Protease proven as target for improving memory.

Vivian Hook, UC San Diego

Researchers at the University of California, San Diego, the Medical University of South Carolina, the University of Cincinnati and American Life Science Pharmaceuticals of San Diego have validated the protease cathepsin B (CatB) as a target for improving memory deficits and reducing the pathology of Alzheimer’s disease in an animal model representative of most Alzheimer’s patients. The study has been published in the online edition of the Journal of Alzheimer’s Disease.

According to investigator Vivian Y. H. Hook, Ph.D., professor of the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and professor of neurosciences, pharmacology and medicine at the UC San Diego School of Medicine, the study is important because it could lead to new therapeutics that improve the memory deficits of Alzheimer’s.

Abnormal accumulation of brain amyloid-β peptides (Aβ) is thought to cause the memory loss and amyloid plaque pathology of the disease. Aβ peptides are “cut” out from a larger protein called the amyloid precursor protein (APP) by an enzymatic “scissor” called β-secretase, and aggregate to form plaques in the brain regions responsible for memory. Inhibiting the β-secretase “scissors” from “cutting” the APP with a drug would reduce brain Aβ levels and thereby improve memory deficits and reduce amyloid plaque pathology. The vast majority of Alzheimer’s patients have wild-type (WT) β-secretase activity and thus the WT β-secretase has been a target of great interest for a long time.

Another protease, BACE1, has long been thought to be the β-secretase involved in Alzheimer’s pathology, because deleting that gene from animal models reduces brain Aβ and plaque pathology. However, deleting the BACE1 gene was reported to make memory deficits worse in a transgenic model having WT β-secretase activity.

Hook and colleagues set out to find a WT β-secretase target, which improves memory deficits while reducing amyloid plaque pathology. In the current paper, the researchers show that CatB is such a target because deleting that gene in a transgenic mouse model having WT β-secretase activity improves memory deficits and reduces amyloid plaque, which develop in this model, mimicking that found in the disease. In contrast, deleting the BACE1 gene in that transgenic model had no effect on memory deficits or pathology.

Co-authors of the study were Gregory Hook, Ph.D.,  of American Life Science Pharmaceuticals in San Diego and Mark Kindy of the Medical University of South Carolina, as well as the Ralph H. Johnson VA Medical Center and Applied Neurotechnology Inc., in Charleston, S.C.; Jin Yu and Hong Zhu, Medical University of South Carolina; and Salim S. El-Amouri, Cincinnati Children’s Hospital Medical Center, University of Cincinnati.

Gregory Hook is an employee and has equity in American Life Science Pharmaceuticals (ALSP); Vivian Hook is chair of ALSP’s scientific advisory board and holds equity in the company; and Kindy holds equity in Applied Neurotechnology, relationships disclosed to their institutions.

The study was supported in part by grants from the National Institute on Aging of the National Institutes of Health, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association.

Scientists pinpoint how vitamin D may help clear amyloid plaques.

Milan Fiala, UCLA

A team of academic researchers has identified the intracellular mechanisms regulated by vitamin D3 that may help the body clear the brain of amyloid beta, the main component of plaques associated with Alzheimer’s disease.

Published in today’s (March 6) issue of the Journal of Alzheimer’s Disease, the early findings show that vitamin D3 may activate key genes and cellular signaling networks to help stimulate the immune system to clear the amyloid-beta protein.

Previous laboratory work by the team demonstrated that specific types of immune cells in Alzheimer’s patients may respond to therapy with vitamin D3 and curcumin, a chemical found in turmeric spice, by stimulating the innate immune system to clear amyloid beta. But the researchers didn’t know how it worked.

“This new study helped clarify the key mechanisms involved, which will help us better understand the usefulness of vitamin D3 and curcumin as possible therapies for Alzheimer’s disease,” said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA and the Veterans Affairs Greater Los Angeles Healthcare System.

For the study, scientists drew blood samples from Alzheimer’s patients and healthy controls and then isolated critical immune cells from the blood called macrophages, which are responsible for gobbling up amyloid beta and other waste products in the brain and body.

The team incubated the immune cells overnight with amyloid beta. An active form of vitamin D3 called 1a,25-dihydroxyvitamin D3, which is made in the body by enzymatic conversion in the liver and kidneys, was added to some of the cells to gauge the effect it had on amyloid beta absorption.

Previous work by the team, based on the function of Alzheimer’s patients’ macrophages, showed that there are at least two types of patients and macrophages: Type I macrophages are improved by addition of 1a,25-dihydroxyvitamin D3 and curcuminoids (a synthetic form of curcumin), while Type II macrophages are improved only by adding 1a,25-dihydroxyvitamin D3.

Researchers found that in both Type I and Type II macrophages, the added 1a,25-dihydroxyvitamin D3 played a key role in opening a specific chloride channel called “chloride channel 3 (CLC3),” which is important in supporting the uptake of amyloid beta through the process known as phagocytosis. Curcuminoids activated this chloride channel only in Type I macrophages.

The scientists also found that 1a,25-dihydroxyvitamin D3 strongly helped trigger the genetic transcription of the chloride channel and the receptor for 1a,25-dihydroxyvitamin D3 in Type II macrophages. Transcription is the first step leading to gene expression.

The mechanisms behind the effects of 1a,25-dihydroxyvitamin D3 on phagocytosis were complex and dependent on calcium and signaling by the “MAPK” pathway, which helps communicate a signal from the vitamin D3 receptor located on the surface of a cell to the DNA in the cell’s nucleus.

The pivotal effect of 1a,25-dihydroxyvitamin D3 was shown in a collaboration between Dr. Patrick R. Griffin from the Scripps Research Institute and Dr. Mathew T. Mizwicki from UC Riverside. They utilized a technique based on mass spectrometry, which showed that 1a,25-dihydroxyvitamin D3 stabilized many more critical sites on the vitamin D receptor than did the curcuminoids.

“Our findings demonstrate that active forms of vitamin D3 may be an important regulator of immune activities of macrophages in helping to clear amyloid plaques by directly regulating the expression of genes, as well as the structural physical workings of the cells,” said study author Mizwicki, who was an assistant research biochemist in the department of biochemistry at UC Riverside when the study was conducted.

According to the team, one of the next stages of research would be a clinical trial with vitamin D3 to assess the impact on Alzheimer’s disease patients. Previous studies by other teams have shown that a low serum level of 25-hydroxyvitamin D3 may be associated with cognitive decline. It is too early to recommend a definitive dosage of vitamin D3 to help with Alzheimer’s disease and brain health, the researchers said. They add that ongoing studies are showing that Vitamin D3 may be beneficial in reducing the incidence of a growing number of human diseases.

The study was funded in part by the Alzheimer’s Association and by the National Institutes of Health.

Other study authors included Danusa Menegaz and Antonio Barrientos-Duran of the department of biochemistry at UC Riverside; Jun Zhang and Patrick R. Griffin of the department of molecular therapeutics at the Scripps Research Institute in Jupiter, Fla.; Stephen Tse of the department of medicine at the David Geffen School of Medicine at UCLA and the Veterans Affairs Greater Los Angeles Healthcare System; and John R. Cashman of the Human BioMolecular Research Institute in San Diego.

UC Riverside scientists identify a protein that plays a crucial role in learning and memory.

Iryna Ethyll (left) and Crystal Pontrello, UC Riverside

Biomedical scientists at the University of California, Riverside, have identified a new link between a protein called beta-arrestin and short-term memory that could open new doors for the therapeutic treatment of neurological disorders, particularly Alzheimer’s disease.

Beta-arrestin is expressed in various cells of the body, including cells of the hippocampus, the region of the brain that is involved in learning and the formation of short-term memories. Beta-arrestin, the absence of which impairs normal learning in mice, is one of many “scaffolding proteins” — proteins that support the connections between neurons in the brain.

As our brain develops, new connections called synapses are formed between neurons. In the hippocampus, the formation of synapses is a continuous process. As we learn something new, new connections are formed and some old ones become stronger through a process known as long-term potentiation (LTP). But because brains have only a limited capacity, other old connections must disassemble through a process known as long-term depression (LTD) in order for new synapses to form.

The researchers report online last week in the Proceedings of the National Academy of Sciences that beta-arrestin plays an important role in the plasticity of synaptic connections and LTD by regulating the “actin cytoskeleton,” a dynamic filamentous network of proteins that forms the “backbone” of neurons and is involved in forming new and disassembling old synaptic connections.

“In some pathological conditions such as Alzheimer’s disease, loss of the old synaptic connections far exceeds the formation of new ones, resulting in overall loss of synapses and short-term memory loss,” said Iryna M. Ethell, an associate professor of biomedical sciences and the lead author of the research paper. “Our work, done on mice, shows that if beta-arrestin is removed from neurons, this loss of synapses is prevented.  But we also know that beta-arrestin is required for normal learning and memory; so a fine balance needs to be established. This balance could be easily achieved by pharmaceutical drugs in the future.”

This is the first time researchers anywhere have linked beta-arrestin to Alzheimer’s and learning/memory.

Ethell explained that beta-arrestin can be visualized as energy supplied to a puppeteer (actin cytoskeleton) controlling the strings of the puppets (inter-neuronal connections).  For normal learning to take place, the puppeteer needs to move the strings in a specific order.  But in patients with Alzheimer’s, this supply of energy over-activates and the strings are pulled in a disorderly fashion that results in the strings being broken (loss of synapses) and the puppets collapsing. While the removal of beta-arrestin would prevent this collapse, a complete loss of beta-arrestin would mean no movement of the puppets at all (that is, no learning in the brain), which is equally undesirable.

“A selective tuning of beta-arrestin activity is therefore necessary to partially reduce synapse disassembly,” said Crystal G. Pontrello, the first author of the research paper and a postdoctoral researcher in Ethell’s lab.  “What you want, ideally, is the elimination of only some unused old synaptic connections so that there is room to make new connections.”

Ethell and Pontrello were joined in the research by UC Riverside’s Min-Yu Sun, Alice Lin, Todd A. Fiacco and Kathryn A. DeFea.

The research was supported by a grant to Ethell by the National Institutes of Health.

UCLA Alzheimer’s expert shares highlights of new research findings.

Gary Small, UCLA

Scientists are working hard to unravel the mysteries of Alzheimer’s, a disease in which waxy plaques and tangled threads of protein crisscross the brain, leading to devastating mental decline in its elderly victims. Dr. Gary Small, director of the UCLA Longevity Center at the Semel Institute for Neuroscience and Human Behavior and the Parlow-Solomon Professor on Aging at the David Geffen School of Medicine, has been studying Alzheimer’s for more than two decades and sharing his findings in bestselling books and frequent media appearances. With Alzheimer’s on the rise as baby boomers age — 5 million people have the disease today, a number that could reach 16 million by 2050 — he shares new research findings and advice in his latest book, “The Alzheimer’s Prevention Program: Keep Your Brain Healthy for the Rest of Your Life” (Workman Press, 2011). Small recently shared a few highlights with UCLA Today’s Judy Lin.

Read the Q&A

UC Davis pursues a transformational opportunity to improve health.

Guadalupe and Leonor Villarreal sought the expertise of a team of specialists at the UC Davis Alzheimer’s Disease Center when Guadalupe Villarreal began forgetting facts of his life as a farmer.

Nestled among the orchards surrounding Hughson is the farm that has been home to Guadalupe Villarreal and his family for 40 years. He and his wife, Leonor, raised their three children there amid tidy rows of peach and almond trees.

Running the farm kept Guadalupe Villarreal more than busy. There was always something to prune, to plant, to irrigate or to harvest. But during the summer of 2007, he began forgetting the facts of his life. He no longer could remember where the road past his house led, grew frustrated looking for his closet and dresser, and kept asking after his long-deceased mother.

Worried, Leonor Villarreal took him to the family’s doctor, and ultimately to the UC Davis Alzheimer’s Disease Center. There, a team of clinicians evaluated his overall health, studied scans of his brain and tested his memory. After ruling out other conditions, the doctors diagnosed him at age 73 with early-stage Alzheimer’s disease.

“At first we were all in denial,” says Leonor Villarreal, his wife of 57 years, “because I could not accept that would be him.”

But the UC Davis center was able to offer the Villarreals guidance on how to deal with the diagnosis. Doctors recommended two medications to slow the progression of the disease, and coordinated Guadalupe Villarreal’s care with the family’s physician. With a diagnosis in hand, the Villarreal family could help keep the patriarch safe.

“The kids don’t let him get on the tractor,” Leonor Villarreal says. “He doesn’t drive into town anymore. I write down on the calendar what he’s done, when he’s fed the dogs or taken his medication.”

The UC Davis Alzheimer’s Disease Center is dedicated to investigating the causes of dementia and mental aging. Led by director and professor of neurology Charles DeCarli, the center follows more than 500 research subjects such as Guadalupe Villarreal, and evaluates more than 200 patients each year. The center has received continuous grant funding from the National Institute on Aging since 1991, the most recent in 2011 with a five-year grant of $6.9 million. For his work at the center using imaging technology to link vascular functioning in the brain with the structural changes seen in Alzheimer’s and dementia, DeCarli was awarded the J. Allyn Taylor International Prize in Medicine in October 2010.

Through the Alzheimer’s Disease Center and other centers of excellence, UC Davis Health System works to bring the most recent scientific and technological developments in neuroscience to patients. Among other centers of investigation are the Center for Neuroscience, which performs basic research on all aspects of the brain and nervous system; the Center for Mind and Brain, which studies memory formation and other building blocks of cognitive function; the Imaging Research Center, which improves ways to visualize the structure and chemistry of the working brain; and the Center for Visual Sciences, which explores the genetic, molecular and neurological mechanisms that enable the body’s keenest sense.

These partnerships among UC Davis physicians and other researchers from many disciplines are greater than the sum of their parts. Together, these researchers are gaining a detailed understanding of brain health and ensuring that patients across California have access to the first-rate neuroscience services they need. This fundamental strength is the key reason neuroscience is one of the four focus areas in UC Davis Health System’s 2011– 2016 Strategic Plan.

Read more

First-ever feat provides new method to understand cause of disease, develop drugs.

Led by researchers at the University of California, San Diego, School of Medicine, scientists have for the first time created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer’s disease, using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder.

“Creating highly purified and functional human Alzheimer’s neurons in a dish — this has never been done before,” said senior study author Lawrence Goldstein, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program. “It’s a first step. These aren’t perfect models. They’re proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it.”

The feat, published in today’s (Jan. 25) online edition of the journal Nature, represents a new and much-needed method for studying the causes of Alzheimer’s disease, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.

“We’re dealing with the human brain. You can’t just do a biopsy on living patients,” said Goldstein. “Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”

Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial Alzeheimer’s (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic Alzheimer’s (the common form, the cause of which is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.

The iPSC-derived neurons from the Alzheimer’s patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of the disease. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.

With the in vitro Alzheimer’s neurons, scientists can more deeply investigate how Alzheimer’s begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, Alzheimer’s research depends heavily upon studies of post-mortem tissues, long after the damage has been done.

“The differences between a healthy neuron and an Alzheimer’s neuron are subtle,” said Goldstein. “It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”

The researchers already have produced some surprising findings. “In this work, we show that one of the early changes in Alzheimer’s neurons thought to be an initiating event in the course of the disease turns out not to be that significant,” Goldstein said, adding that they discovered a different early event plays a bigger role.

The scientists also found that neurons derived from one of the two patients with sporadic Alzheimer’s exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of Alzheimer’s patients.

Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer’s neurons present a huge opportunity in a desperate fight. “At the end of the day, we need to use cells like these to better understand Alzheimer’s and find drugs to treat it. We need to do everything we can because the cost of this disease is just too heavy and horrible to contemplate. Without solutions, it will bankrupt us — emotionally and financially.”

Funding for this research came in part from the California Institute for Regenerative Medicine, the Weatherstone Foundation, the National Institutes of Health, the Hartwell Foundation, the Lookout Fund and the McDonnell Foundation.

A patent application has been filed on this technology by the University of California, San Diego. For more information, visit http://techtransfer.universityofcalifornia.edu/NCD/22199.html.

Co-authors are Mason A. Israel and Sol M. Reyna, Howard Hughes Medical Institute and UC San Diego Department of Cellular and Molecular Medicine and UC San Diego Biomedical Sciences Graduate Program; Shauna H. Yuan, Howard Hughes Medical Institute and UC San Diego Department of Cellular and Molecular Medicine and UC San Diego Department of Neurosciences; Cedric Bardy and Yangling Mu, The Salk Institute for Biological Studies; Cheryl Herrera, Howard Hughes Medical Institute and UC San Diego Department of Cellular and Molecular Medicine; Michael P. Hefferan, UC San Diego Department of Anesthesiology; Sebastiaan Van Gorp, Department of Anesthesiology, Maastricht University Medical Center, Netherlands; Kristopher L. Nazor, Department of Chemical Physiology, Scripps Research Institute; Francesca S. Boscolo and Louise C. Laurent, UC San Diego Department of Reproductive Medicine; Christian T. Carson, BD Biosciences; Martin Marsala, UC San Diego Department of Anesthesiology and Institute of Neurobiology, Slovak Academy of Sciences, Slovakia; Fred H. Gage, Salk Institute of Biological Studies; Anne M. Remes, Department of Clinical Medicine, Neurology and Clinical Research Center, University of Oulu, Finland; and Edward H. Koo, UC San Diego Department of Neurosciences.

About Alzheimer’s disease
An estimated 5.4 million Americans have Alzheimer’s disease, according to the Alzheimer’s Association. Two-thirds are women. By 2050, as many as 16 million Americans are projected to have the disease. In 2011, the economic cost of caring for Alzheimer’s patients exceeded $183 billion, projected to rise to $1.1 trillion by 2050. Alzheimer’s is the sixth leading cause of death in the United States, killing more than 75,000 Americans annually. Currently there are no drugs to prevent, alter or cure the disease.

Lifelong habits of cognitive stimulation are linked to fewer deposits of beta-amyloid protein.

A molecular model of amyloid protein fibrils

A new study led by researchers at the University of California, Berkeley, provides even more reason for people to read a book or do a puzzle, and to make such activities a lifetime habit.

Brain scans revealed that people with no symptoms of Alzheimer’s who engaged in cognitively stimulating activities throughout their lives had fewer deposits of beta-amyloid, a destructive protein that is the hallmark of the disease.

While previous research has suggested that engaging in mentally stimulating activities — such as reading, writing and playing games — may help stave off Alzheimer’s later in life, this new study identifies the biological target at play. This discovery could guide future research into effective prevention strategies.

“These findings point to a new way of thinking about how cognitive engagement throughout life affects the brain,” said study principal investigator Dr. William Jagust, a professor with joint appointments at UC Berkeley’s Helen Wills Neuroscience Institute, the School of Public Health and Lawrence Berkeley National Laboratory. “Rather than simply providing resistance to Alzheimer’s, brain-stimulating activities may affect a primary pathological process in the disease. This suggests that cognitive therapies could have significant disease-modifying treatment benefits if applied early enough, before symptoms appear.”

An estimated 5.4 million Americans live with Alzheimer’s disease, but the numbers are growing as baby boomers age. Between 2000 and 2008, deaths from Alzheimer’s increased 66 percent, making it the sixth-leading killer in the country. There currently is no cure, but a draft of the first-ever National Alzheimer’s Plan, released this week, revealed that the U.S. government is aiming for effective Alzheimer’s treatments by 2025.

The new study, to be published today (Jan. 23) in the Archives of Neurology, puts the spotlight on amyloid — protein fibers folded into tangled plaques that accumulate in the brain. Beta-amyloid is considered the top suspect in the pathology of Alzheimer’s disease, so finding a way to reduce its development has become a major new direction of research.

The researchers note that the buildup of amyloid can also be influenced by genes and aging — one-third of people age 60 and over have some amyloid deposits in their brain — but how much reading and writing one does is under each individual’s control.

“This is the first time cognitive activity level has been related to amyloid buildup in the brain,” said study lead author Susan Landau, research scientist at the Helen Wills Neuroscience Institute and the Berkeley Lab. “Amyloid probably starts accumulating many years before symptoms appear. So it’s possible that by the time you have symptoms of Alzheimer’s, like memory problems, there is little that can be done to stop disease progression. The time for intervention may be much sooner, which is why we’re trying to identify whether lifestyle factors might be related to the earliest possible changes.”

The researchers asked 65 healthy, cognitively normal adults aged 60 and over (average age was 76) to rate how frequently they participated in such mentally engaging activities as going to the library, reading books or newspapers, and writing letters or email. The questions focused on various points in life from age 6 to the present.

The participants took part in extensive neuropsychological testing to assess memory and other cognitive functions, and received positron emission tomography (PET) scans at the Berkeley Lab using a new tracer called Pittsburgh Compound B that was developed to visualize amyloid. The results of the brain scans of healthy older individuals with various levels of lifetime cognitive activity were compared with those of 10 patients diagnosed with Alzheimer’s disease and 11 healthy people in their 20s.

The researchers found a significant association between higher levels of cognitive activity over a lifetime and lower levels of beta-amyloid in the PET scans. They analyzed the impact of other factors such as memory function, physical activity, self-rated memory ability, level of education and gender, and found that lifelong cognitive engagement was independently linked to amyloid deposition.

Notably, the researchers did not find a strong connection between amyloid deposition and levels of current cognitive activity alone.

“What our data suggests is that a whole lifetime of engaging in these activities has a bigger effect than being cognitively active just in older age,” said Landau.

The researchers are careful to point out that the study does not negate the benefits of kicking up brain activity in later years.

“There is no downside to cognitive activity. It can only be beneficial, even if for reasons other than reducing amyloid in the brain, including social stimulation and empowerment,” said Jagust. “And actually, cognitive activity late in life may well turn out to be beneficial for reducing amyloid. We just haven’t found that connection yet.”

Other study authors include researchers from UC San Francisco’s Memory and Aging Center and Department of Neurology, and Rush University Medical Center’s Alzheimer’s Disease Center in Chicago.

The National Institutes of Health and the Alzheimer’s Association helped support this research.

National initiative will support military members and their families.

The UC Davis School of Medicine participated yesterday in the kickoff of academic medicine’s formal involvement in first lady Michelle Obama’s Joining Forces initiative, which aims to bring attention to the needs of America’s military families in the areas of employment, education and wellness.

Hosted by Obama, the kickoff event took place at Virginia Commonwealth University School of Medicine. Timothy Albertson, acting chair of the UC Davis Department of Internal Medicine, represented the UC Davis medical school at the ceremony.

“We are proud that UC Davis has had long and successful partnerships with different facets of the U.S. military, and we look forward to contributing to Joining Forces,” said Albertson. Albertson is a U.S. Army combat veteran who was awarded the Combat Medical Badge.

The Association of American Medical Colleges formally supports Joining Forces, and is encouraging medical schools and teaching hospitals to address the health care needs of military service members, veterans and their families. The schools and hospitals that are supporting Joining Forces have pledged to mobilize their integrated missions in education, research and clinical care to train the nation’s physicians to meet veterans and their families’ unique health care needs, including post traumatic stress disorder (PTSD) and traumatic brain injury (TBI).

A summary of some of the UC Davis programs that support Joining Forces is as follows:

• David Grant USAF Medical Center partnership
  • Since the summer of 2005, the entire residency program of David Grant Medical Center, located at Travis Air Force Base, has been merged with the UC Davis Medical Center residency program. Military surgeons who received trauma training and completed surgical residencies at UC Davis applied the organizational principles they learned there while serving in Iraq and Afghanistan, to great effect. At Kirkuk Air Base in Northern Iraq, a surgeon who had been trained at UC Davis Medical Center implemented what became known as “the Davis system.”
• Vascular Surgery Residency Program
  • The integrated residency program in vascular surgery accepts two residents per year for the five-year program, one civilian and one from the U.S. Air Force. Several factors have made integrated residencies in vascular surgery an increasingly desirable option, including a shortened training timeline compared to completion of a fellowship after general surgery residency.
• Internal Medicine Residency Program
  • In 2009, David Grant Medical Center established an internal medicine residency training program with the UC Davis Department of Internal Medicine. Currently four active-duty Air Force residents are in the program, with another two who have matched scheduled to begin in July 2012. The residents receive the majority of their training at UC Davis Medical Center, and at the medical center’s affiliated VA and Kaiser affiliates.
• Military Student Interest Group
  • The Military Medicine Student Interest Group is primarily intended for UC Davis medical students pursuing careers in the armed forces. The group serves as an important resource for sharing information about opportunities and challenges in training for and later providing medical care to U.S. soldiers, sailors, airmen and marines.
• Military Faculty Mentors
  • The School of Medicine’s Office of Student Wellness has assembled a group of faculty members who have served in the military or still retain some form of active status to serve as mentors to medical students who are veterans, or are considering a career in military medicine. The faculty members have agreed to make themselves available to these students to provide counseling, advice and other support to help them avoid feelings of burnout and isolation.
• John A. Majda, MD Foundation Grant
  • The Office of Student Wellness, in collaboration with two student leaders, was recently awarded a two-year grant from the John A. Majda, MD Foundation to pursue additional support for military students. Specifically, the goal of this project aims is to identify and characterize the factors that protect against burnout in military medical students.
• Partnership with U.S. Department of Veterans Affairs
  • UC Davis Health System has a long and successful partnership with the VA Northern California Health Care System. For example, UC Davis Medical Center provides care for veterans needing specialized services that are not available on-site at the VA. The VA serves as an outstanding teaching center for many UC Davis medical students and residents. UC Davis collaborates with VA colleagues on a variety of research studies, including studies conducted at the Sacramento VA Medical Center facility and the VA Outpatient Clinic and Center for Rehabilitation and Extended Care in Martinez.
• CTSC Clinical Research Center, Sacramento Veterans Administration Hospital
  • Located at the former Mather Air Force Base, the CTSC Clinical Research Center is one of only four such facilities housed at any of the nation’s 158 VA medical centers. It is a highly specialized patient unit that provides medical scientists with opportunities for the careful study of disease. Substantial numbers of veterans have participated in trials and benefited from being provided novel treatment and diagnostic opportunities.
• UC Davis Alzheimer’s Disease Center
  • The UC Davis Alzheimer’s Disease Center is one of only 29 research centers designated by the National Institutes of Health’s National Institute on Aging. The center’s goal is to translate research advances into improved diagnosis and treatment for patients while focusing on the long-term goal of finding a way to prevent or cure Alzheimer’s disease. It conducts trials in Sacramento and in Martinez at the VA Medical Center to understand how common factors like age, ethnicity, race and socioeconomic status contribute to the onset of neurodegenerative diseases.

Read full, detailed descriptions of these programs.

First lady Michelle Obama and Jill Biden created Joining Forces to bring Americans together to recognize, honor and take action to support veterans and military families as they serve our country and throughout their lives. The initiative aims to educate, challenge, and spark action from all sectors of society to ensure veterans and military families have the support they have earned. The initiative focuses on key priority areas — employment, education, and wellness while raising awareness about the service, sacrifice, and needs of America’s veterans and military families. More information is available at: www.JoiningForces.gov.

UCLA discovery may lead to better understanding of the disease, possible therapies.

John Ringman, UCLA

With a lack of effective treatments for Alzheimer’s, most of us would think long and hard about whether we wanted to know years in advance if we were genetically predisposed to develop the disease. For researchers, however, such knowledge is a window into Alzheimer’s disease’s evolution.

Understanding the biological changes that occur during the clinically “silent” stage — the years before symptoms appear — provides clues about the causes of the disease and may offer potential targets for drugs that will stop it from progressing.

In a new study, researchers at UCLA have identified chemical changes taking place in the brains of people destined to develop familial Alzheimer’s disease at least 10 years before symptoms or diagnoses occur. Reporting in the current online edition of the journal Archives of Neurology, John Ringman, a UCLA associate professor of neurology, and colleagues identified changes in 56 proteins, including increases in the amyloid protein long associated with Alzheimer’s, inflammatory markers and other proteins related to the brain’s synapses, the connections between neurons through which these brain cells communicate with each other.

Familial Alzheimer’s and sporadic, late-onset Alzheimer’s are distinct forms of what many consider a single disease. The majority of Alzheimer’s cases are sporadic and late-onset, developing after age 65; the causes of this disease type are not completely understood but are at least partly genetic. Familial Alzheimer’s (FAD), a rare form of the disease caused by certain gene mutations, affects less than 2 percent of patients. It is typically early-onset, developing before age 65, and it is inherited — all offspring in the same generation have a 50-50 chance of developing FAD if one of their parents had it.

For this study, researchers developed protein profiles drawn from the cerebrospinal fluid of 14 FAD mutation carriers and compared them with five related non-carriers. In all, they identified 56 proteins that showed significant differences between carriers and non-carriers. Fourteen of these proteins had been reported in prior studies on late-onset Alzheimer’s (including APP, transferrin and other inflammatory markers), but many others were unique to this study, including calsyntenin 3, AMPA 4 glutamate receptor and osteopontin. Normally, these proteins are thought to play a role in the growth and remodeling of synapses, and their alteration in pre-symptomatic Alzheimer’s may represent an early manifestation of the loss of these critical structures.

“Unfortunately, we do not yet have effective medications to stop the progression of Alzheimer’s,” said Ringman, who works at UCLA’s Mary S. Easton Center for Alzheimer’s Disease Research. “In this study, we’ve identified chemical changes occurring in the brains of persons destined to develop Alzheimer’s disease 10 years or more prior to the expression of symptoms. By studying the cerebrospinal fluid of persons developing Alzheimer’s disease at a relatively young age with cutting-edge protein chemical techniques, we found changes in markers reflecting inflammation as well as the breakdown of synapses.

“This provides potential new targets for drug interventions, and it helps elucidate the degree to which FAD and late-onset Alzheimer’s are similar and to what degree they are distinct. Such knowledge may ultimately allow us to tailor our treatments to individuals, depending on the ‘type’ of Alzheimer’s they have.”

The study, funded in part by the pharmaceutical company Pfizer Inc., a grant from the state of California and other sources, was performed at UCLA’s Easton Center, one of 10 centers currently receiving funding from the state. State funding helps these centers provide specialized care for patients with Alzheimer’s disease and other forms of dementia and their families, and it enables the centers to provide training for those engaged in the diagnosis and care of patients with dementia in California.

Additional study authors included Gregory Cole, Sophie Sokolow, Karen Gylys, Daniel H. Geschwind, Jeffrey L. Cummings and Hong I. Wan from UCLA; Howard Schulman, Chris Becker and Ted Jones from Caprion Proteomics U.S.; and Yuchen Bai and Fred Immermann from Pfizer Inc.

The Mary S. Easton Center for Alzheimer’s Disease Research at UCLA is part of the UCLA Department of Neurology, which encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranked first among its peers nationwide in National Institutes of Health funding (2002-09).

UCLA study provides more evidence linking depression to possible dementia later in life.

Abnormal protein deposits (green) in MDD brain.

Depression is one of the most common mental disorders in the elderly, but little is known about the underlying biology of its development in older adults.

In a small study published in the November issue of the peer-reviewed journal Archives of General Psychiatry, UCLA researchers used a unique brain scan to assess the levels of amyloid plaques and tau tangles in older adults with a type of severe depression called major depressive disorder (MDD).

Previous research has suggested that plaque and tangle deposits in the brain — hallmarks of Alzheimer’s disease and many dementias — are associated not only with memory loss but also with mild symptoms of depression and anxiety in middle-aged and older individuals. The team wanted to see what the brain-scanning technique developed at UCLA would find in older people with MDD.

UCLA researchers have created a chemical marker called FDDNP that binds to both plaque and tangle deposits, which can then be viewed through a positron emission tomography (PET) brain scan, providing a “window into the brain.” Using this method, researchers are able to pinpoint where in the brain these abnormal protein deposits are accumulating.

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Finding could offer new avenues for treating a variety of similar conditions.

Steven Finkbeiner

Scientists at the Gladstone Institutes have discovered how a form of the protein linked to Huntington’s disease influences the timing and severity of its symptoms, offering new avenues for treating not only this disease, but also a variety of similar conditions.

In a paper being published today in Nature Chemical Biology, the laboratory of Gladstone Senior Investigator Steven Finkbeiner, M.D., Ph.D., singles out one form of a misfolded protein in neurons that best predicts whether the neuron will die. Neuronal death is key to the development of Huntington’s symptoms — including erratic behavior, memory loss and involuntary muscle movement. This research underscores the value of the cross-disciplinary work done at Gladstone — a leading and independent biomedical–research organization — while revealing techniques that scientists anywhere can apply to conditions involving misfolded proteins, such as Alzheimer’s disease and type 1 diabetes.

“Effective treatments for diseases such as Huntington’s and Alzheimer’s have been slow to develop,” said Finkbeiner, whose research at Gladstone investigates the interactions between genes, neurons and memory. “We hope that our newfound understanding of precisely which misfolded proteins contribute to disease symptoms will speed up drug development for sufferers.”

Huntington’s, an ultimately fataldisease that affects more than a quarter of a million people nationwide,is caused by mutations in the gene that creates the huntingtin, or htt, protein. As the mutated gene produces htt, a segment of the protein called polyglutamine is mistakenly expanded, distorting htt’s natural shape and function. As a result, the misfolded protein malfunctions and can be toxic.

Previous researchinto Huntington’s found that misfolded proteins in the brain lead to the dysfunction and subsequent death of neurons. In this study, Finkbeiner set out to find which misfolded htt types were the most toxic. In laboratory experiments on mice, he and his colleagues screened numerous antibodies that each bind uniquely to one type of misfolded htt in order to identify and tag each type. These antibodies acted as molecular tracking devices that Finkbeiner monitored with an automated microscope and specialized software, both of which his lab created. Experiments revealed that one of the antibodies, 3B5H10, bound to a form of htt closely linked to neuron death and, therefore, disease progression.

“Now that our experiments have identified — at a cellular level — when neurons will die, it will be easier to develop drugs that target the toxic form of htt that causes Huntington’s symptoms,” said Finkbeiner, who is also a professor of neurology and physiology at the University of California, San Francisco, with which Gladstone is affiliated.

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UC Santa Cruz researchers awarded for research that has potential to improve human health.

(From left) Nicholas Shikuma, Kelly Peach and Walter Bray, UC Santa Cruz

A team of UC Santa Cruz researchers searching for drugs to fight cholera won the Deloitte QB3 Award for Innovation, presented by representatives of QB3 and Deloitte Thursday (Oct. 27) at a ceremony at UC San Francisco Mission Bay.

The team — graduate students Kelly Peach and Nicholas Shikuma, with research specialist Walter Bray — developed a high-throughput screening method to identify drugs that prevent Vibrio cholerae, the cholera pathogen, from forming biofilms: thin, tough sheets in which bacteria are shielded from antibiotics.

Biofilms are also a source of infection following operations to implant medical devices, and the team’s method could equally be applied to screen for drugs that disrupt other bacteria.

The $10,000 Award for Innovation, given to a graduate student, postdoc, staff scientist or team working in QB3 laboratories at UC Berkeley, UC Santa Cruz and UCSF, recognizes research that has the potential to improve human health.

The competition began in June when QB3 faculty nominated 38 candidates. By September, a jury panel drawn from industry, venture capital, academia and the media had narrowed the field to five. QB3 then invited the entire Berkeley, UCSF and Santa Cruz campus communities to vote, “American Idol” style, for the ultimate winner. (San Francisco Business Times reporter Ron Leuty covered the competition.) Santa Cruz featured its team in a news article on its website, while on Twitter, the universities (and the Gladstone Institutes) waged a sporadic battle for votes. In the end more than 1500 votes were cast—over half of them for the Santa Cruz team.

In a paper published this year in the journal Molecular Biosystems, the Santa Cruz team explained that biofilms are involved in over 60 percent of bacterial infections in humans. Bacteria often lie dormant in biofilms, encased in material that protects them from a host’s immune response — or drugs. Most antibiotics target cells that are actively dividing, so bacteria in a biofilm can sit out a course of treatment and emerge later to multiply. Drugs that disrupt biofilms make bacteria more vulnerable. Ideally, disruptors would be used in “cocktails” with antibiotics to kill free-floating bacteria.

Cholera remains a major Third World pathogen; an outbreak following the 2010 earthquake in Haiti sickened half a million and killed over 5,000. Biofilms are crucial to the virulence of V. cholerae, but no therapeutics exist to disrupt them. In a step toward solving this problem, Bray, Peach, Shikuma, and colleagues developed a technique to grow cholera biofilms in 384-well plates, and an automated method that uses fluorescence microscopy to measure how much biofilm is present in each well. Theirs is the first reported technique in the scientific literature to use images to analyze V. cholerae biofilms.

In a demonstration run, from a relatively small library of 3080 compounds, the team identified 29 compounds that disrupt cholera biofilm without killing the cells. The 29 compounds are “leads” — starting points for a company to test and refine into an actual drug therapy through many rounds of screens and clinical trials.

The work brought together scientists in three QB3 labs at UC Santa Cruz: those of Roger Linington, Scott Lokey and Fitnat Yildiz. Nadine Gassner, currently the grant program administrator at QB3-Santa Cruz, also contributed.

Four other finalists were in the running:

• Jonathan Galazka, a UC Berkeley graduate student, for engineering a strain of yeast that digests two types of sugar, thus speeding our path to biofuels and improving our access to clean, reliable, and affordable energy sources

• Patrick Goodwill, Ph.D. , a UC Berkeley research associate, for a magnetic particle imaging technique that could enable real-time angiography without radiation or iodine tracer

• Ellen Yeh, M.D., Ph.D., a resident fellow at UCSF, for identifying a potential drug target in the malaria parasite

• Daniel Zwilling, Ph.D., a postdoc, and Lily Huang, a research assistant, both at UCSF and the Gladstone Institutes, for discovering a potential treatment to slow neural breakdown in Alzheimer’s and Huntington’s diseases.