1. Study suggests reasons why head and face pain causes more suffering

    November 22, 2017 by Ashley

    From the Duke University press release:

    Hate headaches? The distress you feel is not all in your — well, head. People consistently rate pain of the head, face, eyeballs, ears and teeth as more disruptive, and more emotionally draining, than pain elsewhere in the body.

    Duke University scientists have discovered how the brain’s wiring makes us suffer more from head and face pain. The answer may lie not just in what is reported to us by the five senses, but in how that sensation makes us feel emotionally.

    The team found that sensory neurons that serve the head and face are wired directly into one of the brain’s principal emotional signaling hubs. Sensory neurons elsewhere in the body are also connected to this hub, but only indirectly.

    The results may pave the way toward more effective treatments for pain mediated by the craniofacial nerve, such as chronic headaches and neuropathic face pain.

    “Usually doctors focus on treating the sensation of pain, but this shows the we really need to treat the emotional aspects of pain as well,” said Fan Wang, a professor of neurobiology and cell biology at Duke, and senior author of the study. The results appear online Nov. 13 in Nature Neuroscience.

    Pain signals from the head versus those from the body are carried to the brain through two different groups of sensory neurons, and it is possible that neurons from the head are simply more sensitive to pain than neurons from the body.

    But differences in sensitivity would not explain the greater fear and emotional suffering that patients experience in response to head-face pain than body pain, Wang said.

    Personal accounts of greater fear and suffering are backed up by functional Magnetic Resonance Imaging (fMRI), which shows greater activity in the amygdala — a region of the brain involved in emotional experiences — in response to head pain than in response to body pain.

    “There has been this observation in human studies that pain in the head and face seems to activate the emotional system more extensively,” Wang said. “But the underlying mechanisms remained unclear.”

    To examine the neural circuitry underlying the two types of pain, Wang and her team tracked brain activity in mice after irritating either a paw or the face. They found that irritating the face led to higher activity in the brain’s parabrachial nucleus (PBL), a region that is directly wired into the brain’s instinctive and emotional centers.

    Then they used methods based on a novel technology recently pioneered by Wang’s group, called CANE, to pinpoint the sources of neurons that caused this elevated PBL activity.

    “It was a eureka moment because the body neurons only have this indirect pathway to the PBL, whereas the head and face neurons, in addition to this indirect pathway, also have a direct input,” Wang said. “This could explain why you have stronger activation in the amygdala and the brain’s emotional centers from head and face pain.”

    Further experiments showed that activating this pathway prompted face pain, while silencing the pathway reduced it.

    “We have the first biological explanation for why this type of pain can be so much more emotionally taxing than others,” said Wolfgang Liedtke, a professor of neurology at Duke University Medical Center and a co-author on Wang’s paper, who is also treating patients with head- and face-pain. “This will open the door toward not only a more profound understanding of chronic head and face pain, but also toward translating this insight into treatments that will benefit people.”

    Chronic head-face pain such cluster headaches and trigeminal neuralgia can become so severe that patients seek surgical solutions, including severing the known neural pathways that carry pain signals from the head and face to the hindbrain. But a substantial number of patients continue to suffer, even after these invasive measures.

    “Some of the most debilitating forms of pain occur in the head regions, such as migraine,” said Qiufu Ma, a professor of neurobiology at Harvard Medical School, who was not involved in the study. “The discovery of this direct pain pathway might provide an explanation why facial pain is more severe and more unpleasant.”

    Liedtke said targeting the neural pathway identified here can be a new approach toward developing innovative treatments for this devastating head and face pain.


  2. Injury from contact sport has harmful, though temporary effect on memory

    by Ashley

    From the McMaster University press release:

    McMaster University neuroscientists studying sports-related head injuries have found that it takes less than a full concussion to cause memory loss, possibly because even mild trauma can interrupt the production of new neurons in a region of the brain responsible for memory.

    Though such losses are temporary, the findings raise questions about the long-term effects of repeated injuries and the academic performance of student athletes.

    The researchers spent months following dozens of athletes involved in high-contact sports such as rugby and football, and believe that concussions and repetitive impact can interrupt neurogenesis — or the creation of new neurons — in the hippocampus, a vulnerable region of the brain critical to memory.

    The findings were presented today (Tuesday, November 14th) at the Society for Neuroscience’s annual conference, Neuroscience 2017, in Washington D.C.

    “Not only are newborn neurons critical for memory, but they are also involved in mood and anxiety,” explains Melissa McCradden, a neuroscience postdoctoral fellow at McMaster University who conducted the work. “We believe these results may help explain why so many athletes experience difficulties with mood and anxiety in addition to memory problems.”

    For the study, researchers administered memory tests and assessed different types of athletes in two blocks over the course of two years. In the first block, they compared athletes who had suffered a concussion, uninjured athletes who played the same sport, same-sport athletes with musculoskeletal injuries, and healthy athletes who acted as a control group.

    Concussed athletes performed worse on the memory assessment called a mnemonic similarity test (MST), which evaluates a person’s ability to distinguish between images that are new, previously presented, or very similar to images previously presented.

    In the second study, rugby players were given the MST before the season started, halfway through the season, and one month after their last game. Scores for injured and uninjured athletes alike dropped midseason, compared to preseason scores, but recovered by the postseason assessment.

    Both concussed and non-concussed players showed a significant improvement in their performance on the test after a reprieve from their sport.

    For the concussed athletes, this occurred after being medically cleared to return to full practice and competition. For the rugby players, they improved after approximately a month away from the sport.

    If neurogenesis is negatively affected by concussion, researchers say, exercise could be an important tool in the recovery process, since it is known to promote the production of neurons. A growing body of new research suggests that gentle exercise which is introduced before a concussed patient is fully symptom free, is beneficial.

    “The important message here is that the brain does recover from injury after a period of reprieve,” says McCradden. “There is a tremendous potential for the brain to heal itself.”


  3. Study suggests declining sense of smell may help identify patients with mild cognitive impairment

    November 21, 2017 by Ashley

    From the Columbia University Medical Center press release:

    Researchers at Columbia University Medical Center (CUMC) and the New York State Psychiatric Institute (NYSPI) may have discovered a way to use a patient’s sense of smell to treat Alzheimer’s disease before it ever develops. Having an impaired sense of smell is recognized as one of the early signs of cognitive decline, before the clinical onset of Alzheimer’s disease. The researchers at CUMC and NYSPI have found a way to use that effect to determine if patients with mild cognitive impairment may respond to cholinesterase inhibitor drugs to treat Alzheimer’s disease.

    The findings were published online this week in the Journal of Alzheimer’s Disease.

    Cholinesterase inhibitors, such as donepezil, enhance cholinergic function by increasing the transmission of the neurotransmitter acetylcholine in the brain. Cholinergic function is impaired in individuals with Alzheimer’s disease. Cholinesterase inhibitors, which block an enzyme that breaks down acetylcholine, have shown some effectiveness in improving the cognitive symptoms of Alzheimer’s disease. However, they have not been proven effective as a treatment for individuals with mild cognitive impairment (MCI), a condition that markedly increases the risk of Alzheimer’s disease.

    “We know that cholinesterase inhibitors can make a difference for Alzheimer’s patients, so we wanted to find out if we could identify patients at risk for Alzheimer’s who might also benefit from this treatment,” said D.P. Devanand, MBBS, MD, professor of psychiatry, scientist in the Gertrude H. Sergievsky Center at CUMC, and co-director of the Memory Disorders Clinic and the Late Life Depression Clinic at NYSPI. “Since odor identification tests have been shown to predict progression to Alzheimer’s, we hypothesized that these tests would also allow us to discover which patients with MCI would be more likely to improve with donepezil treatment.”

    In this year-long study, 37 participants with MCI underwent odor identification testing with the University of Pennsylvania Smell Identification Test (UPSIT). The test was administered before and after using an atropine nasal spray that blocks cholinergic transmission.

    The patients were then treated with donepezil for 52 weeks, and were periodically reevaluated with the UPSIT and with memory and cognitive function tests. Those who had a greater decline in UPSIT scores, indicating greater cholinergic deficits in the brain, after using the anticholinergic nasal spray test saw greater cognitive improvement with donepezil.

    In addition, short-term improvement in odor identification from baseline to eight weeks tended to predict longer-term cognitive improvement with donepezil treatment over one year.

    “These results, particularly if replicated in larger populations, suggest that these simple inexpensive strategies have the potential to improve the selection of patients with mild cognitive impairment who are likely to benefit from treatment with cholinesterase inhibitors like donepezil,” said Dr. Devanand.


  4. Study suggests biomarker may predict early Alzheimer’s disease

    November 20, 2017 by Ashley

    From the Sanford-Burnham Prebys Medical Discovery Institute press release:

    Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a peptide that could lead to the early detection of Alzheimer’s disease (AD). The discovery, published in Nature Communications, may also provide a means of homing drugs to diseased areas of the brain to treat AD, Parkinson’s disease, as well as glioblastoma, brain injuries and stroke.

    “Our goal was to find a new biomarker for AD,” says Aman Mann, Ph.D., research assistant professor at SBP who shares the lead authorship of the study with Pablo Scodeller, Ph.D., a postdoctoral researcher at SBP. “We have identified a peptide (DAG) that recognizes a protein that is elevated in the brain blood vessels of AD mice and human patients. The DAG target, connective tissue growth factor (CTGF) appears in the AD brain before amyloid plaques, the pathological hallmark of AD.”

    “CTGF is a protein that is made in the brain in response to inflammation and tissue repair,” explains Mann. “Our finding that connects elevated levels of CTGF with AD is consistent with the growing body of evidence suggesting that inflammation plays an important role in the development of AD.”

    The research team identified the DAG peptide using in vivo phage display screening at different stages of AD development in a mouse model. In young AD mice, DAG detected the earliest stage of the disease. If the early appearance of the DAG target holds true in humans, it would mean that DAG could be used as a tool to identify patients at early, pre-symptomatic stages of the disease when treatments already available may still be effective.

    “Importantly, we showed that DAG binds to cells and brain from AD human patients in a CTGF-dependent manner” says Mann. “This is consistent with an earlier report of high CTGF expression in the brains of AD patients.”

    “Our findings show that endothelial cells, the cells that form the inner lining of blood vessels, bind our DAG peptide in the parts of the mouse brain affected by the disease,” says Erkki Ruoslahti, M.D., Ph.D., distinguished professor at SBP and senior author of the paper. “This is very significant because the endothelial cells are readily accessible for probes injected into the blood stream, whereas other types of cells in the brain are behind a protective wall called the blood-brain barrier. The change in AD blood vessels gives us an opportunity to create a diagnostic method that can detect AD at the earliest stage possible.

    “But first we need to develop an imaging platform for the technology, using MRI or PET scans to differentiate live AD mice from normal mice. Once that’s done successfully, we can focus on humans,” adds Ruoslahti.

    “As our research progresses we also foresee CTGF as a potential therapeutic target that is unrelated to amyloid beta (Aß), the toxic protein that creates brain plaques,” says Ruoslahti. “Given the number of failed clinical studies that have sought to treat AD patients by targeting Aß, it’s clear that treatments will need to be given earlier — before amyloid plaques appear — or have to target entirely different pathways.

    DAG has the potential to fill both roles — identifying at risk individuals prior to overt signs of AD and targeted delivery of drugs to diseased areas of the brain. Perhaps CTGF itself can be a drug target in AD and other brain disorders linked to inflammation. We’ll just have to learn more about its role in these diseases.”


  5. Study suggests sleep apnea may increase risk of developing Alzheimer’s disease

    November 19, 2017 by Ashley

    From the American Thoracic Society press release:

    Obstructive sleep apnea (OSA) may put elderly people at greater risk of developing Alzheimer’s disease (AD), according to new research published online in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

    In “Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly: A Longitudinal Study,” researchers report that biomarkers for amyloid beta (Aß), the plaque-building peptides associated with Alzheimer’s disease, increase over time in elderly adults with OSA in proportion to OSA severity. Thus, individuals with more apneas per hour had greater accumulation of brain amyloid over time.

    According to the authors, AD is a neurodegenerative disorder that afflicts approximately five million older Americans. OSA is even more common, afflicting from 30 to 80 percent of the elderly, depending on how OSA is defined.

    “Several studies have suggested that sleep disturbances might contribute to amyloid deposits and accelerate cognitive decline in those at risk for AD,” said Ricardo S. Osorio, MD, senior study author and assistant professor of psychiatry at New York University School of Medicine.

    “However, so far it has been challenging to verify causality for these associations because OSA and AD share risk factors and commonly coexist.”

    He added that the purpose of this study was to investigate the associations between OSA severity and changes in AD biomarkers longitudinally, specifically whether amyloid deposits increase over time in healthy elderly participants with OSA.

    The study included 208 participants, age 55 to 90, with normal cognition as measured by standardized tests and clinical evaluations. None of the participants was referred by a sleep center, used continuous positive airway pressure (CPAP) to treat sleep apnea, was depressed, or had a medical condition that might affect their brain function. The researchers performed lumbar punctures (LPs) to obtain participants’ cerebrospinal fluid (CSF) soluble Aß levels, and then used positron emission tomography, or PET, to measure Aß deposits directly in the brain in a subset of participants.

    The study found that more than half the participants had OSA, including 36.5 percent with mild OSA and 16.8 percent with moderate to severe OSA. From the total study sample, 104 participated in a two-year longitudinal study that found a correlation between OSA severity and a decrease in CSF Aß42 levels over time. The authors said this finding is compatible with an increase in amyloid deposits in the brain; the finding was confirmed in the subset of participants who underwent amyloid PET, which showed an increase in amyloid burden in those with OSA.

    Surprisingly, the study did not find that OSA severity predicted cognitive deterioration in these healthy elderly adults. Andrew Varga, MD, PhD, study coauthor and a physician specializing in sleep medicine and neurology at the Icahn School of Medicine at Mount Sinai in New York, said this finding suggests that these changes were occurring in the preclinical stages of AD.

    “The relationship between amyloid burden and cognition is probably nonlinear and dependent on additional factors,” he added. This study finding may also be attributable to the study’s relatively short duration, highly educated participants and use of tests that fail to discern changes in cognitive abilities that are subtle or sleep-dependent, the authors wrote.

    The high prevalence of OSA the study found in these cognitively normal elderly participants and the link between OSA and amyloid burden in these very early stages of AD pathology, the researchers believe, suggest the CPAP, dental appliances, positional therapy and other treatments for sleep apnea could delay cognitive impairment and dementia in many older adults.

    “Results from this study, and the growing literature suggesting that OSA, cognitive decline and AD are related, may mean that age tips the known consequences of OSA from sleepiness, cardiovascular, and metabolic dysfunction to brain impairment,” Dr. Osorio said. “If this is the case, then the potential benefit of developing better screening tools to diagnose OSA in the elderly who are often asymptomatic is enormous.”


  6. Researchers design social mobile gaming that boosts rehabilitation for physically impaired patients

    November 18, 2017 by Ashley

    From the Imperial College London press release:

    The researchers from Imperial have designed a video game called Balloon Buddies, which is a tool that enables those recovering from conditions such as a stroke to engage and play together with healthy volunteers such as therapists and family members as a form of rehabilitation.

    Balloon Buddies is designed to level the playing field by allowing healthy participants to support the less abled player. The researchers have shown that this type of collaboration makes it more rewarding for the less-abled partner, more challenging for the better partner, and overall more fun for both, as they have to continuously work together to score points.

    The team have trialled Balloon Buddies by getting patients to play it on their own in single player mode and then partnered with healthy volunteers during dual player gameplay. They found that the performance of the patient was boosted when they played with a healthy volunteer, compared to if they were playing the game on their own. In addition, they found that the poorer a patient’s single player performance was, the greater the improvement seen when they played with another during dual-player mode.

    These findings published today in the Journal of NeuroEngineering and Rehabilitation (JNER), suggest that by increasing engagement with healthy volunteers, compared to playing alone, patients may be more likely to increase the effort they put into training, which could ultimately lead to greater gains in physical performance.

    While the pilot study was limited to 16 patients and 32 healthy participants playing in 16 pairs, the researchers believe this form of rehabilitation through gaming may be beneficial to patients recovering from other illnesses such as musculoskeletal injuries, arthritis, and cerebral palsy. The researchers are aiming to further develop the game alongside new multiplayer concepts and show that it can be used in different settings including patients training with their therapist or with other patients, in community centres or even remotely at home.

    Dr Michael Mace, lead author from the Department of Bioengineering at Imperial College London, said: “Video games are a great way of providing repetitive exercise to help patients recover from debilitating illnesses. However, most games are designed for users to play on their own, which can actually discourage and isolate many patients. We developed the Balloon Buddy game to enable patients to train with their friends, family or caregivers in a collaborative and playful manner. The technology is still being developed, but we have shown that playing jointly with another individual may lead to increased engagement and better outcomes for patients.”

    Balloon Buddies uses animation, sounds, and vibration-feedback, similar to conventional video games. It requires users to balance a ball on a beam, which is lifted at each of its ends by balloons controlled by the players. The main aim of the game is for the players to vary the height of the beam so that the ball collides with moving targets in order to collect points. Players are also required to work together to keep the beam horizontal so that the ball doesn’t roll off the platform. It is played with a wireless handgrip called GripAble, enabling people with arm weakness to control video games on any standard tablet device.

    In the study, the researchers tested the game on 16 patients who had arm weakness following a stroke with a healthy volunteer over three months at Charing Cross Hospital, which is part of Imperial College Healthcare NHS Trust, in 2016. Previously, the game was also tested on 16 healthy pairs with different baseline abilities.

    The team will now carry out a larger study to examine whether the game leads to more efficient learning and to examine if patients are more motivated to train for longer periods. They will also explore social implications of interaction such as the effect of patients playing with a relative versus a stranger.


  7. Study investigates patterns of degeneration in Alzheimer’s disease

    by Ashley

    From the Brigham and Women’s Hospital press release:

    Alzheimer’s disease (AD) is known to cause memory loss and cognitive decline, but other functions of the brain can remain intact. The reasons cells in some brain regions degenerate while others are protected is largely unknown. In a paper to be published in Stem Cell Reports, researchers from Brigham and Women’s Hospital have found that factors encoded in the DNA of brain cells contribute to the patterns of degeneration, or vulnerability, in AD.

    AD is characterized by plaques composed of amyloid ?-protein (A?) and tangles composed of Tau protein; accumulation of A? protein leads to disruption of Tau and, eventually, neurodegeneration which affects brain regions in a variety of ways. The front, rostral, portion of the brain is generally more damaged by plaque build-up while the back, caudal, portion is generally spared.

    Though there are several mechanisms that could cause these differences, the team focused on the potential contributions of cell-autonomous factors among neuronal subtypes that could affect both the generation of and the responses to A?. In a novel application of human induced-pluripotent stem cell (iPSC) technology, the team generated powerful culture systems that represent different areas of the brain. The systems were developed by taking skin cells from patients with a familial Alzheimer’s disease mutation and turning these skin cells into stem cells. Stem cells divide to make more stem cells, providing an unlimited supply of cells. Stem cells also can be turned into any type of cell in the body, including brain cells. In this study, the authors showed that vulnerable brain cells made more toxic A? protein compared to brain cells from more protected regions of the brain.

    In addition, the researchers found that brain cells in the protected, caudal portion of the brain have a less toxic response to A? than their rostral counterparts. Though early-onset, familial Alzheimer’s disease (fAD) accounts for a small number of AD cases, the study of fAD patients, or samples in this case, can reveal important aspects of the cell and molecular mechanisms underlying all types of AD. The team is currently using this information to investigate exactly why caudal neurons are protected and what differences in cell type cause neurons to be protected from AD.

    “These findings illuminate our understanding of why some neurons are spared and why others are not spared in AD,” said Christina Muratore, PhD, of the Department of Neurology. “If we can find out more information about why these subtypes of cells are protected, we may be able to use this information to tailor therapies to protect the vulnerable cells.”


  8. Study suggests exercise may be beneficial to mental health regimen

    November 17, 2017 by Ashley

    From the Michigan State University press release:

    More mental health providers may want to take a closer look at including exercise in their patients’ treatment plans, a new study suggests.

    Michigan State University and University of Michigan researchers asked 295 patients receiving treatment at a mental health clinic whether they wanted to be more physically active and if exercise helped improve their mood and anxiety. They also asked if patients wanted their therapist to help them become more active.

    Eighty-five percent said they wanted to exercise more and over 80 percent believed exercise helped improve their moods and anxiety much of the time. Almost half expressed interest in a one-time discussion, with many participants also wanting ongoing advice about physical activity with their mental health provider.

    The study is now published in the journal General Hospital Psychiatry.

    Physical activity has been shown to be effective in alleviating mild to moderate depression and anxiety,” said Carol Janney, lead author of the study and an MSU assistant professor of epidemiology. “Current physical activity guidelines advise at least 30 minutes, five days a week to promote mental and physical health, yet many of those surveyed weren’t meeting these recommendations.”

    More than half of the participants said their mood limited their ability to exercise, which Janney said provides an opportunity for physicians and therapists in clinics to offer additional support.

    “Offering physical activity programs inside the mental health clinics may be one of many patient-centered approaches that can improve the mental and physical health of patients,” Janney said.

    Marcia Valenstein, senior author and professor emeritus in psychiatry at U-M, agreed.

    “Mental health treatment programs need to partner with fitness programs to support their patients’ willingness to exercise more,” she said. “This support might come from integrating personal trainers into mental health clinics or having strong partnerships with the YMCA or other community recreational facilities.”

    Both Valenstein and Janney said that psychiatrists and other providers might discuss with patients the general need to exercise, but few actually sit down with patients and create a comprehensive exercise plan for them or regularly make sure they are adhering to a specific goal.

    “Mental health providers such as psychiatrists and therapists may not have the necessary training to prescribe physical activity as part of their mental health practice,” Janney said. “But by teaming up with certified personal trainers or other exercise programs, it may help them prescribe or offer more recommendations for physical activity in the clinic setting.”

    Results also showed that over half of the patients surveyed showed interest in getting help from a personal trainer and were willing to pay a bit extra, but that the topic of physical activity was rarely discussed by their physician.

    “This is a missed opportunity,” Valenstein said. “If we can make it easier for both therapists and their patients to have easier access to physical activity services, then we are likely to help more patients reduce their depression and anxiety.”

    Once the effectiveness of this approach is proven, she added, health insurers might consider moving in the direction of covering services that help people exercise.

    “Several insurers already do this for diabetes prevention, so it’s not out of the question.”


  9. Researchers develop way to stimulate formation of new neural connections in adult brain

    November 16, 2017 by Ashley

    From the University of Idaho press release:

    A team led by University of Idaho scientists has found a way to stimulate formation of new neural connections in the adult brain in a study that could eventually help humans fend off memory loss, brain trauma and other ailments in the central nervous system.

    Peter G. Fuerst, an associate professor in the College of Science’s Department of Biological Sciences and WWAMI Medical Education Program, and a team that included lead author doctoral student Aaron Simmons, were able to stimulate growth of new neural connections in mice that are needed to connect the cells into neural circuits. Their study, which included scientists from the University of Louisville and University of Puerto Rico-Humacao, is titled “DSCAM-Mediated Control of Dendritic and Axonal Arbor Outgrowth Enforces Tiling and Inhibits Synaptic Plasticity.” It was published today in the Journal Proceedings of the National Academy of Sciences.

    “The paper is a study into factors that prevent adult neurons from making new connections,” Fuerst said. “Regulation of this process is important to prevent several disorders, such as autism, but is also related to the inability of the adult nervous system to readily recover from damage.”

    Researchers studied a cell population that has the unusual ability to make new connections into adulthood, but under normal conditions does not grow the needed axons or dendrites. The team was able to genetically manipulate the cell population in the mice to induce axon and dendrite outgrowth. They found this induced the formation of stable, functional connections with new cells.

    “The idea is that one could stimulate the nervous system to make new connections if there was some kind of trauma,” Fuerst said. “Maybe this is the way to reactivate the cell to build those new connections that we can take advantage of clinically.”

    Their efforts included research through the regional WWAMI Medical Education Program at the University of Washington and could have wide ramifications for other adult neurological conditions that prevent human brains from making those needed connections as an adult.

    “In children in early development it’s very easy to make new connections, but adults lose that ability, and we want to see why that is,” he said.

    The genetic manipulation used in mice as part of the study wouldn’t work in humans. Instead, Fuerst and his team would next like to test small-molecule drugs that regulate these central nervous system processes — currently used to combat cancer in humans — to see if they can help the nervous system make new connections in mice.

    “These contributions by Peter and his team right here at the University of Idaho are helping advance global neurological research,” said Janet Nelson, vice president for research and economic development. “I’m excited by the potential impact of this research on the understanding of the brain and in advancing human health.”


  10. Researchers identify new protective function for a brain protein genetically linked to Alzheimer’s

    by Ashley

    From the Sanford-Burnham Prebys Medical Discovery Institute press release:

    Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new protective function for a brain protein genetically linked to Alzheimer’s. The findings, published in the Journal of Experimental Medicine, could inform novel treatment strategies.

    “We found that a protein called SORLA directly limits the ability of amyloid beta, the toxic protein that causes Alzheimer’s, to trigger the destruction of neuronal connections,” says Huaxi Xu, Ph.D., professor and the Jeanne and Gary Herberger Leadership Chair of SBP’s Neuroscience and Aging Research Center. (SORLA stands for sortilin-related receptor with LDLR class A repeats.) “This is actually the third way that SORLA has been shown to defend against neurodegeneration.”

    “It’s becoming increasingly clear that the SORLA gene has a major influence on Alzheimer’s development — more and more Alzheimer’s-associated mutations in the SORLA gene are being discovered,” Xu adds. “Our findings help explain why they are so important.”

    SORLA is one of many genes in which mutations are associated with increased risk of Alzheimer’s, which affects 5.5 million people in the U.S. The biggest risk factor is age — as the average life expectancy increases, the number of people with Alzheimer’s is expected to almost triple by 2050.

    Alzheimer’s begins when amyloid beta aggregates into small clusters outside neurons. Those clusters, called oligomers, induce toxic signaling that damages the connections between synapses so that neurons can no longer talk to one another. Synapse loss is the reason Alzheimer’s patients develop memory problems.

    Xu and his collaborators suspected that SORLA — a trafficking protein that shuttles molecules between cellular compartments — might help protect against amyloid beta induced toxic signaling based on their prior observations. SORLA has already been shown to counteract production of amyloid beta and eliminate it from the space around neurons.

    Xu’s team recently reported that SORLA physically interacts with EphA4, one of the receptors through which amyloid beta provokes synaptic dysfunction. (EphA4 exists primarily to control the wiring of neuronal networks as the brain develops and regulate the behavior of synapses in the adult brain.)

    In this study, Xu’s team established that SORLA could mitigate the toxic EphA4 signaling caused by amyloid beta. They also showed that increasing levels of SORLA in mice reduced cognitive impairments caused by amyloid beta.

    “These observations suggest that early-stage Alzheimer’s could be treated with drugs that increase levels of SORLA, or that enhance its interaction with EphA4,” comments Xu. “We’re currently searching for drugs that have either of these effects.

    “The researchers also found that EphA4 is over-activated in brain tissue from Alzheimer’s patients, and that over-activation correlates with decreased binding to SORLA, demonstrating the relevance of this discovery to human disease.

    “Our study also provides support to explore EphA4 inhibitors as Alzheimer’s therapeutics,” Xu notes. “There’s preclinical data from disease models suggesting they have some efficacy.”

    “SORLA is becoming a hot topic in Alzheimer’s research. No other protein has yet been found to influence Alzheimer’s pathogenesis in so many ways. And it may do even more — we plan to explore whether it modulates other cell surface amyloid beta receptors such as the cellular prion protein and the NMDA receptor.”