TAG: "Alzheimer’s"

Better cognition seen with gene variant carried by 1 in 5 people


Finding could have implications for treating age-related diseases like Alzheimer’s.

A scientific team led by the Gladstone Institutes and UC San Francisco has discovered that a common form of a gene already associated with long life also improves learning and memory, a finding that could have implications for treating age-related diseases like Alzheimer’s.

The researchers found that people who carry a single copy of the KL-VS variant of the KLOTHO gene perform better on a wide variety of cognitive tests. When the researchers modeled the effects in mice, they found it strengthened the connections between neurons that make learning possible – what is known as synaptic plasticity – by increasing the action of a cell receptor critical to forming memories.

The discovery is a major step toward understanding how genes improve cognitive ability and could open a new route to treating diseases like Alzheimer’s. Researchers have long suspected that some people may be protected from the disease because of their greater cognitive capacity, or reserve. Since elevated levels of the klotho protein appear to improve cognition throughout the lifespan, raising klotho levels could build cognitive reserve as a bulwark against the disease.

“As the world’s population ages, cognitive frailty is our biggest biomedical challenge,” said Dena Dubal, M.D., Ph.D., assistant professor of neurology, the David A. Coulter Endowed Chair in Aging and Neurodegeneration at UCSF and lead author of the study, published today in Cell Reports. “If we can understand how to enhance brain function, it would have a huge impact on people’s lives.”

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Private partnerships for public benefit


Nobel laureate’s research into neurodegenerative diseases gets boost from Japanese firm.

Nobel laureate Stanley Prusiner (left), director of the UCSF Institute of Neurodegenerative Diseases, recently launched a partnership with pharmaceutical company Daiichi Sankyo that will accelerate his research into prion diseases. He credits the partnership largely to groundwork laid by IND’s associate director, David Ramsay (right).

Stanley Prusiner, M.D., is used to overcoming challenges in his career.

In 1982, as a UC San Francisco junior faculty member in the Department of Neurology, Prusiner published an article describing his discovery of an unprecedented class of pathogens that he named “prions.” These infectious proteins are now understood to be involved in numerous neurodegenerative diseases in humans and animals, including Alzheimer’s, Parkinson’s, frontotemporal dementia and Creutzfeldt-Jakob disease (CJD).

The article sparked a firestorm at the time.

Prusiner’s contention that a protein alone could be infectious flew in the face of the commonly held scientific belief that infections could only be transmitted by viruses, bacteria, fungi and parasites – all of which have genomes composed of either DNA or RNA. Proteins, however, are composed of amino acids.

Despite what he described as a “torrent of criticism” from the scientific community, the media and even funders of his research, Prusiner remained undeterred. He took comfort in the unwavering support of close colleagues, and mounting scientific evidence – much of it stemming his UCSF lab – that backed his claims.

The groundbreaking work led to Prusiner’s 1997 Nobel Prize in Physiology or Medicine.

“People often ask me why I persisted in doing research on a subject that was so controversial,” Prusiner said in his Nobel acceptance speech. “I frequently respond by telling them that only a few scientists are granted the great fortune to pursue topics that are so new and different that only a small number of people can grasp [their] meaning initially.”

In the decades since his discovery, Prusiner – now director of the Institute for Neurodegenerative Diseases (IND) at UCSF – has been committed to getting answers about prion diseases, and ultimately treatments and cures.

Even with a Nobel Prize under his belt, the road continues to pose challenges.

Federal funding from the National Institutes of Health (NIH) has been crucial to his research, but the recent recession – and resulting sequestration – highlighted the need to strengthen relationships with private industry. In 2013, the NIH awarded a total of $22.5 billion in funding to U.S. institutions, the lowest amount since 2003.

But this month, Prusiner’s work got a huge boost from an exciting new collaboration between the IND and the Japan-based global pharmaceutical company Daiichi Sankyo Co. Ltd. It will focus on developing therapeutics and molecular diagnostics for multiple neurodegenerative diseases.

“Alzheimer’s alone kills as many people every year as cancer does, but it only receives one-tenth of the funding that we dedicate to cancer research. This collaboration won’t fill that funding gap, but it will offer the tremendous value of Daiichi Sankyo’s scientific expertise to make progress on these diseases,” he said.

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Cancer drugs block dementia-linked brain inflammation


Research represents novel approach to lessening impact of Alzheimer’s, Parkinson’s.

Kim Green, UC Irvine

A class of drugs developed to treat immune-related conditions and cancer – including one currently in clinical trials for glioblastoma and other tumors – eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.

In their study, assistant professor of neurobiology & behavior Kim Green and colleagues discovered that the drugs, which can be delivered orally, eradicated microglia, the primary immune cells of the brain. These cells exacerbate many neural diseases, including Alzheimer’s and Parkinson’s, as well as brain injury.

“Because microglia are implicated in most brain disorders, we feel we’ve found a novel and broadly applicable therapeutic approach,” Green said. “This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases.”

The researchers focused on the impact of a class of drugs called CSF1R inhibitors on microglial function. In mouse models, they learned that inhibition led to the removal of virtually all microglia from the adult central nervous system with no ill effects or deficits in behavior or cognition. Because these cells contribute to most brain diseases – and can harm or kill neurons – the ability to eradicate them is a powerful advance in the treatment of neuroinflammation-linked disorders.

Green said his group tested several selective CSF1R inhibitors that are under investigation as cancer treatments and immune system modulators. Of these compounds, they found the most effective to be a drug called PLX3397, created by Plexxikon Inc., a Berkeley-based biotechnology company and member of the Daiichi Sankyo Group. PLX3397 is currently being evaluated in phase one and two clinical trials for multiple cancers, including glioblastoma, melanoma, breast cancer and leukemia.

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UCSF launches online registry to drive brain disease research


Brain Health Registry brings promise of speeding advances.

A new online project led by researchers at UC San Francisco promises to dramatically cut the time and cost of conducting clinical trials for brain diseases, while also helping scientists analyze and track the brain functions of thousands of volunteers over time.

With easy online registration, the Brain Health Registry is designed to create a ready pool of research subjects for studies on neurological diseases, such as Alzheimer’s and Parkinson’s, as well as depression, post-traumatic stress disorder and many other brain ailments. About one third of the cost of running a clinical trial comes from having to recruit patients, and many trials fail or are delayed because of it.

Michael Weiner, UC San Francisco

The Brain Health Registry is the first neuroscience project to use the Internet on such a scale to advance clinical research, according to Michael Weiner, M.D., founder and principal investigator of the initiative and a professor of radiology, biomedical engineering, medicine, psychiatry and neurology at UCSF. One of his roles is serving as principal investigator of the Alzheimer’s Disease Neuroimaging Initiative, the largest observational study of Alzheimer’s.

“This registry is an innovative 21st century approach to science with tremendous potential,” Weiner said. “The greatest obstacles to finding a cure for Alzheimer’s and other brain disorders are the cost and time involved in clinical trials. This project aims to cut both and greatly accelerate the search for cures.”

Leading funders for the project include the Rosenberg Alzheimer’s Project, the Ray and Dagmar Dolby Family Fund and Kevin and Connie Shanahan. The initial focus will be on the San Francisco Bay Area, and the goal is to recruit 100,000 people by the end of 2017. Nearly 2,000 people already signed up during the online registry’s beta phase.

Volunteers will provide a brief personal history and take online neuropsychological tests in an online game format. The games give the Brain Health Registry scientific team a snapshot of the participant’s brain function. The data collected will help scientists study brains as they age, identify markers for diseases, develop better diagnostic tools to stop disease before it develops and increase the ready pool of pre-qualified clinical trial participants.

A select number of volunteers will be asked by researchers to do more, such as providing saliva or blood samples, or participating in clinical trials to test potential cures. Volunteers can participate as little or as much as they like. All information will be gathered in accordance with federal privacy laws under the Health Insurance Portability and Accountability Act (HIPAA), as well as the highest standards of medical ethics.

“For those of us who know people suffering from Parkinson’s, Alzheimer’s, PTSD and other brain disorders, this is a way we can be involved in the search for a cure,” said Douglas Rosenberg, of the Rosenberg Alzheimer’s Project, which is helping to fund the project. “We’ve worked to make the process very easy and very fulfilling for our volunteers.”

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Early cardiac risks linked to worse cognitive function in middle age


Blood pressure, glucose, cholesterol in 18- to 30-year-olds predicts decline.

Kristine Yaffe, UC San Francisco

Young adults with such cardiac risk factors as high blood pressure and elevated glucose levels have significantly worse cognitive function in middle age, according to a new study by dementia researchers at UC San Francisco.

The findings bolster the view that diseases like Alzheimer’s develop over an individual’s lifespan and may be set in motion early in life. And they offer hope that young adults may be able to lower their risk of developing dementia through diet and exercise, or even by taking medications.

“These cardiovascular risk factors are all quite modifiable,” said senior author Kristine Yaffe, M.D., a professor in the departments of psychiatry, neurology, and epidemiology and niostatistics at UCSF, who holds the Roy and Marie Scola Endowed Chair in Psychiatry.

“We already know that reducing these risk factors in midlife can decrease the risk of dementia in old age,” continued Yaffe, who is also chief of geriatric psychiatry and director of the Memory Disorders Clinic at the San Francisco VA Medical Center. “If it turns out that the damage begins before middle age, we may need to expand our focus and work on reducing heart disease risks in earlier stages of life.”

The study, published today (March 31) in Circulation, examines data from more than 3,300 18- to 30-year-olds in the Coronary Artery Risk Development in Young Adults (CARDIA) study, which began enrolling thousands of participants nationwide in 1985 to understand how heart disease develops in black and white adults.

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New dean is biological sciences booster


Frank LaFerla, renowned for his Alzheimer’s work, hopes to raise UC Irvine school’s profile.

Frank LaFerla, UC Irvine

For a scientist widely considered an international leader in Alzheimer’s disease research, Frank LaFerla joined the UC Irvine faculty in 1995, interestingly enough, without ever having taken a single neuroscience class.

LaFerla had received a doctorate in virology and was studying AIDS-related dementia when he sat in on his first neurobiology course, one taught by James McGaugh and Norman Weinberger, two of the nation’s top learning and memory researchers. The lessons obviously made a great impression on the young scientist.

Since that time, LaFerla has made key research breakthroughs that show promise for treating Alzheimer’s and other neurodegenerative diseases. He has served in numerous leadership roles, including as chair of the Department of Neurobiology & Memory and director of the campus’s Institute for Memory Impairments and Neurological Disorders (UCI MIND), a research center internationally acclaimed for its work on disorders of the brain, particularly those that are age-related.

Last December, LaFerla became the Hana & Francisco J. Ayala Dean of the newly renamed Francisco J. Ayala School of Biological Sciences, heading the third-largest school on campus, with nearly 4,000 students majoring in one of its four undergraduate degree programs.

“Frank brings enormous enthusiasm and optimism to everything he does,” says McGaugh, a research professor of neurobiology & behavior and former biological sciences dean. “He wants to take actions that emphasize the character and the contributions of the school to the campus and to the public. It’s hard to imagine a more qualified person for the position.”

And with UC Irvine approaching its golden anniversary, LaFerla says, he aims to “take the school to the next level.”

He assumes the helm at a time when the biological sciences are critical to addressing such global concerns as sustainable food production, ecosystem restoration, optimized biofuel manufacturing and improved human health. And he wants to ensure that UC Irvine plays a part.

“Our brand is ‘Understanding Life: Transforming Our World,’” LaFerla says. “We will be excellent ambassadors of science who are trying to solve very important issues.”

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New therapeutic target discovered for Alzheimer’s disease


Drug candidate blocks production of disease-causing neurotoxins in mouse models.

Vivian Hook, UC San Diego

A team of scientists from the UC San Diego School of Medicine, the Medical University of South Carolina and San Diego-based American Life Science Pharmaceuticals Inc., report that cathepsin B gene knockout or its reduction by an enzyme inhibitor blocks creation of key neurotoxic pGlu-Aβ peptides linked to Alzheimer’s disease (AD). Moreover, the candidate inhibitor drug has been shown to be safe in humans.

The findings, based on AD mouse models and published online in the Journal of Alzheimer’s Disease, support continued development of cysteine protease inhibitors as a new drug target class for AD. “No other therapeutic program is investigating cysteine protease inhibitors for treating AD,” said collaborator Vivian Hook, Ph.D., professor in the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and in the UC San Diego School of Medicine.

Current AD drugs treat some symptoms of the devastating neurological disorder, but none actually slow its progress, prevent or cure it. No new AD drug has been approved in more than a decade.

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Blood test IDs those at risk for Alzheimer’s


UC Irvine researchers among authors of study.

Claudia Kawas, UC Irvine

Researchers – including those at UC Irvine – have discovered and validated a blood test that can predict with greater than 90 percent accuracy whether a healthy person will develop mild cognitive impairment or Alzheimer’s disease within three years.

Described in the April issue of Nature Medicine, the study heralds the potential for developing treatment strategies for Alzheimer’s at an earlier stage, when therapy would be more effective at slowing or preventing symptoms.

It’s the first known published report of blood-based biomarkers for preclinical Alzheimer’s. The test identifies 10 lipids, or fats, in the blood that predict disease onset. It could be ready for use in clinical studies in as few as two years, and researchers say that other diagnostic uses are possible.

Dr. Claudia Kawas, the Nichols Chair in Neuroscience at UC Irvine, is among the authors of the study, which was led by Dr. Howard Federoff of Georgetown University. It involved 525 healthy participants aged 70 and older who gave blood samples upon enrolling and at various points in the study. More than 100 of them came from UC Irvine’s Orange County Aging Study.

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Researchers hone in on Alzheimer’s disease


Gordon supercomputer helps guide new drug designs.

Researchers studying peptides using the Gordon supercomputer at the San Diego Supercomputer Center (SDSC) at UC San Diego have found new ways to elucidate the creation of the toxic oligomers associated with Alzheimer’s disease.

Igor Tsigelny, a research scientist with SDSC, the UCSD Moores Cancer Center and the Department of Neurosciences, focused on the small peptide called amyloid-beta, which pairs up with itself to form dimers and oligomers.

The scientists surveyed all the possible ways to look at the dynamics of conformational changes of these peptides and the possibility that they might organize into the oligomers theorized to be responsible for the degenerative brain disease. In the Feb. 14 issue of the Journal of Alzheimer’s Disease, the researchers suggest their results may generate new targets for drug development.

“Our research has identified amino acids for point mutations that either enhanced or suppressed the formation and toxicity of oligomer rings,” said Tsigelny, the study’s lead author. “Aggregation of misfolded neuronal proteins and peptides may play a primary role in neurodegenerative disorders, including Alzheimer’s disease.”

Tsigelny also noted that recent improvements in computational processing speed have allowed him and other researchers to use a variety of tools, including computer simulations, to take new approaches to examining amyloid-beta, which has proven too unstable for traditional approaches such as X-ray crystallography.

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High good, low bad cholesterol levels are healthy for the brain, too


Study suggests potential new approach to lowering prevalence of Alzheimer’s disease.

Bruce Reed, UC Davis

Bruce Reed, UC Davis

High levels of “good” cholesterol and low levels of “bad” cholesterol are correlated with lower levels of the amyloid plaque deposition in the brain that is a hallmark of Alzheimer’s disease, in a pattern that mirrors the relationship between good and bad cholesterol in cardiovascular disease, UC Davis researchers have found.

“Our study shows that both higher levels of HDL — good — and lower levels of LDL — bad — cholesterol in the bloodstream are associated with lower levels of amyloid plaque deposits in the brain,” said Bruce Reed, lead study author and associate director of the UC Davis Alzheimer’s Disease Center.

“Unhealthy patterns of cholesterol could be directly causing the higher levels of amyloid known to contribute to Alzheimer’s, in the same way that such patterns promote heart disease,” he said.

The relationship between elevated cholesterol and increased risk of Alzheimer’s disease has been known for some time, but the current study is the first to specifically link cholesterol to amyloid deposits in living human study participants, Reed said.

The study, “Associations Between Serum Cholesterol Levels and Cerebral Amyloidosis,” is published online today (Dec. 30) in JAMA Neurology.

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UC Irvine names new dean of biological sciences


Noted Alzheimer’s researcher Frank LaFerla will take school’s reins Jan. 1.

Frank LaFerla, UC Irvine

Frank LaFerla, UC Irvine

UC Irvine Chancellor Michael V. Drake announced today (Dec. 23) that Frank M. LaFerla has been appointed the Hana & Francisco J. Ayala Dean of the School of Biological Sciences, effective Jan. 1, 2014.

LaFerla, Chancellor’s Professor and chair of the Department of Neurobiology & Behavior since 2011, joined UC Irvine in 1995 as an assistant professor in the then-named Department of Psychobiology. Since that time, he has served in numerous leadership roles, including as associate director and now director of the Institute for Memory Impairments and Neurological Disorders (UCI MIND), a research center internationally acclaimed for its work on brain disorders, particularly those that are age-related.

He was also founding director of the Interdepartmental Neuroscience Program, which united several departments and faculty concerned with neuroscience under one major programmatic initiative and has since facilitated the recruitment to UC Irvine of numerous outstanding graduate students.

LaFerla, who holds a doctorate from the University of Minnesota and a bachelor’s degree from St. Joseph’s University in Philadelphia, has several research interests, including the molecular biology of Alzheimer’s disease and other neurodegenerative disorders, presenilins and calcium signaling, learning and memory, and transgenic and genetically modified animal models. He was the first to engineer mice that develop the cerebral plaques and tangles that characterize Alzheimer’s, providing researchers with a crucial “living laboratory” of the disease. LaFerla’s mice have made a huge impact on his work and on Alzheimer’s research around the world.

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UC San Diego launches unprecedented Down syndrome study


Goal: gain better understanding of adults with the disease, discover indicators of Alzheimer’s.

William Mobley, UC San Diego

William Mobley, UC San Diego

To many, Down syndrome (DS) is a childhood condition. But improved health care means that individuals with DS now routinely reach age 50 or 60 years of age, sometimes beyond.  However, if they live long enough, people with Down syndrome are almost certain to develop Alzheimer’s disease (AD).

Risk estimates vary, but the National Down Syndrome Society says that nearly 25 percent of individuals with DS over the age of 35 show signs of Alzheimer’s-type dementia, a percentage that dramatically increases with age. Almost all develop dementia by the age of 60.

“The more we learn about Down syndrome and Alzheimer’s disease, the more we realize these conditions – one seen at birth, the other quite late in life – are two sides of the same coin,” said William C. Mobley, M.D., Ph.D., professor and chair of the Department of Neurosciences at UC San Diego School of Medicine. “Autopsies of DS and AD brains reveal virtually identical pathologies – the same telltale amyloid plaques and neurofibrillary tangles.”

Under the auspices of the Alzheimer’s Disease Cooperative Study (ADCS), based at the UC San Diego School of Medicine, a new clinical study called the Down Syndrome Biomarker Initiative (DSBI) was launched in March. According to the study’s director, Michael Rafii, M.D., Ph.D. – medical director of the ADCS – its aim is to discover indicators of Alzheimer’s and study progression of the disease, with the ultimate goal of better understanding brain aging and AD in adults with Down syndrome.

The three-year pilot study has enrolled 12 participants, aged 30 to 60 years of age. Study participants will be screened for various biomarkers of AD, using tests that include three types of brain scans, retinal amyloid imaging and blood tests, among others.

“Findings to date using MRI and amyloid PET scans indicate that individuals with Down syndrome show the same brain patterns as those in the general population with the earliest stages of the memory-robbing disease, called prodromal AD,” said Rafii. He added that indications of increased brain amyloid deposition – the insoluble protein aggregates found in the brains of patients with AD that are thought to be an underlying cause of the disease – is similar in individuals with DS and those in the general population with AD.

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