he found that the light-triggered contractions were much more similar to normal muscle activity.

Muscles are made up of two different fibers: small, slow, fatigue-resistant fibers that are typically used for tasks that require fine motor control over longer periods, and larger, faster fibers that can produce higher forces but are more fatigue-prone. In the body, the small, slow fibers are activated first, with the large, fast fibers reserved for quick bursts of power or speed. When muscles are stimulated with electrical pulses, the fast fibers activate first. With the optogenetic switch, however, the fibers were recruited in the normal, physiological order: slow fibers first, fast fibers second. By altering the intensity of the light, Llewellyn found that he could even trigger only the slow fibers--a feat not possible with electrical stimulation.

In the near term, Delp says, the technology will improve the studies that his lab and others do on muscle activity in animal models of stroke, palsies, ALS, and other neuromuscular disorders. He also hopes that in time--a long time, he concedes--such optical switches could be used to help patients with physical disabilities caused by nerve damage such as stroke, spinal cord injury, or cerebral palsy. One possibility, he says, would be to use optical stimulation in place of functional electrical stimulation (FES), in which electrical current is applied to specific nerves or muscles to trigger muscle contractions. The U.S. Food and Drug Administration has already approved FES devices that can restore hand function and bladder control to some paralyzed people. However, FES can quickly lead to muscle fatigue. Delp hopes that, particularly with grasping functions, using optical stimulation might result in better fatigue resistance and perhaps finer muscle control.

"This is a brilliant study, really beautiful science," says Robert Kirsch, a bioengineer at Case Western Reserve University and associate director of the Cleveland Functional Electrical Stimulation Center; he was not involved in the research. "I think there are many [clinical implications]," he says, although, like Delp and Llewellyn, he notes that many high hurdles must be cleared--not least of which is developing a safe, effective way to deliver the channelrhodopsin-2 gene to nerve cells in humans. Otherwise, Kirsch says, "my one objection would be their implication that they've solved the fatigue problem with FES. I'm pretty sure that hasn't happened." Instead, Kirsch believes that most of the fatigue seen in FES patients is due to muscle atrophy and weakness that develop in the chronically paralyzed.

C.J. Heckman, a professor of physiology at Northwestern University's Feinberg School of Medicine, agrees: "It is true that a lot of the fatigue seen in FES patients is due to chronic muscle atrophy." But, he says, "if you could stimulate the muscles in the correct recruitment order repeatedly over time, you could potentially recover a lot of muscle function." This could help paralysis patients preserve their slow muscle fibers, "which would be a huge deal," Heckman says. This is because those fibers do a huge percentage of the work muscles do--everything from maintaining posture to typing on a keyboard.

Delp also thinks that stimulation-based exercise could be an important application for optical muscle control, as could helping wheelchair-bound people stand to reach for books or plates in a cabinet. "I'm not super-high on controlling locomotion"--that is, walking--"with either electrical or optical stimulation, though," Delp says. "It's an incredibly complicated command-and-control scheme that's really hard to coordinate."

In the meantime, Delp and Llewellyn have begun an effort to use a different light-sensitive protein, halorhodopsin, to inhibit motor nerves in mice, with the idea of treating or even curing muscle spasticity, often a serious side effect to brain or spinal injury. Current treatments are far from ideal; doctors may inject botulinum toxin into the affected muscles every few months to paralyze them, use oral medications such as Valium that affect the whole body instead of just the affected muscle, or, in the most severe cases, cut the nerves or tendons of the spastic muscle--a permanent treatment that leaves the patient with no control over that muscle. Delp hopes that genetically engineering the nerves with halorhodopsin might enable people to use light to reversibly relax muscles affected with spasticity.

"I think that's a great idea for treating spasticity," says Jerry Silver, a neuroscientist at Case Western. There may be some difficulties along the way, though, he says. Working with Case colleagues, Silver has started a company called LucCell to develop clinical applications of optogenetics. In one company project, scientists are trying to use halorhodopsin and other inhibitory opsins in animal models to turn off the muscle that controls the bladder sphincter; their ultimate goal is to restore bladder function to paralyzed people. Though they have seen some physiological changes in how the sphincter muscle behaves, they haven't been able to get it to relax enough. "We're learning it's easier to turn things on than turn things off," he says. Still, the team is persisting, looking for better ways to deliver the gene to nerve cells and for ways to increase production of the protein on the cell's surfaces.

"It all depends on the ability to get the transgene in the right place in the person's genome without causing problems," agrees Llewellyn. "It's the main obstacle."

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Epileptic Seizures May Be Linked to an Ancient Gene Family

Epileptic Seizures May Be Linked to an Ancient Gene Family

  9:20:00 PM    Science Lover

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New research points to a genetic route to understanding and treating epilepsy. Timothy Jegla, an assistant professor of biology at Penn State University, has identified an ancient gene family that plays a role in regulating the excitability of nerves within the brain.

Artist's depiction of neurons firing in the brain. 
(Credit: iStockphoto/Sebastian Kaulitzki)

The research appears in the journal Nature Neuroscience.

"In healthy people, nerves do not fire excessively in response to small stimuli. This function allows us to focus on what really matters. Nerve cells maintain a threshold between rest and excitement, and a stimulus has to cross this threshold to cause the nerve cells to fire," Jegla explained. "However, when this threshold is set too low, neurons can become hyperactive and fire in synchrony. As excessive firing spreads across the brain, the result is an epileptic seizure."

Managing this delicate rest-excitement balance are ion channels -- neuronal "gates" that control the flow of electrical signals between cells. While sodium and calcium channels help to excite neurons, potassium channels help to suppress signaling between cells, increasing the threshold at which nerves fire. However, the genetic mechanisms that control the potassium channels and set this threshold are not fully understood. Jegla's team focused on a particular potassium-channel gene -- called Kv12.2 -- that is active in resting nerve cells and is expressed in brain regions prone to seizure.

"We decided that Kv12.2 was a good candidate for study because it is part of an old gene family that has been conserved throughout animal evolution," Jegla said. "This ancient gene family probably first appeared in the genomes of sea-dwelling creatures prior to the Cambrian era about 542-million years ago. It is still with us and doing something very important in present-day animals." Previous studies have suggested that the Kv12.2 potassium channel has a role in spatial memory, but Jegla and his team focused on how it might be related to seizure disorders.

In collaboration with Jeffrey Noebels at Baylor College of Medicine, the team used an electroencephalography (EEG) device to monitor the brains of mice. They found that mice missing the Kv12.2 gene did indeed have frequent seizures, albeit without convulsions. The team then stimulated mice with a chemical that induces convulsive seizures. They found that normal mice had a much higher convulsive-seizure threshold than mice with a defective Kv12.2 gene. The team also found the same results when they used a chemical inhibitor to block the Kv12.2 potassium channel in normal mice.

"In mice without a functioning Kv12.2 gene, nerve cells had abnormally low firing thresholds. Even small stimuli caused seizures," Jegla explained. "We think that this potassium channel plays a role in the brain's ability to remain 'quiet' and to respond selectively to strong stimuli."

Jegla hopes to open up new avenues of epilepsy research by studying whether activation of the Kv12.2 potassium channel in normal animals can block seizures. "Ion-channel defects have been identified in inherited seizure disorders, but many types of epilepsy don't have a genetic cause to begin with," Jegla explained. "They are often caused by environmental factors, such as a brain injury or a high fever. However, the most effective drugs used to treat epilepsy target ion channels. If we can learn more about how ion channels influence seizure thresholds, we should be able to develop better drugs with fewer side effects."

In addition to Jegla and Noebels, other scientists who contributed to this research include Xiaofei Zhang, Federica Bertaso, Karsten Baumgärtel, and Sinead M. Clancy of the Scripps Research Institute; Jong W. Yoo of the Baylor College of Medicine; and Van Lee, Cynthia Cienfuegos, Carly Wilmot, Jacqueline Avis, Truc Hunyh, Catherine Daguia, and Christian Schmedt of the Genomics Institute of the Novartis Research Foundation. This research was funded by the National Institutes of Health through its National Institute for Neurological Disorders and Stroke.

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Star-shaped Cells In Brain Help With Learning

Star-shaped Cells In Brain Help With Learning

  3:54:00 PM    Science Lover

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Every movement and every thought requires the passing of specific information between networks of nerve cells. To improve a skill or to learn something new entails more efficient or a greater number of cell contacts. Scientists at the Max Planck Institute of Neurobiology in Martinsried can now show, together with an international team of researchers, that certain cells in the brain, the astrocytes, actively influence this information exchange.

Some contact points between nerve cells (red) are surrounded by star-shaped cells known as astrocytes (green). It is now shown that via ephrinA3/EphA4 interactions, astrocytes influence the communication between nerve cells by removing the transmitter molecule glutamate. 

This so far unknown activity also has implications for the ability to learn. 

(Credit: Max Planck Institute of Neurobiology / Schorner, Klein & Paixão)

Until now, astrocytes were thought to have their main role in the development and nutrition of the brain's nerve cells. The new findings improve our comprehension of how the brain learns and remembers. They could also aid in the basic research of diseases such as epilepsy and the amyotrophic lateral sclerosis (ALS).
To live is to learn: Even fruit flies can learn to avoid detrimental odors and also in humans, most abilities are based on what we learn through practice and experience. Thus we are able to perform both fundamental processes such as walking and speaking and also master complex tasks such as logical reasoning and social interactions.

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