TAG: "Alzheimer’s"

Grant supports creation of patient-derived stem cell lines to study Alzheimer’s


UC Irvine MIND effort is part of institute’s larger iPS Cell Bank Initiative.

Frank LaFerla (left) and Mathew Blurton-Jones of UC Irvine will use a special type of stem cell to explore the underlying biology and treatment of Alzheimer's disease.

Frank LaFerla (left) and Mathew Blurton-Jones of UC Irvine will use a special type of stem cell to explore the underlying biology and treatment of Alzheimer's disease.

Researchers at UC Irvine’s Institute for Memory Impairments and Neurological Disorders have received a two-year, $600,000 grant from the National Institute on Aging to develop and study patient-derived stem cell lines.

Led by Frank LaFerla and Mathew Blurton-Jones, the UCI MIND team will create as many as 40 sets of induced pluripotent stem cells to explore the underlying biology of Alzheimer’s disease and test novel therapeutic approaches.

Few discoveries have as much potential to transform modern medical research as iPS cells. They’re capable of giving rise to every cell type in the human body, including the key cell types implicated in Alzheimer’s disease: neurons, astrocytes and microglia.

Because iPS cells can be generated from patients with a given disease, they offer a powerful new way to study the influence of genetics on disease risk and progression. UCI MIND investigators, who do not use embryonic stem cells, have pioneered this avenue of research specifically for Alzheimer’s disease.

“The ability to reprogram cells from adult subjects to make iPS cells is a giant leap forward for science,” said LaFerla, UCI MIND director and Chancellor’s Professor and chair of neurobiology & behavior. “And we’re excited that UCI MIND is at the forefront of using this technology in the battle against Alzheimer’s disease.”

It’s notable that iPS cells can be derived from skin or blood samples. Anyone, even older adults, can easily donate the material needed. Additionally, by harvesting these cells from the patient, transplantation-based therapies could – researchers hope – one day be administered without the need for immunosuppression.

The work funded by the NIA falls under the UCI MIND iPS Cell Bank Initiative, an effort to create a repository of Alzheimer’s disease iPS cells that can be accessed by scientists around the world.

The iPS Cell Bank, which will be part of UCI MIND’s National Institutes of Health-designated Alzheimer’s Disease Research Center, is receiving considerable support through the Keith Swayne Family Challenge.

In honor of his wife, Judy Swayne, who has Alzheimer’s disease, Keith Swayne and his family have pledged $150,000 in the form of a challenge. They will match every dollar raised up to $150,000, bringing the total to $300,000 when the challenge is met. These funds will help establish and expand the UCI MIND iPS Cell Bank.

For more information about the Keith Swayne Family Challenge, go to http://mind.uci.edu/keith-swayne-family-challenge.

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Origin of Alzheimer’s gene discovered


UC Santa Barbara researcher tracks source to a single founder dating from Habsburg Spain.

Kenneth Kosik, UC Santa Barbara

Kenneth Kosik, UC Santa Barbara

The age and origin of the E280A gene mutation responsible for early-onset Alzheimer’s in a Colombian family with an unusually high incidence of the disease has been traced to a single founder dating from the 16th century.

Kenneth S. Kosik, Harriman Professor in Neuroscience at UC Santa Barbara and co-director of the campus’s Neuroscience Research Institute (NRI), conducted the study. The findings appear in the journal Alzheimer’s & Dementia.

“Some mutations just increase your risk, but this mutation is not a risk,” Kosik said. “This mutation is highly penetrant, which means that if you carry the mutation, you will get early-onset Alzheimer’s disease.”

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Understanding a protein’s role in familial Alzheimer’s disease


Findings could inform development of effective drugs for the neurodegenerative disease.

Lawrence Goldstein, UC San Diego

Lawrence Goldstein, UC San Diego

Researchers at the UC San Diego School of Medicine have used genetic engineering of human induced pluripotent stem cells to specifically and precisely parse the roles of a key mutated protein in causing familial Alzheimer’s disease (AD), discovering that simple loss-of-function does not contribute to the inherited form of the neurodegenerative disorder.

The findings, published online in the journal Cell Reports, could help elucidate the still-mysterious mechanisms of Alzheimer’s disease and better inform development of effective drugs, said principal investigator Lawrence Goldstein, Ph.D., professor in the Departments of Cellular and Molecular Medicine and Neurosciences and director of the UC San Diego Stem Cell Program.

“In some ways, this is a powerful technical demonstration of the promise of stem cells and genomics research in better understanding and ultimately treating AD,” said Goldstein, who is also director of the new Sanford Stem Cell Clinical Center at UC San Diego. “We were able to identify and assign precise limits on how a mutation works in familial AD. That’s an important step in advancing the science, in finding drugs and treatments that can slow, maybe reverse, the disease’s devastating effects.”

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Gladstone scientist to receive Pacesetter Award


Lennart Mucke honored for leadership in Alzheimer’s disease research.

Lennart Mucke

Lennart Mucke

Lennart Mucke, M.D., who directs neurological research at the Gladstone Institutes, next week will receive the ARCS Foundation’s 2013 Pacesetter Award for his lifelong dedication to overcoming Alzheimer’s disease — and for mentoring students to take a similar approach.

The award, the second received by a Gladstone scientist, underscores the quality of research being conducted at this independent biomedical-research organization that was founded in San Francisco in 1979. The ARCS Foundation — which provides awards to academically outstanding U.S. citizens studying science, engineering and medical research — will present the award to Mucke at an Oct. 28 luncheon honoring and celebrating ARCS Foundation scholars. Mucke will give the luncheon’s keynote address, speaking about what it will take to defeat Alzheimer’s disease.

“Dr. Mucke leads Gladstone’s neurological research with a strong emphasis on collaboration and multi-pronged approaches to finding new disease solutions,” said Roulhac Austin, ARCS Foundation Northern California Chapter co-president. “The ARCS membership applauds this approach and believes it has contributed to Dr. Mucke’s major insights into Alzheimer’s disease — insights we hope will lead to new and desperately needed treatments.”

To be sure, this acknowledgement of Mucke’s success in Alzheimer’s research comes at a critical time. Currently, there are no effective treatments to slow, prevent or halt this neurodegenerative disease — which robs people of critical brain functions including the ability to retain memories. As our nation’s sixth leading cause of death, Alzheimer’s afflicts one in nine Americans aged 65 or older, according to the Alzheimer’s Association. And the number of those with Alzheimer’s is expected to nearly triple by 2050 — threatening to overwhelm our health care system.

In accepting the Pacesetter Award, Mucke joins the ranks of other pre-eminent San Francisco Bay Area executives who ARCS also has honored, including John Chambers, chairman and CEO of Cisco Systems; Paul Otellini, former president and CEO of Intel; and Susan Desmond-Hellmann, chancellor of  UC San Francisco, with which Gladstone is affiliated.

“I am deeply honored to receive this award from an organization whose objectives are so nicely aligned with Gladstone’s,” said Mucke, who is also a professor of neurology and the Joseph B. Martin Distinguished Professor of Neuroscience at UCSF. “They promote science and medical research — and emphasize the values of using a collaborative, multifaceted approach. These are founding tenets at Gladstone and will be critical to achieving our goals of better treating, preventing and ultimately curing neurological diseases such as Alzheimer’s.”

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Groundbreaking 90+ Study will continue


National Institute on Aging renews funding for UC Irvine’s study of the “oldest old.”

Claudia Kawas, UC Irvine

Claudia Kawas, UC Irvine

UC Irvine’s trailblazing 90+ Study, launched in 2003 to learn more about the “oldest old,” the fastest-growing age group in the U.S., will continue for at least another five years, thanks to a $9.5 million renewal grant from the National Institute on Aging.

Previously funded by two five-year NIA awards totaling $20 million, the 90+ Study is the longest continuing research effort focused exclusively on the distinctive health and lifestyle issues of Americans in their 90s or older.

It’s among the largest studies of the oldest old in the world, with clinical, pathological and genetic research being conducted on more than 1,600 participants. Based at the Clinic for Aging Research & Education in Laguna Woods, the project is co-directed by Dr. Claudia Kawas, a geriatric neurologist and professor of neurology and neurobiology & behavior, and Maria Corrada, an epidemiologist and associate adjunct professor of neurology.

“We are fortunate in this time of sequestration that our comprehensive and robust study continues to receive federal funding,” Kawas said. “There truly isn’t anything like the 90+ Study. Results obtained thus far have provided researchers across the globe with valuable information about aging.”

While there are currently nearly 2 million nonagenarians in the U.S., that number is projected to increase to 10 million to 12 million by the middle of the century, raising concerns that the current health care system may not be able to accommodate this population.

The UC Irvine study is among the few to look at dementia in people over age 90. The progressive brain dysfunction gradually curtails daily activities. The most well-known type of dementia is Alzheimer’s disease. Symptoms include memory loss, cognitive disorientation and behavioral changes. Dementia affects not only patients but also people surrounding them, as long-term care is often required.

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Single gene mutation linked to neurological disorders


From Lesch-Nyhan syndrome to Alzheimer’s, Parkinson’s and Huntington’s diseases.

Theodore Friedmann, UC San Diego

Theodore Friedmann, UC San Diego

A research team, headed by Theodore Friedmann, M.D., professor of pediatrics at the UC San Diego School of Medicine, says a gene mutation that causes a rare but devastating neurological disorder known as Lesch-Nyhan syndrome appears to offer clues to the developmental and neuronal defects found in other, diverse neurological disorders like Alzheimer’s, Parkinson’s and Huntington’s diseases.

The findings, published in today’s (Oct. 9) issue of the journal PLOS ONE, provide the first experimental picture of how gene expression errors impair the ability of stem cells to produce normal neurons, resulting instead in neurological disease. More broadly, they indicate that at least some distinctly different neurodevelopmental and neurodegenerative disorders share basic, causative defects.

The scientists say that understanding defects in Lesch-Nyhan could help identify errant processes in other, more common neurological disorders, perhaps pointing the way to new kinds of therapies.

Lesch-Nyhan syndrome is caused by defects in the HPRT1 gene (short for hypoxanthine guanine phosphoribosyltransferace, the enzyme it encodes), a gene that is well-known for its essential “housekeeping duties,” among them helping generate purine nucleotides – the building blocks of DNA and RNA.

Mutations in the gene result in deficiencies in the HPRT enzyme, leading to defective expression of the neurotransmitter dopamine and subsequent abnormal neuron function. HPRT mutation is known to be the specific cause of Lesch-Nyhan, an inherited neurodevelopmental disorder characterized by uncontrollable repetitive body movements, cognitive defects and compulsive self-mutilating behaviors. The disorder was first described in 1964 by medical student Michael Lesch and his mentor, William Nyhan, M.D., professor emeritus at UC San Diego School of Medicine.

Using mouse embryonic stem cells modified to be HPRT-deficient, Friedmann and colleagues discovered that the cells do not develop normally. Instead, they differentiate from full-fledged neurons into cells that resemble and partially function as neurons, but also perform functions more typical of glial cells, a kind of supporting cell in the central nervous system. In addition, they noted that HPRT deficiency causes abnormal regulation of many cellular functions controlling important operational and reproduction mechanisms, DNA replication and repair and many metabolic processes.

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Early imaging, diagnosis of Alzheimer’s leads to better outcomes


Study comes as Medicare reviews reimbursement policies for PET scans in dementia cases.

Daniel Silverman, UCLA

Daniel Silverman, UCLA

UCLA researchers report for the first time that patients with early symptoms of Alzheimer’s disease who are diagnosed sooner than usual using a brain-imaging test receive medications earlier and have significantly better clinical outcomes over subsequent years.

The findings come from the Metabolic Cerebral Imaging in Incipient Dementia study, an ongoing national clinical trial sponsored by the Centers for Medicare and Medicaid Services (CMS). The interim data show that patients whose doctors gleaned information from a brain PET scan performed with the tracer FDG — which measures energy being used throughout regions of the brain — did better over two years of follow-up than those whose doctors were randomized to not have access to the scan information.

“During the subsequent two years after their PET scans, these patients had superior executive function, better memory abilities and greater preservation of overall cognitive function,” said Dr. Daniel Silverman, a professor of molecular and medical pharmacology at UCLA and the study’s principal investigator.

The research, Silverman said, provides “the first direct evidence that patients whose early Alzheimer’s disease is revealed by FDG–PET will do better than patients with the same condition but with their brain metabolism pattern remaining unknown to their doctors and themselves.”

The findings from the study are being presented Sept. 26 at the Medical Biotech Forum in China.

Medicare currently does not reimburse for PET scans for patients who show signs of persistent cognitive decline but do not yet have dementia, Silverman said. By the time Medicare covers an FDG–PET scan — for which they reimburse about $1,200 per patient — significant damage, some of it irreversible, has already been done to the brain tissue.

Medicare currently is re-examining reimbursement policies for PET scans obtained in dementia cases, specifically with respect to amyloid imaging (which includes Alzheimer’s imaging). A national coverage decision is expected Oct. 1, Silverman said.

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Committed to memory


UC Irvine will host Southern California Alzheimer’s Disease Resarch Conference Sept. 20.

Frank LaFerla, UC Irvine

Frank LaFerla, UC Irvine

As record numbers of Americans reach retirement, finding effective ways to prevent and treat Alzheimer’s disease – the No. 1 age-related disorder – becomes increasingly important. In Orange County, UC Irvine’s Institute for Memory Impairments and Neurological Disorders leads the way in Alzheimer’s research and education.

Each year, UCI MIND hosts one of the field’s most influential events, the Southern California Alzheimer’s Disease Research Conference, which features speakers and presentations showcasing the latest breakthroughs. The 2013 conference will be held Friday, Sept. 20, at the Hilton Orange County/Costa Mesa.

Frank LaFerla, UCI MIND director and Chancellor’s Professor and chair of neurobiology & behavior, helped organize the event. For more than a decade, he and his collaborators have made seminal discoveries about the mechanisms of Alzheimer’s and how to limit associated memory decline.

Read a Q&A with LaFerla

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Brain circuitry loss may be sign of cognitive decline in healthy elderly people


Changes in fornix could point to very early marker for future decline.

A brain showing the fornix structure highlighted.

A brain showing the fornix structure highlighted.

The degeneration of a small, wishbone-shaped structure deep inside the brain may provide the earliest clues to future cognitive decline, long before healthy older people exhibit clinical symptoms of memory loss or dementia, a study by researchers with the UC Davis Alzheimer’s Disease Center has found.

The longitudinal study found that the only discernible brain differences between normal people who later developed cognitive impairment and those who did not were changes in their fornix, an organ that carries messages to and from the hippocampus, and that has long been known to play a role in memory.

“This could be a very early and useful marker for future incipient decline,” said Evan Fletcher, the study’s lead author and a project scientist with the UC Davis Alzheimer’s Disease Center.

“Our results suggest that fornix variables are measurable brain factors that precede the earliest clinically relevant deterioration of cognitive function among cognitively normal elderly individuals,” Fletcher said.

The research is published online today (Sept. 9) in JAMA Neurology.

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Study suggests iron is at core of Alzheimer’s disease


UCLA findings challenge conventional thinking about possible causes of disorder.

George Bartzokis, UCLA

George Bartzokis, UCLA

Alzheimer’s disease has proven to be a difficult enemy to defeat. After all, aging is the No. 1 risk factor for the disorder, and there’s no stopping that.

Most researchers believe the disease is caused by one of two proteins, one called tau, the other beta-amyloid. As we age, most scientists say, these proteins either disrupt signaling between neurons or simply kill them.

Now, a new UCLA study suggests a third possible cause: iron accumulation.

Dr. George Bartzokis, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and senior author of the study, and his colleagues looked at two areas of the brain in patients with Alzheimer’s. They compared the hippocampus, which is known to be damaged early in the disease, and the thalamus, an area that is generally not affected until the late stages. Using sophisticated brain-imaging techniques, they found that iron is increased in the hippocampus and is associated with tissue damage in that area. But increased iron was not found in the thalamus.

The research appears in the August edition of the Journal of Alzheimer’s Disease.

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Why don’t we all get Alzheimer’s?


Every human brain contains ingredients to spark disease, but most don’t develop condition.

Subhojit Roy, UC San Diego

Subhojit Roy, UC San Diego

Though one might think the brains of people who develop Alzheimer’s disease (AD) possess   building blocks of the disease absent in healthy brains, for most sufferers, this is not true. Every human brain contains the ingredients necessary to spark AD, but while an estimated 5 million Americans have AD – a number projected to triple by 2050 – the vast majority of people do not and will not develop the devastating neurological condition.

For researchers like Subhojit Roy, M.D., Ph.D., associate professor in the Departments of Pathology and Neurosciences at the UC San Diego School of Medicine, these facts produce a singular question: Why don’t we all get Alzheimer’s disease?

In a paper published today (Aug. 7) in the journal Neuron, Roy and colleagues offer an explanation – a trick of nature that, in most people, maintains critical separation between a protein and an enzyme that, when combined, trigger the progressive cell degeneration and death characteristic of AD.

“It’s like physically separating gunpowder and match so that the inevitable explosion is avoided,” said principal investigator Roy, a cell biologist and neuropathologist in the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego. “Knowing how the gunpowder and match are separated may give us new insights into possibly stopping the disease.”

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Scientists ID compounds that target amyloid fibrils in Alzheimer’s


UCLA study is first to use “structural” approach in hunt for amyloid-inhibiting agents.

Compounds binding to amyloid fibrils

Compounds binding to amyloid fibrils

UCLA chemists and molecular biologists have for the first time used a “structure-based” approach to drug design to identify compounds with the potential to delay or treat Alzheimer’s disease, and possibly Parkinson’s, Lou Gehrig’s disease and other degenerative disorders.

All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients.

Structure-based drug design, in which the physical structure of a targeted protein is used to help identify compounds that will interact with it, has already been used to generate therapeutic agents for a number of infectious and metabolic diseases.

The UCLA researchers, led by David Eisenberg, director of the UCLA–Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator, report the first application of this technique in the search for molecular compounds that bind to and inhibit the activity of the amyloid-beta protein responsible for forming dangerous plaques in the brain of patients with Alzheimer’s and other degenerative diseases.

In addition to Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA’s California NanoSystems Institute, the team included lead author Lin Jiang, a UCLA postdoctoral scholar in Eisenberg’s laboratory and Howard Hughes Medical Institute researcher, and other UCLA faculty.

The research was published July 16 in eLife, a new open-access science journal backed by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.

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