Posts tagged alzheimer's disease
Articles and news from the latest research reports.
Researchers find that ‘peanut butter’ test can help diagnose Alzheimer’s disease
A dollop of peanut butter and a ruler can be used to confirm a diagnosis of early stage Alzheimer’s disease, University of Florida Health researchers have found.
Jennifer Stamps, a graduate student in the UF McKnight Brain Institute Center for Smell and Taste, and her colleagues reported the findings of a small pilot study in the Journal of the Neurological Sciences.
Stamps came up with the idea of using peanut butter to test for smell sensitivity while she was working with Dr. Kenneth Heilman, the James E. Rooks distinguished professor of neurology and health psychology in the UF College of Medicine’s department of neurology.
She noticed while shadowing in Heilman’s clinic that patients were not tested for their sense of smell. The ability to smell is associated with the first cranial nerve and is often one of the first things to be affected in cognitive decline. Stamps also had been working in the laboratory of Linda Bartoshuk, the William P. Bushnell presidentially endowed professor in the College of Dentistry’s department of community dentistry and behavioral sciences and director of human research in the Center for Smell and Taste.
“Dr. Heilman said, ‘If you can come up with something quick and inexpensive, we can do it,’” Stamps said.
She thought of peanut butter because, she said, it is a “pure odorant” that is only detected by the olfactory nerve and is easy to access.
In the study, patients who were coming to the clinic for testing also sat down with a clinician, 14 grams of peanut butter — which equals about one tablespoon — and a metric ruler. The patient closed his or her eyes and mouth and blocked one nostril. The clinician opened the peanut butter container and held the ruler next to the open nostril while the patient breathed normally. The clinician then moved the peanut butter up the ruler one centimeter at a time during the patient’s exhale until the person could detect an odor. The distance was recorded and the procedure repeated on the other nostril after a 90-second delay.
The clinicians running the test did not know the patients’ diagnoses, which were not usually confirmed until weeks after the initial clinical testing.
The scientists found that patients in the early stages of Alzheimer’s disease had a dramatic difference in detecting odor between the left and right nostril — the left nostril was impaired and did not detect the smell until it was an average of 10 centimeters closer to the nose than the right nostril had made the detection in patients with Alzheimer’s disease. This was not the case in patients with other kinds of dementia; instead, these patients had either no differences in odor detection between nostrils or the right nostril was worse at detecting odor than the left one.
Of the 24 patients tested who had mild cognitive impairment, which sometimes signals Alzheimer’s disease and sometimes turns out to be something else, about 10 patients showed a left nostril impairment and 14 patients did not. The researchers said more studies must be conducted to fully understand the implications.
“At the moment, we can use this test to confirm diagnosis,” Stamps said. “But we plan to study patients with mild cognitive impairment to see if this test might be used to predict which patients are going to get Alzheimer’s disease.”
Stamps and Heilman point out that this test could be used by clinics that don’t have access to the personnel or equipment to run other, more elaborate tests required for a specific diagnosis, which can lead to targeted treatment. At UF Health, the peanut butter test will be one more tool to add to a full suite of clinical tests for neurological function in patients with memory disorders.
One of the first places in the brain to degenerate in people with Alzheimer’s disease is the front part of the temporal lobe that evolved from the smell system, and this portion of the brain is involved in forming new memories.
“We see people with all kinds of memory disorders,” Heilman said. Many tests to confirm a diagnosis of Alzheimer’s disease or other dementias can be time-consuming, costly or invasive. “This can become an important part of the evaluation process.”
Neurological Researchers Find Fat May Be Linked to Memory Loss
Although problems with memory become increasingly common as people age, in some persons, memories last long time, even a life time. On the other hand, some people experience milder to substantial memory problems even at an earlier age.
Although there are several risk factors of dementia, abnormal fat metabolism has been known to pose a risk for memory and learning. People with high amounts of abdominal fat in their middle age are 3.6 times as likely to develop memory loss and dementia later in their life.
Neurological scientists at the Rush University Medical Center in collaboration with the National Institutes of Health have discovered that same protein that controls fat metabolism in the liver resides in the memory center of the brain (hippocampus) and controls memory and learning.
Results from the study funded by the Alzheimer’s Association and the National Institutes of Health were recently published in Cell Reports.
“We need to better understand how fat is connected to memory and learning so that we can develop effective approach to protect memory and learning,” said Kalipada Pahan, PhD, the Floyd A. Davis professor of neurology at Rush University Medical Center.
The liver is the body’s major fat metabolizing organ. Peroxisome proliferator-activated receptor alpha (PPARalpha) is known to control fat metabolism in the liver. Accordingly, PPARalpha is highly expressed in the liver.
“We are surprised to find high level of PPARalpha in the hippocampus of animal models,” said Pahan.
“While PPARalpha deficient mice are poor in learning and memory, injection of PPARα to the hippocampus of PPARalpha deficient mice improves learning and memory,” said Pahan.
Since PPARalpha directly controls fat metabolism, people with abdominal fat levels have depleted PPARalpha in the liver and abnormal lipid metabolism. At first, these individuals lose PPARalpha from the liver and then eventually from the whole body including the brain. Therefore, abdominal fat is an early indication of some kind of dementia later in life, according to Pahan.
By bone marrow chimera technique, researchers were able to create some mice having normal PPARalpha in the liver and depleted PPARalpha in the brain. These mice were poor in memory and learning. On the other hand, mice that have normal PPARalpha in the brain and depleted PPARalpha in the liver showed normal memory.
“Our study indicates that people may suffer from memory-related problems only when they lose PPARalpha in the hippocampus”, said Pahan.
CREB (cyclic AMP response element-binding protein) is called the master regulator of memory as it controls different memory-related proteins. “Our study shows that PPARalpha directly stimulates CREB and thereby increases memory-related proteins”, said Pahan.
“Further research must be conducted to see how we could potentially maintain normal PPARalpha in the brain in order to be resistant to memory loss”, said Pahan.
(Source: rush.edu)
DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease
The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.
Cell auto-cleaning mechanism mediates the formation of plaques in Alzheimer’s
Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer’s disease. It might be a potential drug target for the treatment of the disease, concludes new research from the RIKEN Brain Science Institute in Japan. The study sheds light on the metabolism of amyloid beta, and its role in neurodegeneration and memory loss.
In a study published today in the journal Cell Reports, Drs. Per Nilsson, Takaomi Saido and their team show for the first time using transgenic mice that a lack of autophagy in neurons prevents the secretion of amyloid beta and the formation of amyloid beta plaques in the brain. The study also reveals that an accumulation of amyloid beta inside neurons is toxic for the cells.
Alzheimer’s disease, the most common form of dementia, affects nearly 36 million people worldwide, and this number is set to double over the next 20 years. However, the causes of the disease are not well understood and no disease-modifying treatment is available today.
Patients with Alzheimer’s disease have elevated levels of the peptide amyloid beta in their brain and amyloid beta plaques form outside their neurons. This accumulation of amyloid beta causes the neurons to die, but until now the underlying mechanism remained a mystery. And whether the elevated levels of the peptide inside or outside the cells are to blame was unknown.
Autophagy is a cellular cleaning mechanism that normally clears any protein aggregates or other ‘trash’ within the cells, but that is somewhat disturbed in Alzheimer’s patients.
To investigate the role of autophagy in amyloid beta metabolism, Nilsson et al. deleted an important gene for autophagy, Atg7, in a mouse model of Alzheimer’s disease. Contrary to what they were expecting, their results showed that a complete lack of autophagy within neurons prevents the formation of amyloid beta plaque around/outside the cells. Instead, the peptide accumulates inside the neurons, where it causes neuronal death, which in turn leads to memory loss.
“Our study explains how amyloid beta is secreted from the neurons, via autophagy, which wasn’t well understood,” comments Dr Nilsson. “To control amyloid beta metabolism including its secretion is a key to control the disease. Autophagy might therefore be a potential drug target for the treatment of Alzheimer’s disease,” he adds.
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. Photo: Colin MacDiarmid and David Eide/Journal of Biological Chemistry
Zinc discovery may shed light on Parkinson’s, Alzheimer’s
Scientists at UW-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.
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.
Fattah Introduces House Resolution Recognizing World Alzheimer’s Month
Congressman Chaka Fattah (PA-02), a Congressional champion of research and funding for brain-related diseases, introduced a resolution Friday in the U.S. House of Representatives recognizing September as World Alzheimer’s Month. Worldwide, more than 35 million people suffer from Alzheimer’s, and in the United States more than five million individuals live with the debilitating disease.
“The impact of Alzheimer’s is too great for us not to pour more energy and funding into finding a cure for this debilitating disease,” Fattah said. “Beyond the millions worldwide and here at home who suffer from the disease, it puts a significant toll on the millions more family and friends who care for loved ones living with Alzheimer’s and dementia. We must continue to rally stakeholders around the world in the effort to prevent and treat Alzheimer’s.”
The resolution, H. Res. 364 supports the goals of World Alzheimer’s Month: to increase awareness about the disease, its impact on the lives of those affected by it, and the efforts of those seeking to cure Alzheimer’s. It also acknowledges the progress and improvements neurological research has made in the diagnosis and treatment of Alzheimer’s and other forms of dementia.
"As World Alzheimer’s Awareness Month comes to an end, it’s worth remembering that for millions of families across the country, every month is Alzheimer’s month," said George Vradenburg, chairman and co-founder of USAgainstAlzheimer’s. "However, with continued leadership from members of Congress like Rep. Chaka Fattah (PA-02) and others, we can secure the funding resources necessary to stop this disease by 2025."
Fattah added: “This month and every month we must continue to work to elevate the issue, seek new early prevention and treatment strategies, and work towards ultimately finding a cure. We know that neurological research advances this progress, and brings us ever closer to a cure.”
Throughout September, Congressman Fattah continued his work heightening awareness of Alzheimer’s and other neurological diseases. On Saturday, Fattah addressed a day-long conference on Traumatic Brain Injury (TBI) at the University of Pennsylvania. Earlier in the month, Fattah spoke at a California Mental Health Symposium that helped raised more than $2.8 million for research and education.
Fattah is the Ranking Democrat on the House Appropriations Committee’s Subcommittee on Commerce, Justice, Science and Related Agencies, which oversees funding for a significant amount of government-sponsored research. In 2011, Fattah created the Fattah Neuroscience Initiative (FNI) to expand the dialogue around brain diseases and foster cross-sector collaboration for research and funding opportunities.
New mechanism for protein misfolding may link to ALS
Proteins play important roles in the human body, particularly neuroproteins that maintain proper brain function.
Brain diseases such as ALS, Alzheimer’s, and Parkinson’s are known as “tangle diseases” because they are characterized by misfolded and tangled proteins which accumulate in the brain.
A team of Australian and American scientists discovered that an unusual amino acid called BMAA can be inserted into neuroproteins, causing them to misfold and aggregate. BMAA is produced by cyanobacteria, photosynthetic bacteria that form scums or mats in polluted lakes or estuaries.
BMAA has been detected in the brain tissues of ALS patients.
In an article published in PLOS ONE scientists at the University of Technology Sydney and the Institute for Ethnomedicine in Jackson Hole, Wyoming, report that BMAA mimics a dietary aminoacid, L-Serine, and is mistakenly incorporated into neuroproteins, causing the proteins to misfold. The misfolded proteins build up in cells, eventually killing them.
"We found that BMAA inserts itself by seizing the transfer RNA for L-Serine. This, in essence, puts a kink in the protein causing it to misfold," says lead author Dr. Rachael Dunlop, a cell biologist in Sydney working in the laboratory of Dr. Ken Rodgers.
"The cells then begin programmed cell death, called apoptosis. "Even more importantly, the scientists found that extra L-Serine added to the cell culture can prevent the insertion of BMAA into neuroproteins. The possibility that L-Serine could be used to prevent or slow ALS is now being studied."
Even though L-serine occurs in our diet, its safety and efficacy for ALS patients should be properly determined through FDA-approved clinical trials before anyone advocates its use,” says American co-author Dr. Paul Cox.
In ALS, motor neurons in the brain and spinal cord die, progressively paralyzing the body until even swallowing and breathing becomes impossible.
The disease is relatively rare but has affected a number of high-profile people including Professor Stephen Hawking and Yankee baseball player Lou Gehrig.
"For many years scientists have linked BMAA to an increased risk of motor neuron disease but the missing pieces of the puzzle relate to how this might occur. Finally, we have one of those pieces," said Dr Sandra Banack, a co-author on the paper.
(Source: eurekalert.org)
Alzheimer’s progression tracked prior to dementia
For years, scientists have attempted to understand how Alzheimer’s disease harms the brain before memory loss and dementia are clinically detectable. Most researchers think this preclinical stage, which can last a decade or more before symptoms appear, is the critical phase when the disease might be controlled or stopped, possibly preventing the failure of memory and thinking abilities in the first place.
Important progress in this effort is reported in October in Lancet Neurology. Scientists at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University School of Medicine in St. Louis, working in collaboration with investigators at the University of Maastricht in the Netherlands, helped to validate a proposed new system for identifying and classifying individuals with preclinical Alzheimer’s disease.
Their findings indicate that preclinical Alzheimer’s disease can be detected during a person’s life, is common in cognitively normal elderly people and is associated with future mental decline and mortality. According to the scientists, this suggests that preclinical Alzheimer’s disease could be an important target for therapeutic intervention.
A panel of Alzheimer’s experts, convened by the National Institute on Aging in association with the Alzheimer’s Association, proposed the classification system two years ago. It is based on earlier efforts to define and track biomarker changes during preclinical disease.
According to the Washington University researchers, the new findings offer reason for encouragement, showing, for example, that the system can help predict which cognitively normal individuals will develop symptoms of Alzheimer’s and how rapidly their brain function will decline. But they also highlight additional questions that must be answered before the classification system can be adapted for use in clinical care.
“For new treatments, knowing where individuals are on the path to Alzheimer’s dementia will help us improve the design and assessment of clinical trials,” said senior author Anne Fagan, PhD, research professor of neurology. “There are many steps left before we can apply this system in the clinic, including standardizing how we gather and assess data in individuals, and determining which of our indicators of preclinical disease are the most accurate. But the research data are compelling and very encouraging.”
The classification system divides preclinical Alzheimer’s into three stages:
- Stage 1: Levels of amyloid beta, a protein fragment produced by the brain, begin to fall in the spinal fluid. This indicates that the substance is beginning to form plaques in the brain.
- Stage 2: Levels of tau protein start to rise in the spinal fluid, indicating that brain cells are beginning to die. Amyloid beta levels are still abnormal and may continue to fall.
- Stage 3: In the presence of abnormal amyloid and tau biomarker levels, subtle cognitive changes can be detected by neuropsychological testing. By themselves, these changes cannot establish a clinical diagnosis of dementia.
The researchers applied these criteria to research participants studied from 1998 through 2011 at the Knight Alzheimer Disease Research Center. The center annually collects extensive cognitive, biomarker and other health data on normal and cognitively impaired volunteers for use in Alzheimer’s studies.
The scientists analyzed information on 311 individuals age 65 or older who were cognitively normal when first evaluated. Each participant was evaluated annually at the center at least twice; the participant in this study with the most data had been followed for 15 years.
At the initial testing, 41 percent of the participants had no indicators of Alzheimer’s disease (stage 0); 15 percent were in stage 1 of preclinical disease; 12 percent were in stage 2; and 4 percent were in stage 3. The remaining participants were classified as having cognitive impairments caused by conditions other than Alzheimer’s (23 percent) or did not meet any of the proposed criteria (5 percent).
“A total of 31 percent of our participants had preclinical disease,” said Fagan. “This percentage matches findings from autopsy studies of the brains of older individuals, which have shown that about 30 percent of people who were cognitively normal had preclinical Alzheimer’s pathology in their brain.”
Scientists believe the rate of cognitive decline increases as people move through the stages of preclinical Alzheimer’s. The new data support this idea. Five years after their initial evaluation, 11 percent of the stage 1 group, 26 percent of the stage 2 group, and 52 percent of the stage 3 group had been diagnosed with symptomatic Alzheimer’s.
Individuals with preclinical Alzheimer’s disease were six times more likely to die over the next decade than older adults without preclinical Alzheimer’s disease, but researchers don’t know why.
“Risk factors for Alzheimer’s disease might also be associated with other life-threatening illnesses,” Fagan said. “It’s also possible that the presence of Alzheimer’s hampers the diagnosis and treatment of other conditions or contributes to health problems elsewhere in the body. We don’t have enough data yet to say, but it’s an issue we’re continuing to investigate.”
(Source: news.wustl.edu)
Memory-related brain network shrinks with aging
Brain regions associated with memory shrink as adults age, and this size decrease is more pronounced in those who go on to develop neurodegenerative disease, reports a new study published Sept. 18 in the Journal of Neuroscience. The volume reduction is linked with an overall decline in cognitive ability and with increased genetic risk for Alzheimer’s disease, the authors say.
Image: Network of brain regions, highlighted in red and yellow, show atrophy in both healthy aging and neurodegenerative disease. The regions highlighted are susceptible to normal aging and dementia.
“Our results identify a specific pattern of structural brain changes that may provide a possible brain marker for the onset of Alzheimer’s disease,” said Nathan Spreng, assistant professor of human development and the Rebecca Q. and James C. Morgan Sesquicentennial Faculty Fellow in Cornell’s College of Human Ecology.
The study is one of the first to measure structural changes in a collection of brain regions – not just one single area – over the adult life course and from normal aging to neurodegenerative disease, said Spreng, who co-authored the study with Gary R. Turner of York University in Toronto.
Overall, they studied brain data from 848 individuals spanning the adult lifespan, using data from the Open Access Series of Imaging Studies and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). About half of the ADNI sample was assessed multiple times over several years, allowing the researchers to measure brain changes over time and determine who did and did not progress to dementia.
The researchers found that brain volume in the default network (a set of brain regions associated with internally generated thoughts such as memory) declined in both healthy and pathological aging. The researchers noted the greatest decline in Alzheimer’s patients and in those who progressed from mild cognitive impairment to Alzheimer’s disease. Reduced brain volumes in these regions were associated with declines in cognitive ability, the presence of known biological markers of Alzheimer’s disease and with carrying the APOE4 variant of APOE gene, a known risk factor for Alzheimer’s.
“While elements of the default network have previously been implicated in aging and neurodegenerative disease, few studies have examined broad network changes over the full adult life course with such large participant samples and including both behavioral and genetic data,” said Spreng. “Our findings provide evidence for a network-based model of neurodegenerative disease, in which progressive brain changes spread through networks of connected brain regions.”
(Source: news.cornell.edu)
Versatile proteins could be new target for Alzheimer’s drugs
NIH-funded discovery began with asking how the brain learns to see
A class of proteins that controls visual system development in the young brain also appears to affect vulnerability to Alzheimer’s disease in the aging brain. The proteins, which are found in humans and mice, join a limited roster of molecules that scientists are studying in hopes of finding an effective drug to slow the disease process.
Image: PirB (red) is heavily concentrated on the surface of growing nerve cells. Courtesy of Dr. Carla Shatz, Stanford.
"People are just beginning to look at what these proteins do in the brain. While more research is needed, these proteins may be a brand new target for Alzheimer’s drugs," said Carla Shatz, Ph.D., the study’s lead investigator. Dr. Shatz is a professor of biology and neurobiology at Stanford University in California, and the director of Stanford’s interdisciplinary biosciences program, BioX.
She and her colleagues report that LilrB2 (pronounced “leer-bee-2”) in humans and PirB (“peer-bee”) in mice can physically partner with beta-amyloid, a protein fragment that accumulates in the brain during Alzheimer’s disease. This in turn triggers a harmful chain reaction in brain cells. In a mouse model of Alzheimer’s, depleting PirB in the brain prevented the chain reaction and reduced memory loss.
The research was funded in part by the National Eye Institute, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), all part of the National Institutes of Health. It is reported in the Sept. 20 issue of Science.
"These findings provide valuable insight into Alzheimer’s, a complex disorder involving the abnormal build-up of proteins, inflammation and a host of other cellular changes," said Neil Buckholtz, Ph.D., director of the neuroscience division at NIA. "Our understanding of the various proteins involved, and how these proteins interact with each other, may one day result in effective interventions that delay, treat or even prevent this dreaded disease."
Alzheimer’s disease is the most common cause of dementia in older adults, and affects as many as 5 million Americans. Large clumps—or plaques—of beta-amyloid and other proteins accumulate in the brain during Alzheimer’s, but many researchers believe the disease process starts long before the plaques appear. Even in the absence of plaques, beta-amyloid has been shown to cause damage to brain cells and the delicate connections between them.
Dr. Shatz’s discovery took a unique path. She is a renowned neuroscientist, but Alzheimer’s disease is not her focus area. For decades, she has studied plasticity—the brain’s capacity to learn and adapt—focusing mostly on the visual system.
"Dr. Shatz has always been a leader in the field of plasticity, and now she’s taken yet another innovative step—giving us new insights into the abnormal plasticity that occurs in Alzheimer’s disease," said Michael Steinmetz, Ph.D., a program director at NEI. "These findings rest squarely on basic research into the development of the visual system." NEI has funded Dr. Shatz for more than 35 years.
During development, the eyes compete to connect within a limited territory of the brain—a process known as ocular dominance plasticity. The competition takes place during a limited time in early life. If visual experience through one eye is impaired during that time—for example, by a congenital cataract (present from birth)—it can permanently lose territory to the other eye.
"Ocular dominance is a classic example of how a brain circuit can change with experience," Dr. Shatz said. "We’ve been trying to understand it at a molecular level for a long time."
Her search eventually led to PirB, a protein on the surface of nerve cells in the mouse brain. She discovered that mice without the gene for PirB have an increase in ocular dominance plasticity. In adulthood, when the visual parts of their brains should be mature, the connections there are still flexible. This established PirB as a “brake on plasticity” in the healthy brain, Dr. Shatz said.
It wasn’t long before she began to wonder if PirB might also put a brake on plasticity in Alzheimer’s disease. In the current study, she pursued that question with Taeho Kim, Ph.D., a postdoctoral fellow in her lab, and Christopher M. William, M.D., Ph.D., a neuropathology fellow at Massachusetts General Hospital in Boston. Bradley Hyman, M.D., Ph.D., a professor of neurology at Mass General, was a collaborator on the project.
First, the team repeated the genetic experiment that Dr. Shatz had done in normal mice—but this time, they deleted the PirB gene in the Alzheimer’s mice. By about nine months of age, these mice typically develop learning and memory problems. But that didn’t happen in the absence of PirB.
Next, the researchers began thinking about how PirB might fit into the Alzheimer’s disease process, and particularly how it might interact with beta-amyloid. Dr. Kim theorized that since PirB resides on the surface of nerve cells, it might act as a binding site—or receptor—for beta-amyloid. Indeed, he found that PirB binds tightly to beta-amyloid, especially to tiny clumps of it that are believed to ultimately grow into plaques.
Beta-amyloid is known to weaken synapses—the connections between nerve cells. The researchers found that PirB appears to be an accomplice in this process. Without PirB, synapses in the mouse brain were resistant to the effects of beta-amyloid. Other experiments showed that binding between PirB and beta-amyloid can trigger a cascade of harmful reactions that can lead to the breakdown of synapses.
Although PirB is a mouse protein, humans have a closely related protein called LilrB2. The researchers found that this protein also binds tightly to beta-amyloid. By examining brain tissue from people with Alzheimer’s disease, they also found evidence that LilrB2 may trigger the same harmful reactions that PirB can trigger in the mouse brain.
"These are novel results, and direct interaction between beta-amyloid and PirB-related proteins opens up welcome avenues for investigating new drug targets for Alzheimer’s disease," said Roderick Corriveau, Ph.D., a program director at NINDS.
Dr. Shatz said she hopes to interest other researchers to work on developing drugs to block PirB and LilrB2. Currently, no drugs treat the underlying causes of Alzheimer’s disease. Most of the interventions that have reached clinical testing are designed to clear away beta-amyloid. To date, only two other beta-amyloid receptors (PrP-C and EphB2) have been found and are being pursued as drug targets.
(Source: nei.nih.gov)