Wednesday, 5 March 2014
Stem cells from patients offer model and drug-discovery platform for early-onset form of disease
Wednesday, 05 March 2014
Harvard stem cell scientists have successfully converted skins cells from patients with early-onset Alzheimer's into the types of neurons that are affected by the disease, making it possible for the first time to study this leading form of dementia in living human cells. This may also make it possible to develop therapies far more quickly and accurately than before.
The research, led by Tracy Young-Pearse, PhD, and published in the journal Human Molecular Genetics, confirmed what had long been observed in mouse models — that the mutations associated with early-onset Alzheimer's disease are directly related to protein cleavage errors that cause a rise in amyloid-beta (Aβ) protein 42, which all people produce but somehow clump together to form plaques in Alzheimer's patients.
"We see this mild increase in Aβ42 in cells from patients with Alzheimer's disease, which seems to be enough to trigger disease processes," said Young-Pearse, a Harvard Stem Cell Institute Affiliated Faculty member at Brigham and Women's Hospital.
"We also see increases of a smaller species of amyloid-beta called Aβ38, which was unexpected as it should not be very aggregation prone. We don't fully understand what it means, but it may combine with other forms of amyloid-beta to stimulate plaque formation."
The patient-derived cells also possessed the second hallmark of Alzheimer's disease, high amounts of the tau protein, or more accurately tau that has been distorted so that the proteins tangle together. The relationship between amyloid-beta and tau is an ongoing chicken-and-egg debate in the Alzheimer's research field, with some researchers associating one or the other, or both, with the cause of the disease. But with the human cells, Young-Pearse and her team, including postdoctoral fellow and study first author Christina Muratore, PhD, could demonstrate that preventing amyloid-beta imbalances reduced levels of distorted tau.
"We used two different antibodies — one of which has been in clinical trials for Alzheimer's — to neutralize the effects of amyloid-beta and showed that you're able to rescue changes in tau," Young-Pearse said.
"Not only is it important experimentally to show that tau elevation is due in some part to altered amyloid-beta accumulation, but it also shows that this is an excellent system for testing different therapeutic options."
Clinical trials to treat neurodegenerative diseases like Alzheimer's have a historically high failure rate, partially because potential drugs are derived from research in non-human models. Young-Pearse and colleagues believe that their strategy of using induced pluripotent stem cells to reprogram patient skin cells into neurons of interest could be used to predict which therapeutics will best help early-onset Alzheimer's patients.
Alzheimer's disease comes in two forms. Both possess the well-known cognitive decline and memory loss, but occur at different times in the patient's life. Early-onset or familial Alzheimer's, which can begin to manifest in a person's 30s, 40s, and 50s, is the less common form. In these cases, genetic mutations have been inherited that lead to the disease. The more common sporadic or late-onset Alzheimer's occurs in a person's 70s, 80s, and 90s, and while certain genes may affect disease prognosis it is not associated with specific mutations.
"In familial Alzheimer's, it's pretty well accepted that a change in amyloid-beta generation sparks something that leads to disease," Young-Pearse said.
"In the sporadic form of the disease, we think the problem isn't necessarily with the generation of amyloid-beta, but possibly with its clearance."
Familial Alzheimer's also affects multiple generations, as the mutations that cause the disease are dominantly inherited and fully penetrant, which means that if a parent has a mutation, they have a 50 percent likelihood of passing the disease on to their children. This early-onset form tends to receive less attention and funding than the late-onset form because it makes up less than 2 percent of all of Alzheimer's cases — still more than half-a-million people.
Young-Pearse is next interested in using the patient-derived cells to figure out why Alzheimer's patients only show disease in areas of the brain, like the hippocampus, which is crucial for memory recall, and not the cerebellum, important for balance and movement. Her lab will examine amyloid-beta and tau in neurons not typically associated with the disease to understand why they remain unaffected. This work may also help identify which form of amyloid-beta is the most toxic.
Other Harvard Stem Cell Institute laboratories are also using patient-derived stem cells to study nervous system disease, like spinal muscular atrophy and amyotrophic lateral sclerosis, more commonly known as Lou Gehrig's disease. A therapeutic screening centre, heading by Lee Rubin, PhD, at the Harvard Department of Stem Cell and Regenerative Biology, is dedicated to using induced pluripotent stem cells to find new drugs for genetic diseases.
"Because of the Harvard Stem Cell Institute, we were able to work with other researchers to make patient cells into any type of neuron," said Young-Pearse, whose lab spent two years fine-tuning protocols with collaborators to generate the neurons needed for her early-onset Alzheimer's study.
"The environment provides a really nice system for testing many kinds of hypotheses."
Source: Harvard University
Contact: B.D. Colen
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Tuesday, 4 March 2014
Discovery advances efforts to replace damaged heart muscle
Tuesday, 04 March 2014
In a study that began in a pair of infant siblings with a rare heart defect, Johns Hopkins researchers say they have identified a key molecular switch that regulates heart cell division and normally turns the process off around the time of birth. Their research, they report, could advance efforts to turn the process back on and regenerate heart tissue damaged by heart attacks or disease.
In the heart muscle cell above, the arrows
show an early sign of replication. Credit:
Johns Hopkins Medicine.
"This study offers hope that we can someday find a way to restore the ability of heart cells to divide in response to injury and to help patients recover from many kinds of cardiac dysfunction," says cardiologist Daniel P. Judge, M.D., director of the Johns Hopkins Heart and Vascular Institute's Center for Inherited Heart Diseases.
"Things usually heal up well in many parts of the body through cell division, except in the heart and the brain. Although other work has generated a lot of excitement about the possibility of treatment with stem cells, our research offers an entirely different direction to pursue in finding ways to repair a damaged heart."
Unlike most other cells in the body that regularly die off and regenerate, heart cells rarely divide after birth. When those cells are damaged by heart attack, infection or other means, the injury is irreparable.
Judge's new findings, reported online March 4 in the journal Nature Communications, emerged from insights into a genetic mutation that appears responsible for allowing cells to continue replicating in the heart in very rare cases.
The discovery, Judge says, began with the tale of two infants, siblings born years apart but each diagnosed in their earliest weeks with heart failure. One underwent a heart transplant at three months of age; the other at five months. When pathologists examined their damaged hearts after they were removed, they were intrigued to find that the babies' heart cells continued to divide — a process that wasn't supposed to happen at their ages.
The researchers then hunted for genetic abnormalities that might account for the phenomenon by scanning the small percent of their entire genome responsible for coding proteins. One stood out: ALMS1, in which each of the affected children had two abnormal copies.
The Johns Hopkins researchers also contacted colleagues at The Hospital for Sick Children in Toronto, Canada, who had found the same heart cell proliferation in five of its infant patients, including two sets of siblings. Genetic analysis showed those children had mutations in the same ALMS1 gene, which appears to cause a deficiency in the Alström protein that impairs the ability of heart cells to stop dividing on schedule. The runaway division may be responsible for the devastating heart damage in all of the infants, Judge says.
These mutations, it turned out, were also linked to a known rare recessive disorder called Alström syndrome, a condition associated with obesity, diabetes, blindness, hearing loss and heart disease.
In further experiments, the Johns Hopkins researchers cultured mouse heart cells, and then turned off the ALMS1 gene. Compared to those with normal ALMS1 genes, the number of heart cells in samples without this gene increased by an additional 10 percent. The researchers then contacted colleagues at Jackson Laboratory in Maine who had genetically engineered and bred mice with an ALMS1 mutation. They found that the animals with the mutation had increased proliferation of heart cells after two weeks of age, compared to mice with a normal version of the ALMS1 gene. The cell proliferation did eventually stop in the mice, says Judge, an associate professor at the Johns Hopkins University School of Medicine.
Judge says precise knowledge of the regulatory role played by the ALMS1 mutation should advance the search for ways to help regenerate heart muscle tissue in a controlled fashion. Much work in the field of regeneration has been focused on the use of stem cells, which have the remarkable potential to develop into many different cell types.
Judge cautions that efforts to manipulate ALMS1 to repair damage would be tricky, because uncontrolled proliferation may lead to serious and even lethal complications.
"The children who helped us recognize the importance of this gene were born with a rare condition that leads to heart failure and many other problems, such as diabetes, obesity, blindness and deafness," he says.
"Now we hope to apply these discoveries to help millions of others with heart disease."
Source: Johns Hopkins Medicine
Contact: Stephanie Desmon
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Wednesday, 26 February 2014
Researchers Generate New Neurons in Brains, Spinal Cords of Living Adult Mammals
Wednesday, 26 February 2014
UT Southwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.
Although the research indicates it may someday be possible to regenerate neurons from the body's own cells to repair traumatic brain injury or spinal cord damage or to treat conditions such as Alzheimer's disease, the researchers stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements, a goal for future research.
Spinal cord injuries can lead to an irreversible loss of neurons, and along with scarring, can ultimately lead to impaired motor and sensory functions. Scientists are hopeful that regenerating cells can be an avenue to repair damage, but adult spinal cords have limited ability to produce new neurons. Biomedical scientists have transplanted stem cells to replace neurons, but have faced other hurdles, underscoring the need for new methods of replenishing lost cells.
Scientists in UT Southwestern's Department of Molecular Biology first successfully turned astrocytes – the most common non-neuronal brain cells – into neurons that formed networks in mice. They now successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. The latest findings are published today in Nature Communications and follow previous findings published in Nature Cell Biology.
"Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons," said Dr. Chun-Li Zhang, assistant professor of molecular biology at UT Southwestern and senior author of both studies.
"Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration," Dr. Zhang explained.
"Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming."
The scientists' two-step approach first introduces a biological substance that regulates the expression of genes, called a transcription factor, into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. Of 12 transcription factors tested, only SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said.
In the second step, the researchers gave the mice a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons. VPA has been used to treat epilepsy for more than half a century and also is prescribed to treat bipolar disorder and to prevent migraine headaches, he said.
The current study reports neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice, Dr. Zhang said. Researchers now are searching for ways to boost the number and speed of neuron creation. Neuroblasts took four weeks to form and eight weeks to mature into neurons, slower than neurogenesis reported in lab dish experiments, so researchers plan to conduct experiments to determine if the slower pace helps the newly generated neurons properly integrate into their environment.
In the spinal cord study, SOX2-induced mature neurons created from reprogramming of astrocytes persisted for 210 days after the start of the experiment, the longest time the researchers examined, he added.
Because tumour growth is a concern when cells are reprogrammed to an earlier stage of development, the researchers followed the mice in the Nature Cell Biology study for nearly a year to look for signs of tumour formation and reported finding none.
Source: UT Southwestern Medical Center
Contact: Deborah Wormser
In vivo conversion of astrocytes to neurons in the injured adult spinal cord
Zhida Su, Wenze Niu, Meng-Lu Liu, Yuhua Zou, Chun-Li Zhang
Nature Communications, 25 February 2014, 5, 3338, doi:10.1038/ncomms4338
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