In The Spotlight - DementiaToday

Excessive Nerve Cell Pruning Leads to Disease

October 9, 2013 posted by dementiatoday

Scientists at the Montreal Neurological Institute and Hospital-The Neuro, McGill University, have made important discoveries about a cellular process that occurs during normal brain development and may play an important role in neurodegenerative diseases. The study’s findings, published in Cell Reports, a leading scientific journal, point to new pathways and targets for novel therapies for Alzheimer’s, Parkinson’s, ALS and other neurodegenerative diseases that affect millions of people world-wide.

Studies have shown that protecting cell bodies from death has no impact on disease progression whereas blocking preceding axon breakdown has a significant benefit. (Credit: © Andrii Muzyka / Fotolia)

Research into neurodegenerative disease has traditionally concentrated on the death of nerve cell bodies. However, it is now certain that in most cases that nerve cell body death represents the final event of an extended disease process. Studies have shown that protecting cell bodies from death has no impact on disease progression whereas blocking preceding axon breakdown has a significant benefit. The new study by researchers at The Neuro shifts the focus to the loss or degeneration of axons, the nerve-cell ‘branches’ that receive and distribute neurochemical signals among neurons.

During early development, axons are pruned to ensure normal growth of the nervous system. Emerging evidence suggests that this pruning process becomes reactivated in neurodegenerative disease, leading to the aberrant loss of axons and dendrites. Axonal pruning in development is significantly influenced by proteins called caspases.

“The idea that caspases are even involved in axonal degeneration during development is very recent”

said Dr. Philip Barker, a principal investigator at The Neuro and senior author of the study.

Dr. Barker and his colleagues show that the activity of certain ‘executioner’ caspases (caspase-3 and caspase-9) induce axonal degeneration and that their action is suppressed by a protein termed XIAP (X-linked inhibitor of apoptosis). “We found that caspase-3- and -9 play crucial roles in axonal degeneration and that their activities are regulated by XIAP. XIAP acts as a brake on caspase activity and must be removed for degeneration to proceed” added Dr. Barker.

This balancing act between caspases and XIAP ensure that caspases do not cause unnecessary or excessive destruction. However, this balance may shift during neurodegenerative disease.

“If we understand the pathways that regulate XIAP levels, we may be able to develop therapies that reduce caspase-dependent degeneration during neurodegenerative disease.”

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Nobel Prize Winners’ Cell Research Delivers Alzheimer’s Insights

October 7, 2013 posted by dementiatoday

Americans James Rothman and Randy Schekman and Germany’s Thomas Suedhof won the 2013 Nobel medicine prize for their work on how hormones are transported within and outside cells, giving insight into diseases such as diabetes and Alzheimer’s.

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A screenshot from the Nobel Prize Medicine Website shows (L-R) Americans James E. Rothman and Randy W. Schekman and German Thomas C. Suedhof, winners of the Nobel medicine prize. [AFP/Getty Images]

The Nobel Committee said the work of the three scientists had great implications for neurological conditions as well as conditions affecting key organs.

“Without this wonderfully precise organization, the cell would lapse into chaos,” the Nobel Assembly at Sweden’s Karolinska Institute said in a statement when awarding the prize of $1.2 million.

“Through their discoveries, Rothman, Schekman and Suedhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo,” the committee said.

For example, their research sheds light on how insulin is manufactured and released into the blood at the right place at the right time, the Nobel committee said in the statement.

Medicine is the first of the Nobel prizes awarded each year. Prizes for achievements in science, literature and peace were first awarded in 1901 in accordance with the will of dynamite inventor and businessman Alfred Nobel.

Rothman is professor at Yale University, Schekman is a professor at the University of California at Berkeley, while Suedhof is a professor at Stanford University.

A portrait of U.S. scientist Randy W. Schekman and drafts of his work are displayed on a screen during a press conference to announce the laureates of the 2013 Nobel Prize in Physiology or Medicine on Monday at the Karolinska Institute in Stockholm.

“These beautiful discoveries have importance for the understanding of the human body and obviously implications for diseases in various organs such as the nervous system, diabetes and immune disorders,” Jan-Inge Henter, professor of clinical child oncology at the Karolinska Institute, said at a news conference.

Their work centered on the ‘vesicle’ system by which cells take up nutrients, move substances around and release chemicals like hormones and growth factors.

“There are many organs where this is important,” said Henter.

“For quite some time, it’s been known that this is important in the signaling between neurons, that is nerve cells. We have billions of nerve cells and they have to communicate with each other and they do so with this vesicle transport system.”

“Now, we’ve realized that this is also important in for instance diabetes, because we know that insulin is released by these vesicles and we know that the immune system is regulated also by this vesicle transport mechanism.”

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Zinc Discovery May Shed Light On Parkinson’s, Alzheimer’s

October 3, 2013 posted by dementiatoday

Scientists at the University of Wisconsin-Madison have made a discovery that, if replicated in humans, suggests a shortage of zinc may contribute to diseases like Alzheimer’s and Parkinson’s, which have been linked to defective proteins clumping together in the brain.

The green spots above are clumps of protein inside yeast cells that are deficient in both zinc and a protein that prevents clumping. Research by Colin MacDiarmid and David Eide is exploring how a shortage of zinc can contribute to diseases. (Credit: Colin MacDiarmid and David Eide/Journal of Biological Chemistry)

With proteins, shape is everything. The correct shape allows some proteins to ferry atoms or molecules about a cell, others to provide essential cellular scaffolding or identify invading bacteria for attack. When proteins lose their shape due to high temperature or chemical damage, they stop working and can clump together — a hallmark of Parkinson’s and Alzheimer’s.

The UW researchers have discovered another stress that decreases protein stability and causes clumping: a shortage of zinc, an essential metal nutrient.

Zinc ions play a key role in creating and holding proteins in the correct shape. In a study just published in the online Journal of Biological Chemistry, Colin MacDiarmid and David Eide show that the gene Tsa1 creates “protein chaperones” that prevent clumping of proteins in cells with a zinc shortage. By holding proteins in solution, Tsa1 prevents damage that can otherwise lead to cell death.

For simplicity, the researchers studied the system in yeast — a single-celled fungus. Yeast can adapt to both shortages and excesses of zinc, says MacDiarmid, an associate scientist. “Zinc is an essential nutrient but if there’s too much, it’s toxic. The issue for the cell is to find enough zinc to grow and support all its functions, while at the same time not accumulating so much that it kills the cell.”

Cells that are low in zinc also produce proteins that counter the resulting stress, including one called Tsa1.

The researchers already knew that Tsa1 could reduce the level of harmful oxidants in cells that are short of zinc. Tsa1, MacDiarmid says, “is really a two-part protein. It can get rid of dangerous reactive oxygen species that damage proteins, but it also has this totally distinct chaperone function that protects proteins from aggregating. We found that the chaperone function was the more important of the two.”

“In yeast, if a cell is deficient in zinc, the proteins can mis-fold, and Tsa1 is needed to keep the proteins intact so they can function,” says Eide, a professor of nutritional science. “If you don’t have zinc, and you don’t have Tsa1, the proteins will glom together into big aggregations that are either toxic by themselves, or toxic because the proteins are not doing what they are supposed to do. Either way, you end up killing the cell.”

While the medical implications remain to be explored, there are clear similarities between yeast and human cells. “Zinc is needed by all cells, all organisms, it’s not just for steel roofs, nails and trashcans,” Eide says. “The global extent of zinc deficiency is debated, but diets that are high in whole grains and low in meat could lead to deficiency.”

If low zinc supply has the same effect on human cells as on yeast, zinc deficiency might contribute to human diseases that are associated with a build-up of “junked” proteins, such as Parkinson’s and Alzheimer’s. Eide says a similar protective system to Tsa1 also exists in animals, and the research group plans to move ahead by studying that system in human cell culture.

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Global Alzheimer’s Epidemic Creating Shortage of Caregivers and Lack of Support for Family Members

September 23, 2013 posted by dementiatoday

The World Alzheimer Report 2013 ‘Journey of Caring: An analysis of long-term care for dementia‘, calls for governments around the world to make dementia a priority by implementing national plans, and by initiating urgent national debates on future arrangements for long-term care.

Alzheimer’s Disease International (ADI) and Bupa commissioned a team of researchers, led by Professor Martin Prince from King’s College London, to produce the report.

The report reveals that, as the world population ages, the traditional system of “informal” care by family, friends, and community will require much greater support. Globally, 13% of people aged 60 or over require long-term care. Between 2010 and 2050, the total number of older people with care needs will nearly treble from 101 to 277 million. Long-term care is mainly about care for people with dementia; around half of all older people who need personal care have dementia, and 80% of older people in nursing homes are living with dementia. The worldwide cost of dementia care is currently over US$600 billion (£395 billion), or around 1% of global GDP.

The report states that more attention needs to be paid to maintaining and enhancing quality of life; helping those affected, and their families to ‘live well with dementia’.

Ten-fold increases in research funding are needed to re-energise the work on dementia prevention, treatment and care. This investment is essential to mitigate the impact of the global dementia epidemic on future long-term care needs, and improve quality of care.

The Report recommends that:

Systems should to be in place to monitor the quality of dementia care in all settings - whether in care homes or in the community
Autonomy and choice should be promoted at all stages of the dementia journey, prioritising the voices of people with dementia and their caregivers
Health and social care systems should be better integrated and coordinated to meet people’s needs
Front-line caregivers must be adequately trained and systems will need to be in place to ensure paid and unpaid carers receive appropriate financial reward in order to sustain the informal care system and improve recruitment and retention of paid carers
Care in care homes is a preferred option for a significant minority - quality of life at home can be as good, and costs are comparable if the unpaid work of family caregivers is properly valued
The quality of care in care homes should be monitored through the quality of life and satisfaction of their residents, in addition to routine inspections, as care homes will remain an important component of long-term care.

Professor Martin Prince, from King’s College London’s Institute of Psychiatry and author of the report, said:

“People with dementia have special needs. Compared with other long-term care users they need more personal care, more hours of care, and more supervision, all of which is associated with greater strain on caregivers, and higher costs. Their needs for care start early in the disease course, and evolve constantly over time, requiring advanced planning, monitoring, and coordination. We need to value the unpaid contribution of family caregivers more, and reward paid caregivers better. We can build quality into our care systems, but to do so while containing costs and achieving equity of access for all will be a challenge.”

Marc Wortmann, Executive Director, Alzheimer’s Disease International said: “We need to value those that provide frontline care for people with dementia. This includes paid, as well as unpaid family caregivers, who share much in common. Governments need to acknowledge the role of caregivers and ensure that there are policies in place to support them. ”

Dr Paul Zollinger-Read, Chief Medical Officer, Bupa, said: “An ageing population around the world means that improving dementia care and support is one of our generation’s greatest healthcare challenges - a challenge we must tackle. We’re calling on governments around the world to make dementia a national health priority by developing national dementia plans. National plans ensure that people living with dementia have a good quality of life and friends and family, who often take on the important role of a carer, are properly supported too.”

In response to the global Alzheimer’s epidemic, Alzheimer’s Disease International and Home Instead Senior Care®, have joined together to host Living with Alzheimer’s: A Journey of Caring World Alzheimer Report 2013 Release & Roundtable Discussions. The events, held in three international capitals, address the global impact of the disease during World Alzheimer’s Month. The first event was held in Washington, DC. The other two events are in London on 20 September and Beijing on 26 September.

Roger Baumgart, CEO of Home Instead Senior Care, said:

“Studies consistently show that older adults overwhelmingly prefer to age at home, and with support, they can age at home. However, two-thirds of the calls we get every day are from families in crisis. Caregiver stress is a driver for transition to institutional care. Interventions that provide support, education and training for caregivers have considerable potential to reduce or delay transition into institutional settings. It is our responsibility as a society to determine how we can better support their needs. We are working actively to raise awareness of the needs and challenges for families and to offer the support, educational classes and materials we’ve developed widely available around the world.”

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Test of Alzheimer’s Drug Gets Large Federal Grant

September 18, 2013 posted by dementiatoday

In the most significant sign yet of a broad shift in the focus of Alzheimer’s research from treating to preventing the disease, the federal government announced on Wednesday its largest grant so far to test an Alzheimer’s drug on healthy people at greatest risk for the most common form of the disease.

The $33.2 million grant, and several other prevention studies awarded federal money in the last year, follow years of unsuccessful trials of treatments on people who already have dementia. Those failures have led to the realization that these drugs appear to be ineffective by the time memory and thinking problems have taken hold. At the same time, scientific advances have allowed researchers to identify people at risk for Alzheimer’s long before symptoms emerge.

With five million Americans suffering from Alzheimer’s and their ranks projected to surge as baby boomers age, federal health officials consider the disease such a priority that Dr. Francis S. Collins, director of the National Institutes of Health, scraped money together when forced budget cuts slashed the Obama administration’s promise of $100 million in additional funding for Alzheimer’s for 2013. Dr. Collins said he dipped into the budgets of the 27 N.I.H. agencies to supply $40 million awarded Wednesday for several Alzheimer’s research projects. Another $5 million was provided by the National Institute on Aging.

“The worst thing we could do would be to just hunker down and hold off tackling very important problems,” Dr. Collins said, adding, “Obviously, this is high-risk research, but goodness, the stakes are so high that we felt we had to go forward even in the face of the most difficult budget environment that anyone can remember in the N.I.H.”

The idea is to approach Alzheimer’s with a strategy similar to that used for heart disease and other conditions, said Laurie Ryan, program director for Alzheimer’s disease clinical trials at the National Institute on Aging, part of the N.I.H. “We’re going to look at people at risk, just like we do with people who have high cholesterol and are at risk for cardiovascular disease,” she said. “If we intervene now, can we prevent or at least delay the disease?”

The $33.2 million grant, part of the government’s national Alzheimer’s plan, will help finance a clinical trial to test a treatment on people 60 to 75 who have no symptoms of the disease, but do have two copies of a gene known to greatly increase the risk of getting it as people age.

The project, led by Dr. Eric M. Reiman and Dr. Pierre N. Tariot of the Banner Alzheimer’s Institute in Phoenix, will test a drug or placebo on 650 adults in several locations, mostly in the United States. All of the participants will have two copies of the gene, ApoE4, having inherited it from both parents.

Studies have found that more than half the people with two ApoE4 genes will develop Alzheimer’s, compared with about one-fourth of people with one copy and 10 percent of people with no copies. People with two copies also develop symptoms earlier, around age 68, years before most people with one copy and more than a decade before most people without the gene.

People with two ApoE4 genes make up only about 3 percent of the population, but because they develop the conventional late-onset form of Alzheimer’s, they are important to study. About 25 percent of people possess one copy of the gene.

The Banner project has not yet chosen the drug to be tested, but it will be a treatment that attacks amyloid, a protein that accumulates in plaques in the brains of people with Alzheimer’s.

Expected to begin in 2015, the project will ultimately cost more than $100 million, most of which is expected to be financed by the pharmaceutical industry, with some money from nonprofit sources, Dr. Reiman said. Researchers will use sophisticated tests to measure whether the drug helps delay memory or cognitive decline over five years, although Dr. Reiman said the tests may be able to record some results in as little as two years. The study will also measure brain and neurological changes over time.

Jamie Tyrone, 53, a retired nurse in Ramona, Calif., said she felt traumatized when she learned while participating in a different research effort that she has two copies of ApoE4.

“For the first time I feel hopeful,” she said. While too young to participate in the trial, she recently formed a nonprofit organization called Beating Alzheimer’s by Embracing Science (Babes), which will soon have its inaugural fund-raiser, featuring the celebrities Helen Reddy and Marilu Henner.

She said the new trial “means so much to me because if this study has a positive outcome, guess what — I can be treated and I don’t have to live in fear anymore.”

The new grant is the latest of several grants for Alzheimer’s prevention studies. In 2012, the N.I.H. awarded $16 million to a project led by the same researchers and Dr. Francisco Lopera, a Colombian neurologist. The researchers will test an anti-amyloid drug on members of a Colombian family, the largest extended family in the world with a gene mutation that causes them to develop Alzheimer’s early, showing cognitive impairment by around age 45. In that trial, expected to start this year, family members as young as 30 will receive the drug, Crenezumab, manufactured by Genentech, which is financing the largest portion of that $100 million trial.

Earlier this year, the N.I.H. gave a significant grant to a study that, like the Banner trial, will focus on people at risk for common late-onset Alzheimer’s. Led by Dr. Reisa Sperling, who runs the Alzheimer’s program at Brigham and Women’s Hospital in Boston, the trial will test the anti-amyloid drug solanezumab on 1,000 people in various locations who do not have symptoms of Alzheimer’s but do have amyloid plaques in their brains. The three-year trial will receive about $7 million in federal money its first year, and a possible total of $36 million.

On Wednesday, the N.I.H. also awarded $1.5 million to a trial of three anti-amyloid drugs on people with rare gene mutations that lead to early-onset Alzheimer’s. The trial, run by the Dominantly Inherited Alzheimer Network led by Dr. Randall Bateman of Washington University in St. Louis, may receive a total of $6 million over four years.

Dr. Ronald Petersen, director of the Mayo Clinic’s Alzheimer’s center, who is not involved in these prevention trials, said the studies complemented each other and had the potential to answer questions about the role of amyloid as a potential cause of Alzheimer’s and whether attacking it can prevent dementia.

“That doesn’t mean we abandon people who need treatment,” Dr. Petersen said. “But from a public health perspective, if you want to prevent millions of people from getting the disease, this is the way we have to go.”

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World Alzheimer’s Day Sept 21

September 15, 2013 posted by dementiatoday

Photo: A man and woman at the beach

September 21st is World Alzheimer’s Day. Learn more about Alzheimer’s disease and efforts to address the nation’s sixth leading cause of death.

Facts about Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia among older adults. It involves parts of the brain that control thought, memory, and language and can seriously affect a person’s ability to carry out daily activities.
Although not a normal part of aging, the risk of developing Alzheimer’s disease increases with age. Most individuals with Alzheimer’s disease are over the age of 65. However, people younger than age 65 also can develop Alzheimer’s disease.
Scientists do not know what causes Alzheimer’s disease, but it is believed that it is similar to other chronic conditions and develops as a result of multiple factors rather than a single cause.

Global Alzheimer’s Disease

According to the World Health Organization (WHO), approximately 18 million people worldwide have Alzheimer’s disease. By 2025, this estimate is projected to grow to 34 million people, with the highest increase expected among developing countries.

Alzheimer’s Disease in the United States

It is currently estimated that approximately 2.6 million to 5.2 million Americans currently have Alzheimer’s disease, depending upon the approach used for identifying individuals with dementia.
If no cure is developed and present population trends continue, as many as 16 million individuals may have Alzheimer’s disease by the year 2050.
Alzheimer’s disease ranks as the 6th leading cause of death among adults aged 18 years and older, and is the 5th leading cause of death for adults aged 65 years and older.
For people with Alzheimer’s disease and other dementias, the total payments for health care, long-term care, and hospice are projected to increase from $183 billion in 2011 to $1.1 trillion in 2050 (in 2011 U.S. dollars).

Current Efforts

A coordinated approach involving public and private partners is needed to address Alzheimer’s disease and its devastating effects on individuals, families, and the health care system. There are several new and existing activities currently underway. Some of these efforts are described below.

CDC Healthy Brain Initiative

The CDC Healthy Brain Initiative began in 2005, and aims to better understand the public health burden of cognitive impairment, including Alzheimer’s disease, through conducting surveillance; building a strong evidence base for policy, communication, and programmatic interventions for improving cognitive health; and translating that foundation into effective public health practice in states and communities. This work is guided by the strategic public health framework outlined in The Healthy Brain Initiative: A National Public Health Road Map to Maintaining Cognitive Health.

Released in September 2011, the CDC Healthy Brain Initiative Progress: 2006–2011 Adobe PDF file [PDF - 1.53MB] and Executive Summary Progress Report 2006–2011: The CDC Healthy Brain Initiative [PDF - 857KB] outline progress to date of the CDC Healthy Brain Initiative.

National Alzheimer’s Project Act

The National Alzheimer’s Project Act (NAPA) was signed into law on January 4, 2011, by the President of the United States. NAPA (Public Law 111-375) calls for creating an Advisory Council comprising CDC and other federal and nonfederal partners to develop a national strategic plan for federal agencies to address and overcome the rapidly escalating crisis of Alzheimer’s disease. Once the plan is developed, it will help coordinate Alzheimer’s disease efforts across the federal government by specifying outcome-driven objectives, recommendations, implementation steps, and accountability. More information about NAPA and the Advisory Council.

New Diagnostic Guidelines for Alzheimer’s Disease

In April 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association revised the diagnostic criteria for Alzheimer’s disease and characterized research guidelines on the basis of findings from decades of research. Originally developed in 1984, the previous criteria focused on the later stages of the disease after the patient showed clinical symptoms. The newly revised criteria cover the full spectrum of the disease as it gradually changes over many years, beginning with preclinical changes in the brain that likely occur before any symptoms are noticed, progressing to mild cognitive impairment, and eventually dementia due to Alzheimer’s disease.

Notably, the guidelines now include the use of imaging and biomarkers in blood and spinal fluid that occur with Alzheimer’s disease. Biomarkers are measures that indicate the presence or absence of disease or factors that can increase or decrease a person’s risk of disease. An example of a biomarker is elevated blood cholesterol as a risk factor for heart disease. Biomarkers for Alzheimer’s disease are increasingly used in the research setting to detect onset of the disease and to track progression, but cannot yet be used routinely in clinical diagnosis without further testing and validation. More information about the new diagnostic guidelines.

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Nebraska Educational Television Series - “Now What?” on Alzheimer’s

September 12, 2013 posted by dementiatoday

Dear Readers:

I was recently contacted by Allan Schur, from Bellevue Nebraska, about an informative TV series on Alzheimer’s produced by Nebraska Educational Television (Nebraska’s PBS and NPR stations). He thought you would be interested in viewing it. So, without further ado, here is Allan’s email and information about the series.

Please watch and let me know what you think.

~ Jennifer

“Now What?” is a series on Nebraska Educational Television that is available on their website - http://www.netnebraska.org/basic-page/television/now-what. I think your readers would be interested in viewing it.

The website describes the series:

Now what? Many families facing memory issues ask themselves this daily. Not knowing where to go or what to do can be challenging for caregivers. The NET Television series Now What?, co-produced with the Consortium of Dementia Alternatives, will help to identify memory issues in the elderly and work toward finding solutions to the problems families encounter every day.

Living with Dementia is the first installment of the series. In this episode, experts explain the different types of dementia, including the most common type, Alzheimer’s. The panelists also give viewers advice on the next steps to take when there has been a noticeable change in behavior of a loved one.

The Dementia Journey discusses eldercare issues that arise after a patient has been diagnosed with Dementia. The topics will include, but are not limited to, services for eldercare, financial and estate issues, living wills, power of attorney and understanding Medicare and Medicaid.

A Holistic Approach to Care discusses, with a panel of experts, end-of-life planning and includes discussion about hospice and palliative care. There are many misconceptions about end-of-life care. These treatments take a holistic approach in the care of the patient treating all the needs of the individual. A team will care for the physical, mental, emotional and spiritual needs of a patient, with their needs front and center.

The Caregiver, the fourth episode in the series, discusses issues surrounding the caregivers of dementia patients. The panel, featuring Dr. Deborah Hoffnung and Michaela Williams, defines the word caregiver as well as examines the burden and stress put on the family. They give resources available for caregivers such as support groups and respite services and also discuss advocacy importance as caregivers continue on their journey.

Very well done with more very educational shows to come including a show concerning rural health that will be broadcast tomorrow (Thursday) night and should be available online within the next day or so.

Allan Schur

Bellevue Nebraska

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Faulty Internal Recycling by Brain’s Trash Collectors May Contribute to Alzheimer’s

September 9, 2013 posted by dementiatoday

A defective trash-disposal system in the brain’s resident immune cells may be a major contributor to neurodegenerative disease, a scientific team from the Stanford University School of Medicine has found.

Preliminary observations show that this defect appears in the brains of patients who died of Alzheimer’s disease, so correcting it may someday prove to be an effective way of preventing or slowing the course of the disease.

“We were fortunate in being able to compare microglia - the brain’s own immune cells - from five patients who died of Alzheimer’s disease with five who died of other causes,” said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences at the medical school and senior research career scientist at the Veterans Affairs Palo Alto Health Care System. “And we discovered that in Alzheimer’s disease, the microglia are defective. One of these cells’ main functions, removing garbage, is impaired.”

Wyss-Coray is the senior author of the study, which will be published Sept. 4 in Neuron. The lead author was postdoctoral scholar Kurt Lucin, PhD.

Microglia, one of several important cell types in the brain, serve as both cops and trash collectors. These immune cells continuously police the brain, making sure everything is running smoothly. When they sense a pathogen, they pull out the molecular equivalent of a pistol. If they spot a dead cell or a clump of protein detritus, they don a pair of overalls and hasten to remove it.

They do this by engulfing and ingesting the target in a process called phagocytosis. Many cells can do this, but microglia are the pros - and they’d better be, said Wyss-Coray.

“If they don’t clear up all the detritus in the brain efficiently, debris left lying around can trigger inflammation and consequent injury to neurons,” he said.

Proteins called phagocytic receptors on the surface of microglia look out for characteristic earmarks of detritus, dead cells and potentially toxic substances such as A-beta, a protein widely implicated in Alzheimer’s disease. A-beta is prone to clump into plaques that abound in the brains of people with Alzheimer’s and, to a lesser extent, in the rest of us as we grow older.

When a targeted protein or piece of cellular debris is bound by a phagocytic receptor, part of the microglial cell’s outer membrane forms a bubble that encloses the target, migrates inward and fuses with the cell’s high-powered digestive machinery, which breaks down the ingested contents.

The phagocytic receptors, which have come along for the ride on the membranes engulfing the ingested materials, aren’t digested, though. They are recycled, Wyss-Coray said.

“Microglia don’t constantly make brand-new receptors. Instead, existing ones are returned to the cell membrane by a very sophisticated multiprotein complex called the retromer, which effectively grabs the internalized receptors and shuttles them back to the cell surface.”

But a defect in microglia’s internal recycling program, the new study shows, can result in faulty phagocytosis, which in turn could allow A-beta to accumulate in aging brains. For example, it was recently discovered that a rare mutation in a key phagocytic receptor that binds to A-beta confers a three- to four-fold additional risk for Alzheimer’s disease.

The researchers believe they have determined a culprit: beclin, a protein expressed in every cell in the body and known to be crucial to survival. They found that deficiencies in this protein impair the retromer’s ability to steward phagocytic receptors back to microglial cell surfaces, with nasty consequences for neurons in the brain.

Beclin and the retromer apparatus are similar in mice and humans. So Wyss-Coray and his colleagues first looked at mouse microglia that had been altered to reduce beclin levels by more than half. These beclin-deficient microglia turned out to be less efficient at gobbling up latex beads, a proxy for cellular debris, than microglia with normal levels.

When the scientists injected A-beta into the brains of normal mice, their microglia cleared up this substance quickly, said Wyss-Coray. But in beclin-deficient mice, the microglia took much longer to get the job done.

The researchers also showed that in beclin-deficient cells, the recycling of a phagocytic receptor that binds A-beta was severely impaired.

Apparently beclin is required for adequate retromer function, Wyss-Coray said. “To our surprise, if beclin levels were low, all key components of the retromer were quite dramatically reduced. So, the receptor can’t get back because the retromers aren’t there.”

When his team compared autopsied brains from five Alzheimer’s patients and five people who had died of other causes, they saw that levels of both beclin and at least one of the retromer’s protein components were diminished by as much as 80 percent in Alzheimer’s brains.

“We didn’t expect to see such dramatic differences in these proteins in human tissue. This has not been previously shown for any proteins in human microglia,” Wyss-Coray said. “We have to take our findings about microglia in human brains with a grain of salt because we looked at only 10 brains in all. But the findings are exciting. If they’re accurate, they show one way that microglia can become dysfunctional, and what the consequences can be.”

Wyss-Coray said he still doesn’t know what initially causes the drop in beclin levels. But other experiments suggested that beclin deficits in Alzheimer’s brains are likely not resulting from the accumulation of A-beta deposits but preceding it, and may be contributing to it.

“Most research has focused on neurons,” he said. “Our findings suggest that we should also be looking at other cell types that may be malfunctioning in the brain. If microglia don’t work the way they’re designed to work, a lot of problems may result.”

These findings may also be relevant not just for Alzheimer’s but for other age-related brain diseases. A mutation in one retromer protein has been implicated in Parkinson’s, Wyss-Coray said.

“If beclin decline turns out to be a part of normal aging, eventually A-beta or other protein aggregates, such as those that occur in Parkinson’s disease, could arise.”

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