Dementia memory loss explained

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The Dementia Caregiver's Little Book of Hope [Kindle Edition]

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http://news.nd.edu/news/27476-walking-through

-doorways-causes-forgetting-new-research-shows/

EVER WALK INTO A ROOM with some purpose in 

mind, only to forget what it was? It turns out, doors

 themselves are to blame for these strange memory lapses

. Can this contribute to dementia's wandering,

 confusion and problems with traveling?

---

Psychologists at the University of Notre Dame have

 discovered that passing through a doorway triggers 

what's known as an event boundary in the mind, se

parating one set of thoughts and memories from the 

next.

Your brain files away the thoughts you had in the 

previous room and prepares a blank slate for the new 

locale. 

It is referred to as a location-updating effect, and it

 results in a decline in memory when people move

 from one location to another. 

This may help explain the confusion a person with

 dementia experiences when they transition from one 

place to another, as well as when they wander or 

travel.

MORE INFORMATION:
Walking through doorways causes forgetting:
Further explorationsGabriel A. Radvansky, Sabine A. Krawietz, and Andrea K. Tamplin
Department of Psychology, University of Notre Dame, Notre Dame, IN, USA

Decrease dementia risk with normal blood sugars

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The Dementia Caregiver's Little Book of Hope [Kindle Edition]

Group Health Research Institute.

17 levels of sugar in 2000 people were tested for dementia risk. 17 times out of 17, higher sugar levels meant more risk. See the results. Learn the researchers' conclusions. 

---

A joint Group Health-University of Washington (UW) study in the New England Journal of Medicine has found that higher blood sugar levels are associated with higher dementia risk, even among people who do not have diabetes. (Continued below video.)

Continued below video...

Blood sugar levels averaged over a five-year period were associated with rising risks for developing dementia, in this report about more than 2,000 Group Health patients age 65 and older in the Adult Changes in Thought (ACT) study.

There was No Level Where Risk Leveled Off

For example, in people without diabetes, risk for dementia was 18 percent higher for people with an average glucose level of 115 milligrams per deciliter compared to those with an average glucose level of 100 mg/dl. And in people with diabetes, whose blood sugar levels are generally higher, dementia risk was 40 percent higher for people with an average glucose level of 190 mg/dl compared to those with an average glucose level of 160 mg/dl.

"The most interesting finding was that every incrementally higher glucose level was associated with a higher risk of dementia in people who did not have diabetes," said first author Paul K. Crane, MD, MPH, an associate professor of medicine at the UW School of Medicine, adjunct associate professor of health services at the UW School of Public Health, and affiliate investigator at Group Health Research Institute. "There was no threshold value for lower glucose values where risk leveled off."

Very Rich Data

"One major strength of this research is that it is based on the ACT study, a longitudinal cohort study, where we follow people for many years as they lead their lives," said senior author Eric B. Larson, MD, MPH, a senior investigator at Group Health Research Institute who also has appointments at the UW Schools of Medicine and Public Health. "We combine information from people's research visits every other year with data from their visits to Group Health providers whenever they receive care. And this gave us an average of 17 blood sugar measurements per person: very rich data."

These measurements included blood glucose (some fasting, some not) and glycated hemoglobin (also known as HbA1c). Blood sugar levels rise and fall in peaks and valleys throughout each day, but glycated hemoglobin doesn't vary as much over short intervals.

Combining glucose and glycated hemoglobin measures into a composite measure required special statistical techniques, which Drs. Crane and Larson's co-authors Rod Walker, MS, a biostatistician, and Rebecca Hubbard, PhD, an associate investigator, both from Group Health Research Institute, had developed. (Dr. Hubbard is also an affiliate assistant professor of biostatistics at the UW School of Public Health.) These sophisticated statistical models required specialized data on the relationships between glycated hemoglobin and glucose levels, and they used data generated by co-author David M. Nathan, MD, a professor of medicine at Harvard Medical School and director of the Diabetes Center at Massachusetts General Hospital.

Related Videos & Articles:

• Sugar & Alzheimer's
• Less Sugar, More Memory (Video + Article)

So should people try to eat less sugar -- or foods with a lower "glycemic index"? Not necessarily, Dr. Crane said: "Your body turns your food into glucose, so your blood sugar levels depend not only on what you eat but also on your individual metabolism: how your body handles your food." But he does suggest that taking walks couldn't hurt: The ACT study has previously linked physical activity to later onset and reduced risk of dementia, including Alzheimer's disease.

Furthermore, Dr. Crane emphasized that these results come from an observational study: "What we found was that people with higher levels of glucose had a higher risk of dementia, on average, than did people with lower levels of glucose," he said. "While that is interesting and important, we have no data to suggest that people who make changes to lower their glucose improve their dementia risk. Those data would have to come from future studies with different study designs."

Source:

Group Health Research Institute.

Where Alzheimer's Begins

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Columbia University Medical Center.

ROOTS OF ALZHEIMER'S: 

Columbia University researchers have pinpointed 3 discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better. 

---

Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journalNature Neuroscience.

Alzheimer's disease starts in the entorhinal cortex (yellow). Using fMRI in mouse (left) and human (right) brains, the researchers provide evidence that the disease spreads from the entohrinal cortex (yellow) to other cortical regions (red) -- the perirhinal cortex and posterior parietal cortex. (Credit: Usman Khan/lab of Scott A. Small, MD, Columbia University Medical Center.)

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. "But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's," said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.

"Dr. Richard Mayeux's WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer's disease," said Dr. Small. "This study has given us a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage."

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) -- a measure of metabolic activity -- in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small's lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.

The study has implications for both research and treatment. "Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions," said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.

For Elderly with Dementia, Better Eating Slows Depression, Improves BMI

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MPR

 

(HealthDay News) – For elderly adults with dementia, symptoms of depression can be improved through nutritional improvement interventions, according to a study published in the Journal of Advanced Nursing.
Hua-Shan Wu, PhD, RN, from Chung Shan Medical University in Taiwan, and Li-Chan Lin, PhD, RN, from National Yang-Ming University in Taiwan tested the effectiveness of a combination of methods to teach eating procedures to elderly adults (mean age, 82.8 years) with dementia. A group of 25 participants received fixed spaced retrieval memory training combined with Montessori-based activities over 24 sessions, through which structured activities relating to daily life were sequentially and repetitively practiced. The same intervention was delivered to 38 participants in an individualized group, which made adjustments for each participant's learning response. A routine care group included 27 participants. At the pre-test, posttest, and at one, three, and six months of follow-up, body mass index was recorded and participants were scored according to the Chinese version of the Mini-Nutritional Assessment and Cornell Scale for Depression in Dementia.
The researchers found that, over time, the Mini-Nutritional Assessment scores and body mass index of the fixed and individualized groups increased significantly. As a result of the improvement in the Mini-Nutritional Assessment scores arising from the individualized intervention, the Cornell Scale for Depression in Dementia scores were significantly reduced.
"Individualized spaced retrieval combined with Montessori-based activities produced nutritional improvements that could moderate depressive symptoms in residents with dementia," write the authors.

Discovery of new drug targets for memory impairment in Alzheimer's disease

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The Dementia Caregiver's Little Book of Hope [Kindle

Medical Xpress

 

Research team in Korea has discovered that reactive astrocytes, which have been commonly observed in Alzheimer's patients, aberrantly and abundantly produce the chief inhibitory neurotransmitter GABA and release it through the Best1 channel. The released GABA strongly inhibits neighboring neurons to cause impairment in synaptic transmission, plasticity and memory. This discovery will open a new chapter in the development of new drugs for treating such diseases.

 Alzheimer's disease, which is the most common cause of dementia, is fatal and currently, there is no cure. In Alzheimer's disease, brain cells are damaged and destroyed, leading to devastating memory loss. It is reported that 1 in 8 Americans aged 65 or over have Alzheimer's disease. In 2011, 7,600 elderly people with dementia lost their way back home and became homeless in Korea. However, to date, there has been no clear understanding of the mechanisms underlying dementia in Alzheimer's disease. So far, neuronal death is the only proposed mechanism available in scientific literature.

The research team led by Dr. C. Justin Lee at Korea Institute of Science and Technology (KIST) and Dr. Daesoo Kim(KAIST) discovered that reactive astrocytes in the brains of Alzheimer's disease model mice produce the inhibitory transmitter GABA by the enzyme Monoamine oxidase B (MAO-B) and release GABA through the Bestrophin-1 channel to suppress normal information flow during synaptic transmission. Based on this discovery, the team was able to reduce the production and release of GABA by inhibiting MAO-B or Bestrophin-1, and successfully ameliorate impairments in neuronal firing, synaptic transmission and memory in Alzheimer's disease model mice.

In the behavioral test, the team used the fact that mice tend to prefer dark places. If a mouse experiences an electric shock in a dark place, it will remember this event and avoid dark places from then on. However, a mouse with modeled Alzheimer's disease cannot remember if such shock is related to dark places and keeps going back to dark places. The team demonstrated that treating these mice with a MAO-B inhibitor fully recovered the mice's memory. The selegiline is currently used in Parkinson's disease as an adjunct therapy and considered as a one of best promising medicine for MAO-B inhibitor. But it has been previously shown to be less effective in Alzheimer's

 

Diet may improve Alzheimer's

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News Fix

 
A study suggests that a high fat, low carbohydrate diet can help improve Alzheimer’s disease in mice.
It’s been previously suggested that a high fat diet may predispose the brain to Alzheimer’s disease, perhaps by clogging up the arteries. Researchers in Colorado seem to be suggesting the opposite – at least from animal studies.
They have been looking at a group of mice with the equivalent of Alzheimer’s disease. Giving the animals a diet that is high in fat, low in carbohydrate, reduces the amount of beta-amyloid, the brain protein deposits which are the hallmarks of Alzheimer’s disease. The researchers explain their results suggesting that insulin and insulin-related growth factor may be involved. In this kind of diet, insulin seems to be able to break up the amyloid deposits. Other studies have looked at fat in the presence of high carbohydrate. When the carbohydrates are reduced, insulin may behave in a more positive way.

 

Alzheimer's Disease Symptoms Reversed in Mice (part 2)

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Scientific American

 

by Gary Stix

 

The study also provides the most compelling evidence to date of how the biggest risk factor for Alzheimer's later in life—having the so-called Apolipoprotein E (APOE) gene, identified in the early 1990s—might yield a strategy for new therapies. The gene for apolipoprotein E comes in three versions, one of which, the e4 variant, confers a significantly higher risk of getting the disease—a roughly 60 percent chance at age 80 for those who carry a copy from both their mother and father, as against a less than 10 percent overall risk at that age in the general population. The gene variant, known informally as the Alzheimer's gene, is common: about 20 percent of the U.S. population has at least one copy. The e4 carriers may be vulnerable to Alzheimer's because they have a diminished ability to clear amyloid, a hypothesis that seems to be reinforced by this Case Western study.

Jumping the gun?
That idea, though, is not universally endorsed. Some experiments have shown that the e4 version may also impair the brain in other ways, perhaps by bollixing the biochemical functioning at the synapses, the connection points between neurons, or by producing toxic fragments of the lipoprotein that damage neurons. If so, increasing the production of this form of apolipoprotein E could actually worsen the pathology of the disease and would complicate greatly bexarotene's development.
This potential hurdle does not dissuade one researcher experienced in Alzheimer's clinical trials. "I am not particularly concerned" about potential toxic effects of extra e4 production, says Paul Aisen of the University of California, San Diego, who heads the Alzheimer's Disease Cooperative Study, which organizes clinical trials for drugs to combat the illness. "If it significantly enhances amyloid clearance and reduces the burden of brain amyloid, there is a good chance it will succeed." David Holtzman, a prominent Alzheimer's researcher from Washington University in Saint Louis, echoes the sentiment about bexarotene's prospects: "I do think it is promising to go into humans."
Landreth and Cramer certainly think so. They have formed a company called ReXceptor Therapeutics that intends to begin a preliminary trial in humans in the next few months to determine whether the drug crosses the blood–brain barrier and clears amyloid, as it does in mice. If those processes occur, clinical trials on the drug's effectiveness in humans could begin even this year, and they would probably last from 18 months to three years. The drug loses patent protection for cancer this year, but Case Western has filed for patents for its use in Alzheimer's.
Many unknowns
Despite their optimism, scientists say it's important not to overplay the progress. After all, drugs that work in mice do not necessarily help humans. Moreover, the genetically engineered version of mice used in this study do not recapitulate every aspect of the human disease. For instance, the mice do not experience the effects of dying neurons (despite having impaired cognition), and they do not go on to develop a hallmark characteristic of a later disease stage in humans—namely, the accretion of so-called tau proteins that seem to abet the killing of nerve cells. "Transgenic mouse experiments have not reliably predicted therapeutic effects in humans," Aisen says, "so caution is essential until human studies confirm target engagement," that is, the removal of amyloid plaques.
And bexarotene does not come without risk: it raises levels of triglycerides, blood fats implicated in cardiovascular disease and diabetes. The Case Western mouse work suggests that Alzheimer's patients may benefit with doses lower than those ingested for cancer treatment, which might produce less of an effect on fat levels. Whether the drug remains effective over time is another question. The levels of amyloid plaques—although not the apparently more toxic soluble form of the peptide—rose after 90 days, a suggestion that the drug may be metabolized differently after ingestion over long periods.
The enthusiasm generated for a mouse study stems from the desperation for new ideas as the number of Alzheimer's cases, now at 5.4 million in the U.S., is expected to more than double by the year 2050 as the nation's demographic profile continues to gray. A better understanding of the disease process—the knowledge that pathology begins 10 or 20 years before the first symptom—has shifted focus toward earlier drug trials. New technologies that combine brain imaging and spinal fluid tests might identify at-risk patients and test new drugs. A relatively inexpensive drug that can be ingested orally, such as bexarotene, could then be prescribed to at-risk but symptom-free patients, who would take them over the course of their lifetimes, like a cholesterol-lowering drug.
As ReXceptor moves forward with its clinical trial plans, it will inevitably have to contend with the demands of the families of Alzheimer's patients. Landreth emphasizes that calling your physician after reading an article like this one is a bad idea. "Don't try this at home," he cautions, "because we don't know we what dose to give, we don't know how frequently to give it, and there are a few nuances to its administration. So one shouldn't be prescribing it off-label." It is also unclear whether a drug like bexarotene would work at a middle or advanced stage of the disease, when neurodegenerative processes have already set in.
Bexarotene's genesis as an Alzheimer's treatment comes as an outgrowth of Landreth's long-time fundamental work on cell receptors. If it succeeds, it will demonstrate that new ideas for treating this seemingly intractable disease may come from beyond the sometimes narrowly focused strategies of large pharmaceutical companies.

Alzheimer's Disease Symptoms Reversed in Mice

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Scientific American

 

A cancer drug given to mice eliminates brain-damaging proteins, leading to improved cognition within days, but will it work in humans?

By Gary Stix

 

A nearly 13-year-old skin cancer drug rapidly alleviates molecular signs of Alzheimer's disease and improves brain function, according to the results of a new mouse study being hailed as extremely promising. Early-stage human clinical trials could begin within months.

In the study, published online February 9 by Science, researchers from Case Western Reserve University in Cleveland and colleagues used mice genetically engineered to exhibit some of the symptoms of Alzheimer's. Most notably, the mice produced amyloid beta peptides—toxic protein fragments that gum up neurons and lead to cell death—and showed signs of forgetfulness.

Amyloid beta (red areas) peptides clear from the brain of an Alzheimer's mouse after three days of treatment with a cancer drug (right image). Source: AAAS/Science
The Case Western team, led by Gary Landreth, decided to try the drug bexarotene (Targretin), approved in 1999 for cutaneous T cell lymphomas. The team chose this drug because of its long experience working with proteins in the nucleus of brain cells that can induce biochemical processes that affect amyloid beta.
Landreth and his colleagues fed bexarotene to the demented mice, and with just a single dose it lowered the most toxic form of the amyloid beta peptide by 25 percent within six hours, an effect that lasted for up to three days. Mice that were cognitively impaired by the amyloid buildup resumed normal behaviors after 72 hours: They began to crinkle toilet paper placed nearby to make nests, a skill lost as amyloid increased in their brains.
"We have successfully reversed all of the known pathological features and behavioral deficits found in mouse models of Alzheimer's disease," Landreth says. "Never before has anyone observed clearance of amyloid plaques with such speed in mouse models."
Other Alzheimer's researchers hail the work. "I think this is extremely promising," says Samuel Gandy, a professor of neurology and psychiatry at Mount Sinai School of Medicine and associate director of the hospital's Alzheimer's Disease Research Center. "One of the drugs that has been on our wish list for 25 years is a drug that would clear existing amyloid deposits."
"Landreth's paper is impressive," adds Kenneth Kosik, a neuroscientist at the University of California, Santa Barbara. "The effects in mice, including some restoration of cognitive abilities, are dramatic."
Neural sanitation
In a field littered with drug failures, the study offers hope that the strategy of clearing the brain of the toxic peptide can work. Bexarotene does not do so directly, however; instead, it activates retinoid receptors on brain cells that increase production of a fat-protein complex, apolipoprotein E, that helps rid excess amyloid in the fluid-filled space between neurons. It also appears to enhance another cleanup process, called phagocytosis.
Bexarotene functions differently than an amyloid-clearance approach using monoclonal antibodies, which are further down the drug development pipeline. These antibodies bind directly to amyloid and then remove it, but they have sometimes caused fluid to fill brain tissue. Bexarotene may be less likely to cause such swelling. "I think the fact that we're inducing a natural process by turning on these receptors doesn't lend itself to water on the brain," says Paige Cramer, Landreth's graduate student who performed much of the research. Unlike bexarotene, which is taken orally, monoclonals are more troublesome to administer, because they must be delivered intravenously, and if they receive U.S. Food and Drug Administration approval, they would likely be significantly more expensive.

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Genetic markers may predict dementia

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Fox News

 

Scientists have identified early genetic markers that can potentially predict who is at an increased risk for developing Alzheimer’s, Medical Daily reported.
Currently, in order to determine if someone will develop Alzheimer’s disease, doctors use tests that analyze the amount of Tau protein buildup in the central nervous system. The more Tau in an individual’s system, the more likely he or she will progress towards dementia.
However, there was no system to help determine who will start expressing this protein years ahead of time – until now.
Researchers from Washington University School of Medicine in St. Louis have identified genetic mutations that can influence the accumulation of Tau proteins, according to Medical Daily. This discovery could potentially lead to an early genetic test, which could help reveal those who are most at risk for Alzheimer’s – leading to earlier, more effective treatments.
"We have identified several genes that influence the levels of soluble tau in the cerebrospinal fluid,” senior author Dr. Alison Goate, of WU School of Medicine, told Medical Daily, “and we show that one of these genes also influences risk for Alzheimer's disease, rate of cognitive decline in Alzheimer's disease, and density of tangle pathology in the brain."
After performing a genetic analysis on 1,269 patients, Goate and her team identified genetic mutations in a previously implicated region, found in the gene TREM2, as putting people at risk for Alzheimer’s. A receptor gene, TREM2 can actually influence the development of another similar gene TREML2.
According to the researchers, the two genes – while similar – acted oppositely in association with the Tau protein levels. The first was associated with risk for Alzheimer’s and the other was protective against the disease.
Goate said the team would continue to perform more studies to determine the full effects of the gene mutations on nervous systems in the brain.
The research was published in the journal Neuron.

 

Converting a Person's Own Cells into Functional Neurons with PTB

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UC San Diego

Repression of a single protein in ordinary fibroblasts is sufficient to directly convert the cells – abundantly found in connective tissues – into functional neurons. The findings, which could have far-reaching implications for the development of new treatments for neurodegenerative diseases like Huntington’s, Parkinson’s and Alzheimer’s, will be published online in advance of the January 17 issue of the journal Cell.

In recent years, scientists have dramatically advanced the ability to induce pluripotent stem cells to become almost any type of cell, a major step in many diverse therapeutic efforts.  The new study focuses upon the surprising and singular role of PTB, an RNA-binding protein long known for its role in the regulation of alternative RNA splicing.

Confocal micrograph of a primary human fibroblast cell grown in  culture stained blue for actin, a highly abundant protein that makes up the cytoskeleton of cells. Energy-producing mitochondria are shown in green. Image courtesy of Matthew Daniels, University of Oxford and Wellcome Images.

In in vitro experiments, scientists at University of California, San Diego School of Medicine and Wuhan University in China describe the protein’s notable regulatory role in a feedback loop that also involves microRNA – a class of small molecules that modulate the expression of up to 60 percent of genes in humans. Approximately 800 miRNAs have been identified and characterized to various degrees.

One of these miRNAs, known as miR-124, specifically modulates levels of PTB during brain development. The researchers found that when diverse cell types were depleted of PTB, they became neuronal-like cells or even functional neurons – an unexpected effect. The protein, they determined, functions in a complicated loop that involves a group of transcription factors dubbed REST that silences the expression of neuronal genes in non-neuronal cells.

According to principal investigator Xiang-Dong Fu, PhD, professor of cellular and molecular medicine at UC San Diego, it’s not known which neuronal signal or signals turn on the loop, which in principle can happen at any point in the circle. But the ability to artificially manipulate PTB levels in cells, inducing them to become neurons, offers tantalizing possibilities for scientists seeking new treatments for an array of neurodegenerative diseases.

It is estimated that over a lifetime, one in four Americans will suffer from a neurodegenerative disease, from Alzheimer’s and Parkinson’s to multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig’s disease).

“All of these diseases are currently incurable. Existing therapies focus on simply trying to preserve neurons or slow the rate of degeneration,” said Fu. “People are working with the idea of replacing lost neurons using embryonic stem cells, but there are a lot of challenges, including issues like the use of foreign DNA and the fact that it’s a very complex process with low efficiency.”

Fu explained that REST is expressed in cells everywhere except in neurons. PTB is itself a target of miR-124, but also acts as a break for this microRNA to attack other cellular targets that include REST, which is responsible for repressing miR-124. 

In non-neuronal cells, REST keeps miR-124 down and PTB enforces this negative feedback loop, but during neural induction, miR-124 is induced, which diminishes PTB, and without PTB as a break, REST is dismantled, and without REST, additional miR-124 is produced.  This loop therefore becomes a positive feed forward, which turns non-neuronal cells into neurons.

“If we learn how to manipulate PTB, which appears to be a kind of master regulator, we might eventually be able to avoid some of these problems by creating new neurons in patients using their own cells adjacent deteriorating neurons,” said Fu.

Co-authors are Yuanchao Xue and Yu Zhou, Wuhan University, China and UCSD Department of Cellular and Molecular Medicine; Kunfu Ouyang, Gang Wang and Ju Cheng, UCSD Department of Medicine; Jie Huang, Qijia Wu, Yanzhen Bi, Li Jiang, Zhiqiang Cai, Hui Sun, UCSD Department of Cellular and Molecular Medicine; Hong Ouyang and Kang Zhang, UCSD Institute of Genomic Medicine; Hairi Li and Chaoliang Wei, UCSD Department of Cellular and Molecular Medicine; and Yi Zhang, Wuhan University, China and Center for Genome Analysis, Wuhan, China.

Funding for this research came, in part, from National Institutes of Health grants (GM049369, GM052872 and HG004659) and the China 973 programs.

# # #

Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu