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

    November 16, 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 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.”

     


  2. New research shows where in the brain the earliest signs of Alzheimer’s occur

    November 8, 2017 by Ashley

    From the Lund University press release:

    Researchers at Lund University in Sweden have for the first time convincingly shown where in the brain the earliest signs of Alzheimer’s occur. The discovery could potentially become significant to future Alzheimer’s research while contributing to improved diagnostics.

    In Alzheimer’s, the initial changes in the brain occur through retention of the protein, ?-amyloid (beta-amyloid). The process begins 10-20 years before the first symptoms become noticeable in the patient.

    In Nature Communications, a research team headed by Professor Oskar Hansson at Lund University has now presented results showing where in the brain the initial accumulation of ?-amyloid occurs. It is in the inner parts of the brain, within one of the brain’s most important functional networks — known as the default mode network.

    “A big piece of the puzzle in Alzheimer’s research is now falling into place. We previously did not know where in the brain the earliest stages of the disease could be detected. We now know which parts of the brain are to be studied to eventually explain why the disease occurs,” says Sebastian Palmqvist, associate professor at Lund University and physician at Skåne University Hospital.

    The default mode network is one of several networks, each of which has a different function in the brain. It is most active when we are in an awake quiescent state without interacting with the outside world, for example, when daydreaming. The network belongs to the more advanced part of the brain. Among other things, it processes and links information from lower systems.

    The study, conducted in collaboration with Michael Schöll, associate senior lecturer at the University of Gothenburg, and William Jagust, professor at the University of California, is based on data from more than 400 people in the United States who have an increased risk of developing Alzheimer’s, and about as many participants from the Swedish research project, BioFINDER. The brain status of all the participants was monitored for two years, and compared to a control group without any signs of Alzheimer’s.

    The difficulty of determining which individuals are at risk of developing dementia later in life, in order to subsequently monitor them in research studies, has been an obstacle in the research world. The research team at Lund University has therefore developed a unique method to identify, at an early stage, which individuals begin to accumulate ?-amyloid and are at risk.

    The method combines cerebrospinal fluid test results with PET scan brain imaging. This provides valuable information about the brain’s tendency to accumulate ?-amyloid.

    In addition to serving as a roadmap for future research studies of Alzheimer’s disease, the new results also have a clinical benefit:

    “Now that we know where Alzheimer’s disease begins, we can improve the diagnostics by focusing more clearly on these parts of the brain, for example in medical imaging examinations with a PET camera,” says Oskar Hansson, professor at Lund University, and medical consultant at Skåne University Hospital.

    Although the first symptoms of Alzheimer’s become noticeable to others much later, the current study shows that the brain’s communication activity changes in connection with the early retention of ?-amyloid. How, and with what consequences, will be examined by the research team in further studies.


  3. Inflammation in middle age may be tied to brain shrinkage decades later

    November 5, 2017 by Ashley

    From the American Academy of Neurology press release:

    People who have biomarkers tied to inflammation in their blood in their 40s and 50s may have more brain shrinkage decades later than people without the biomarkers, according to a study published in the November 1, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. The brain cell loss was found especially in areas of the brain that are affected by Alzheimer’s disease.

    “These results suggest that inflammation in mid-life may be an early contributor to the brain changes that are associated with Alzheimer’s disease and other forms of dementia,” said study author Keenan Walker, PhD, of Johns Hopkins University School of Medicine in Baltimore, Md. “Because the processes that lead to brain cell loss begin decades before people start showing any symptoms, it is vital that we figure out how these processes that happen in middle age affect people many years later.”

    People with the inflammation markers and brain shrinkage also had lower scores on average on a memory test.

    For the study, researchers tested the levels of five markers of inflammation in the blood, including the white blood cell count, in 1,633 people with an average age of 53. An average of 24 years later, the participants took a memory test and had brain scans to measure the volume of several areas of the brain.

    The participants were divided into three groups based on how many elevated levels of inflammation they had among the five biomarkers.

    Compared to the people with no elevated levels, people with elevated levels on three or more biomarkers had on average 5 percent lower volume in the hippocampus and other areas of the brain associated with Alzheimer’s disease.

    Walker said that the effect of one standard deviation increase in the overall inflammation score in mid-life on brain volume decades later was similar to the effect associated with having one copy of the apolipoprotein E (APOE) e4 gene that increases the risk of Alzheimer’s disease.

    Every standard deviation increase in the inflammation score was also associated with a hippocampus volume that was 110 cubic millimeters smaller and the volume of other areas affected by Alzheimer’s disease was 532 cubic millimeters smaller.

    On the memory test, where people were asked to remember a list of 10 words, the people with no elevated markers remembered an average of about 5.5 words, while those with three or more elevated markers remembered an average of about five words.

    Limitations of the study include that the biomarkers were measured only once. Walker said it’s not clear whether a single measurement can adequately determine that people have chronic inflammation.


  4. Study suggests saving neurons may offer new approach for treating Alzheimer’s disease

    by Ashley

    From the University of Iowa Health Care press release:

    Treatment with a neuroprotective compound that saves brain cells from dying also prevents the development of depression-like behavior and the later onset of memory and learning problems in a rat model of Alzheimer’s disease. Although the treatment protects the animals from Alzheimer’s-type symptoms, it does not alter the buildup of amyloid plaques and neurofibrillary tangles in the rat brains.

    “We have known for a long time that the brains of people with Alzheimer’s disease have amyloid plaques and neurofibrillary tangles of abnormal tau protein, but it isn’t completely understood what is cause or effect in the disease process,” say senior study author Andrew Pieper, MD, PhD, professor of psychiatry in the University of Iowa Carver College of Medicine and associate director of the Iowa Neuroscience Institute at the University of Iowa. “Our study shows that keeping neurons alive in the brain helps animals maintain normal neurologic function, regardless of earlier pathological events in the disease, such as accumulation of amyloid plaque and tau tangles.

    Alzheimer’s disease is a devastating neurodegenerative condition that gradually erodes a person’s memory and cognitive abilities. Estimates suggest that more than 5 million Americans are living with Alzheimer’s disease and it is the sixth leading cause of death in the United States, according the National Institute on Aging. In addition to the impact on cognition and memory, Alzheimer’s disease can also affect mood, with many people experiencing depression and anxiety before the cognitive decline is apparent. In fact, people who develop depression for the first time late in life are at a significantly increased risk of developing Alzheimer’s disease.

    “Traditional therapies have targeted the characteristic lesions in Alzheimer’s disease, amyloid deposition and tau pathologies. The findings of this study show that simply protecting neurons in Alzheimer’s disease without addressing the earlier pathological events may have potential as a new and exciting therapy,” says Jaymie Voorhees, PhD, first author of the study, which is an article-in-press in Biological Psychiatry.

    Saving brain cells protects brain function

    Pieper and Voorhees used an experimental compound called P7C3-S243 to prevent brain cells from dying in a rat model of Alzheimer’s disease. The original P7C3 compound was discovered by Pieper and colleagues almost a decade ago, and P7C3-based compounds have since been shown to protect newborn neurons and mature neurons from cell death in animal models of many neurodegenerative diseases, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury. P7C3 compounds have also been shown to protect animals from developing depression-like behavior in response to stress-induced killing of nerve cells in the hippocampus, a brain region critical to mood regulation and cognition.

    The researchers tested the P7C3 compound in a well-established rat model of Alzheimer’s disease. As these rats age, they develop learning and memory problems that resemble the cognitive impairment seen in people with Alzheimer’s disease. However, the new study revealed another similarity with Alzheimer’s patients. By 15 months of age, before the onset of memory problems, the rats developed depression-like symptoms. Developing depression for the first time late in life is associated with a significantly increased risk for developing Alzheimer’s disease, but this symptom has not been previously seen in animal models of the disease.

    Over a three-year period, Voorhees tested a large number of male and female Alzheimer’s and wild type rats that were divided into two groups. One group received the P7C3 compound on a daily basis starting at six months of age, and the other group received a placebo. The rats were tested at 15 months and 24 months of age for depressive-type behavior and learning and memory abilities.

    At 15-months of age, all the rats — both Alzheimer’s model and wild type, treated and untreated — had normal learning and memory abilities. However, the untreated Alzheimer’s rats exhibited pronounced depression-type behavior, while the Alzheimer’s rats that had been treated with the neuroprotective P7C3 compound behaved like the control rats and did not show depressive-type behavior.

    At 24 months of age (very old for rats), untreated Alzheimer’s rats had learning and memory deficits compared to control rats. In contrast, the P7C3-treated Alzheimer’s rats were protected and had similar cognitive abilities to the control rats.

    The team also examined the brains of the rats at the two time points. They found that the traditional hallmarks of Alzheimer’s disease, amyloid plaques, tau tangles, and neuroinflammation, were dramatically increased in the Alzheimer’s rats regardless of whether they were treated with P7C3 or not. However, significantly more neurons survived in the brains of Alzheimer’s rats that had received the P7C3 treatment.

    “This suggests a potential clinical benefit from keeping the brain cells alive even in the presence of earlier pathological events in Alzheimer’s disease, such as amyloid accumulation, tau tangles and neuroinflammation,” Pieper says. “In cases of new-onset late life depression, a treatment like P7C3 might be particularly useful as it could help stabilize mood and also protect from later memory problems in patients with Alzheimer’s disease.”


  5. Study suggests gene therapy protecting against age-related cognitive, memory deficits

    November 4, 2017 by Ashley

    From the Universitat Autònoma de Barcelona press release:

    Researchers from the Institute of Neurosciences at the Universitat Autònoma de Barcelona (INc-UAB) and the Vall d’Hebron Research Institute (VHIR) are the first to demonstrate that regulation of the brain’s Klotho gene using gene therapy protects against age-related learning and memory problems in mice.

    The study, published in Molecular Psychiatry (Nature group), opens the door to advancing in the research and development of therapies based on this neuroprotective gene.

    Researchers from the UAB demonstrated in a previous study that Klotho regulates age-associated processes, increasing life expectancy when over-expressed and accelerating the development of learning and memory deficiencies when inhibited.

    Now they have demonstrated in vivo for the first time that one dose of this gene injected into the central nervous system prevents the cognitive decline associated with aging in old animals which were treated at a younger age.

    The results, which form part of the PhD thesis of Anna Massó, first author of the article, are part of a study led by INc-UAB researchers Dr Miguel Chillón, ICREA researcher at the Department of Biochemistry and Molecular Biology of the UAB and the VHIR; Dr Lydia Giménez-Llort from the Department of Psychiatry and Legal Medicine of the UAB; and with the collaboration of Dr Assumpció Bosch, also from the Department of Biochemistry and Molecular Biology.

    “The therapy is based on an increase in the levels of this protein in the brain using an adeno-associated viral vector (AAV). Taking into account that the study was conducted with animals which aged naturally, we believe this could have the therapeutic ability to treat dementia and neurodegenerative disorders such as Alzheimer’s or multiple sclerosis, among others,” Miguel Chillón points out.

    The researchers patented their therapy and have licensed it to Kogenix Therapeutics. The company includes UAB participation and is based in the United States. It was launched by Dr Miguel Chillón and Dr Assumpció Bosch, together with the entrepreneur Menachem Abraham and Dr Carmela Abraham, professor of Biochemistry and Pharmacology at the Boston University School of Medicine, a pioneering centre in the study of Klotho in the central nervous system for more than a decade.

    The objective of Kogenix is to achieve the initial capital needed to advance in the pre-clinical trials already being conducted with animal models of Alzheimer’s disease. This will give way to the development of a drug to be used in gene therapy against neurodegenerative diseases based on small molecules which enhance the expression of the gene and/or the use of fragments of the Klotho protein itself.

    “In basic research studies and clinical trials the AAVs have shown to be safe and effective in the implementation of a central nervous system gene therapy. In fact, the Food and Drug Administration made the first gene therapy available in the United States in August and additional approvals are expected,” Dr Assumpció Bosch states.


  6. Study suggests brain’s response to mid-life surge in cell aging starts or ends a path to dementia

    November 2, 2017 by Ashley

    From the University of Texas Health Science Center at Houston press release:

    Researchers at The University of Texas Health Science Center at Houston (UTHealth) School of Dentistry and McGovern Medical School have discovered a previously unknown characteristic of brain-cell aging that could help detect late-onset Alzheimer’s disease decades before symptoms begin.

    The study, “Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice,” appeared online in the journal Translational Psychiatry earlier this year.

    Working with mice, the UTHealth team found that neurons in the brain experienced a sudden increase in aging around the mouse equivalent of age 40 in humans. Normal mice responded with a surge of interleukin33, a protein that activates the body’s repair mechanisms to make the neurons healthy again. Mice lacking the IL33 gene didn’t experience the surge and continued to decline, eventually developing dementia at an age roughly equivalent to 68 in humans.

    “We think we’re getting old gradually, but when we’re talking about these cells, we’ve discovered that it’s not that way,” said Yahuan Lou, Ph.D., a professor in the Department of Diagnostic and Biomedical Sciences at the School of Dentistry.

    Late-onset sporadic Alzheimer’s disease occurs after age 65 and represents approximately 95 percent of all cases, with the other 5 percent believed to be genetic. By the time symptoms appear, the brain has already lost massive numbers of neurons. The UTHealth researchers believe the surge at age 40 may be an ideal time to look for biomarkers that predict Alzheimer’s long before the damage begins.

    Lou first detected the power of IL33 while studying premature ovarian failure in mice. “We observed that when we removed IL33, the ovary shrank much faster than normal. So we wondered: If IL33 does this in the ovary, what does it do in the brain? The brain has an abundance of IL33.”

    Looking for collaborators who could test that question, Lou was surprised to learn that researchers from McGovern Medical School’s Department of Psychiatry and Behavioral Sciences had recently moved into the new UT Behavioral and Biomedical Sciences Building that he and other dental school researchers had also newly occupied. Among his new neighbors were Department of Psychiatry Professor Joao De Quevedo, M.D., Ph.D., and Assistant Professor Ines Moreno-Gonzalez, Ph.D., of the Mitchell Center for Alzheimer’s Disease, who had the expertise and resources for analyzing rodent behavior and correlating it to humans. A collaborative team soon formed, and their mouse study led to the paper in Translational Psychiatry with plans for follow-up studies to explore the tantalizing results.

    Lou said a group of researchers in Singapore recently conducted an experiment using mice that model familial early-onset Alzheimer’s disease. “When they injected IL33 into the [Alzheimer’s] mice, they saw that the plaque load was reduced, but they didn’t know why,” he said. “We’ve figured out why.”

    The IL33 injections seemed to relieve symptoms temporarily, he added, but did not cure the disease. The effects lasted about two weeks in mice — equal to several months in humans. Lou believes finding a way to enhance the brain’s own supply of IL33 may lead to potential treatments for the disease.

    The cause of late-onset Alzheimer’s is a medical mystery with many potential causes under investigation, including neuro-inflammation, abnormal aging, smoking, and infections. IL33 deficiency is another promising lead, with additional studies planned as funding is secured.


  7. Study looks at aspects of caregiving

    October 31, 2017 by Ashley

    From the Michigan Medicine – University of Michigan press release:

    They don’t get pay, recognition, or much of a break. They spend hours a day helping someone who may not even recognize them anymore.

    Now, a new poll gives a glimpse into the lives of the spouses, grown children and other family members and friends who act as caregivers for up to five million Americans with dementia.

    The strain of providing such care for loved ones with Alzheimer’s disease and other conditions came through in the latest results from the National Poll on Healthy Aging, with 78 percent saying caregiving was stressful.

    But the poll also reveals the positive side of caregiving, with 85 percent of family caregivers calling it a rewarding experience. In fact, 45 percent rated it as “very rewarding”, compared to 19 percent who called it “very stressful”. However, 40 percent of those who called dementia caregiving very stressful also said it was not rewarding.

    Another potential benefit? Perspective. Ninety-one percent of the caregivers said they had thought about their own future care needs because of their experience taking care of someone with dementia.

    Right now, though, 66 percent of dementia caregivers say their duties interfere with their own life and work – including 27 percent who said they had neglected something related to their own health because of caregiving’s demands on their time.

    Only 1 in 4 had taken advantage of resources designed to help caregivers, but 41 percent of those who didn’t expressed interest in such support.

    The poll was conducted by the University of Michigan Institute for Healthcare Policy and Innovation. It is sponsored by AARP and Michigan Medicine, U-M’s academic medical center.

    Knowledge to build on

    The results are based on responses from 148 people between the ages of 50 and 80 who take care of a loved one over age 65 with dementia.

    This group made up seven percent of a nationally representative sample, so they represent a sizable number of older adults across the general population. The poll team hopes the findings can form the basis for further exploration of caregiving issues specific to dementia.

    “We need to understand the challenges, benefits and barriers that dementia caregivers face, because of the important role they play for their loved ones, in their families, and in our society and economy,” says Erica Solway, Ph.D., associate poll director and IHPI senior project manager. “We can see from this report that better support to these family caregivers is needed, which health care providers, family, friends, social service organiations, clergy and policymakers can all help to address.”

    Caregivers were most likely to be women, under age 65, and taking care of a parent. Nearly half were employed in addition to being caregivers. They took care of medical needs, household tasks, and other activities to keep their loved one safe. One-quarter said the person they were caring for couldn’t be left alone for more than an hour.

    Solway notes that the experience of caregiving may actually help encourage the kind of planning that many Americans haven’t attended to but should – such as completing advance directives, designating someone to make medical decisions in case of serious illness, or engaging in conversations about their wishes as they age.

    “Caregiving is a complex experience that affects people across every demographic,” says Alison Bryant, Ph.D., senior vice president of research for AARP. “Providing family caregivers with resources to support them in balancing work and life pressures and reducing their stress is critical not only for them but also for those that might care for them in the future.”

    The need for resources

    The rise in the number of people with dementia has led to the creation of many resources for caregivers that can provide vital support. These range from self-help tools and classes for learning new skills that may be needed in the role, to support groups and respite care that can help give caregivers a break from their duties.

    Though the poll didn’t ask why caregivers had or had not turned to such resources, the data do suggest that many caregivers who are not currently doing so want to access them. A lack of time may be a key factor, since two-third of the caregivers in the poll said that their caregiving duties had interfered with work, family time, or even getting to the doctor when they had a health problem.

    Organizations such as AARP are developing and deploying more local and online resources for cargivers. Health care providers who tend to dementia patients’ medical needs could be a key gateway to specific local and electronic resources for their patients’ caregivers, Solways notes.

    But she also observes that health care providers should routinely ask patients if they serve as a caregiver to a loved one, so they can identify and address needs and concerns during the caregiver’s own appointments.

    The poll results are based on answers from those who identified themselves as dementia caregivers among a nationally representative sample of 2,131 people ages 50 to 80. The poll respondents answered a wide range of questions online. Questions were written, and data interpreted and compiled, by the IHPI team. Laptops and Internet access were provided to poll respondents who did not already have it.


  8. Discovery lights path for Alzheimer’s research

    October 30, 2017 by Ashley

    From the Rice University press release:

    A probe invented at Rice University that lights up when it binds to a misfolded amyloid beta peptide — the kind suspected of causing Alzheimer’s disease — has identified a specific binding site on the protein that could facilitate better drugs to treat the disease. Even better, the lab has discovered that when the metallic probe is illuminated, it catalyzes oxidation of the protein in a way they believe might keep it from aggregating in the brains of patients.

    The study done on long amyloid fibrils backs up computer simulations by colleagues at the University of Miami that predicted the photoluminescent metal complex would attach itself to the amyloid peptide near a hydrophobic (water-avoiding) cleft that appears on the surface of the fibril aggregate. That cleft presents a new target for drugs.

    Finding the site was relatively simple once the lab of Rice Chemist Angel Martí used its rhenium-based complexes to target fibrils. The light-switching complex glows when hit with ultraviolet light, but when it binds to the fibril it becomes more than 100 times brighter and causes oxidation of the amyloid peptide.

    “It’s like walking on the beach,” Marti said. “You can see that someone was there before you by looking at footprints in the sand. While we cannot see the rhenium complex, we can find the oxidation (footprint) it produces on the amyloid peptide.

    “That oxidation only happens right next to the place where it binds,” he said. “The real importance of this research is that allows us to see with a high degree of certainty where molecules can interact with amyloid beta fibrils.”

    “The binding sites of the rhenium complex on fibrils were not known experimentally. That’s where our computational techniques became invaluable,” said University of Miami Chemist Rajeev Prabhakar. “Our computer modeling predicted binding sites and the modes of interactions of these molecules at the atomic level.”

    The study appears in the journal Chem.

    “We believe this hydrophobic cleft is a general binding site (on amyloid beta) for molecules,” Martí said. “This is important because amyloid beta aggregation has been associated with the onset of Alzheimer’s disease. We know that fibrillar insoluble amyloid beta is toxic to cell cultures. Soluble amyloid oligomers that are made of several misfolded units of amyloid beta are also toxic to cells, probably even more than fibrillar.

    “There’s an interest in finding medications that will quench the deleterious effects of amyloid beta aggregates,” he said. “But to create drugs for these, we first need to know how drugs or molecules in general can bind and interact with these fibrils, and this was not well-known. Now we have a better idea of what the molecule needs to interact with these fibrils.”

    When amyloid peptides fold properly, they hide their hydrophobic residues while exposing their hydrophilic (water-attracting) residues to water. That makes the proteins soluble, Martí said. But when amyloid beta misfolds, it leaves two hydrophobic residues, known as Valine 18 and Phenylalanine 20, exposed to create the hydrophobic cleft. This binding site was proposed in the Prabhakar lab and was experimentally confirmed in the Martí lab.

    “It’s perfect, because then molecules with hydrophobic domains are driven to bind there,” Martí said. “They are compatible with this hydrophobic cleft and associate with the fibril, forming a strong interaction.”

    These results can lead to the development of photodynamic therapy for Alzheimer’s disease.

    “We found multiple oxygen binding locations adjacent to the oxidation site,” said Prabhakar. “We were quite surprised by the ability of these fibrils to trap oxygen molecules.”

    If the resulting oxidation keeps the fibrils from aggregating farther into the sticky substance found in the brains of Alzheimer’s patients, it may be the start of a useful strategy to stop aggregation before symptoms of the disease appear.

    “It’s a very attractive system because it uses light, which is a cheap resource,” Martí said. “If we can modify complexes so they absorb red light, which is transparent to tissue, we might be able to perform these photochemical modifications in living animals, and maybe someday in humans.”

    He said light activation allows the researchers to have “exquisite control” of oxidation.

    “We imagine it might be possible someday to prevent symptoms of Alzheimer’s by targeting amyloid beta in the same way we treat cholesterol in people now to prevent cardiovascular disease,” Martí said. “That would be wonderful.”


  9. Is Alzheimer’s disease a disorder of energy metabolism?

    October 28, 2017 by Ashley

    From the McLean Hospital press release:

    A team of investigators from McLean Hospital and Harvard Medical School, led by Kai C. Sonntag, MD, PhD, and Bruce M. Cohen, MD, PhD, has found a connection between disrupted energy production and the development of late-onset Alzheimer’s disease (LOAD). The findings appear in the current issue of Scientific Reports.

    “These findings have several implications for understanding and developing potential therapeutic intervention in LOAD,” explained Sonntag, an associate stem cell researcher at McLean Hospital and an assistant professor of psychiatry at Harvard Medical School. “Our results support the hypothesis that impairment in multiple interacting components of bioenergetics metabolism may be a key mechanism underlying and contributing to the risk and pathophysiology of this devastating illness.”

    For three decades, it has been thought that the accumulation of small toxic molecules in the brain — called amyloid beta, or in short, A? — is central to the development of Alzheimer’s disease (AD). Strong evidence came from studying familial or early-onset forms of AD (EOAD) that affect about five percent of AD patients and have associations with mutations leading to abnormally high levels or abnormal processing of A? in the brain. However, the “A? hypothesis” has been insufficient to explain the pathological changes in the more common LOAD, which affects more than 5 million seniors in the United States.

    “Because late-onset Alzheimer’s is a disease of age, many physiologic changes with age may contribute to risk for the disease, including changes in bioenergetics and metabolism,” said Cohen, director of the Program for Neuropsychiatric Research at McLean Hospital and the Robertson-Steele Professor of Psychiatry at Harvard Medical School. “Bioenergetics is the production, usage, and exchange of energy within and between cells or organs, and the environment. It has long been known that bioenergetic changes occur with aging and affect the whole body, but more so the brain, with its high need for energy.”

    According to Sonntag and Cohen, it has been less clear what changes in bioenergetics are underlying and which are a consequence of aging and illness.

    In their study, Sonntag and Cohen analyzed the bioenergetic profiles of skin fibroblasts from LOAD patients and healthy controls, as a function of age and disease. The scientists looked at the two main components that produce energy in cells: (1) glycolysis, which is the mechanism to convert glucose into fuel molecules for consumption by mitochondria, and (2) burning of these fuels in the mitochondria, which use oxygen in a process called oxidative phosphorylation or mitochondrial respiration. The investigators found that LOAD cells exhibited impaired mitochondrial metabolism, with a reduction in molecules that are important in energy production, including nicotinamide adenine dinucleotide (NAD). LOAD fibroblasts also demonstrated a shift in energy production to glycolysis, despite an inability to increase glucose uptake in response to the insulin analog IGF-1. Both the abnormal mitochondrial metabolism and the increase of glycolysis in LOAD cells were disease- and not age-specific, while diminished glucose uptake and the inability to respond to IGF-1 was a feature of both age and disease.

    “The observation that LOAD fibroblasts had a deficiency in the mitochondrial metabolic potential and an increase in the glycolytic activity to maintain energy supply is indicative of failing mitochondria and fits with current knowledge that aging cells increasingly suffer from oxidative stress that impairs their mitochondrial energy production,” said Sonntag.

    Cohen added that because the brain’s nerve cells rely almost entirely on mitochondria-derived energy, failure of mitochondrial function, while seen throughout the body, might be particularly detrimental in the brain.

    The study’s results link to findings from other studies that decreasing energy-related molecules (and specifically NAD) are features of normal aging by suggesting that abnormalities in processes involving these molecules may also be a factor in neurodegenerative diseases like LOAD. Whether modulating these compounds could slow the aging process and prevent or delay the onset of LOAD is unknown. However, several clinical trials are currently under way to test this possibility. Other changes are unique to AD, and these, too, may be targets for intervention.

    While these findings are significant, the paper’s authors emphasize that the pathogenesis of LOAD is multifactorial, with bioenergetics being one part of risk determination and note that the skin fibroblasts studied are not the primary cell type that is affected in LOAD.

    “However, because bioenergetics changes are body-wide, observations made in fibroblasts may also be relevant to brain cells,” said Sonntag. “In fact, metabolic changes like diminished glucose uptake and insulin/IGF-1 resistance may underlie the association between various disorders of aging, such as type 2 diabetes and AD.”

    Sonntag and Cohen are already in the midst of follow-up work aiming to study these bioenergetics features in brain nerve cells and astrocytes generated from LOAD patient-derived induced pluripotent stem cells, as an aging and disease model in the dish. It is the group’s hope that findings from these studies will reveal further insight into the role of bioenergetics in LOAD pathogenesis and novel targets for intervention — both prevention and treatment.


  10. Study illuminates how seniors cope with Alzheimer’s-risk biomarker results

    October 27, 2017 by Ashley

    From the University of Pennsylvania School of Medicine press release:

    Testing drugs to prevent or delay the onset of Alzheimer’s dementia and using them in the clinic will mean identifying and informing adults who have a higher risk of Alzheimer’s but are still cognitively normal. A new study from the Perelman School of Medicine at the University of Pennsylvania has shed light on how seniors cope with such information.

    The study examined cognitively normal adults 65 years and older who had been accepted into a large Alzheimer’s prevention trial based on brain scans showing an “elevated” level of beta amyloid protein plaques. Beta Amyloid plaques are one of the biomarkers of Alzheimer’s-disease. The Penn Medicine researchers found that for many of these seniors, being told that that their amyloid levels were “elevated” on brain scans led to frustration and a desire for more detailed information.

    Clinicians who give these results to people should be prepared to explain how and why measurements of amyloid are termed ‘elevated’ and what that means in terms of Alzheimer’s dementia risk,” said Jason Karlawish, MD, a professor of Medicine, Medical Ethics and Health Policy, and Neurology, and co-director of the Penn Memory Center.

    The study, published on October 23, 2017 in JAMA Neurology, comes as Alzheimer’s researchers and the pharmaceutical industry have begun to think more in terms of preventing dementia than in trying to treat after it has been diagnosed. To date, every candidate drug tested in large-scale clinical trials in patients with Alzheimer’s dementia has failed to show a significant effect in slowing the usual 5-10 year course of this fatal illness.

    Developing a preventive therapy is challenging for a number of reasons, not least because it entails the ethically challenging task of testing potentially risky drugs on people who are cognitively normal. Research over the past two decades has found, however, that certain types of brain scan as well as blood and spinal fluid tests can sort people into categories of higher or lower risk of developing Alzheimer’s dementia.

    For example, positron emission tomography (PET) using a radiotracer that sticks specifically to Alzheimer’s-associated amyloid plaques can measure the extent of amyloid plaques in the brain. Having no plaques means having essentially no near-term risk of Alzheimer’s dementia. Most elderly people will have some amyloid plaque burden, and although that doesn’t make Alzheimer’s dementia a certainty in a normal lifespan, plaque loads beyond a certain threshold have been linked to a higher risk of this illness.

    The most prominent Alzheimer’s prevention trial now underway, the NIH-sponsored A4 trial, has enrolled seniors based on the PET finding elevated amyloid. Karlawish and colleagues sought to determine how these seemingly healthy seniors handled the information that they had elevated brain amyloid.

    The researchers interviewed 50 seniors (ages 65-85) who had enrolled into the A4 trial. They found that about half had expected their amyloid PET scan result, based on a family history of Alzheimer’s or a recent experience with memory problems. Most understood the basic facts provided by the A4 trial clinicians, namely that their brain amyloid levels were elevated, indicating a higher but not certain risk of developing Alzheimer’s dementia. A smaller percentage appeared to believe mistakenly that they either had no increased risk of dementia or had 100 percent risk — even “early Alzheimer’s.”

    A large minority of the subjects (20 of the 50) were dissatisfied with the ambiguity of the message that their brain amyloid level was “elevated.” One 71-year old woman commented, accurately enough: “I don’t know how elevated the risk is. It could be like right over the edge, and other people are right under the edge.” Similarly a 75-year old man complained that he found the uncertainty frustrating: “my background is in a technical area, and I’m used to having facts and data.”

    “What this is telling us is that, in the future, Alzheimer’s biomarkers will have to get more predictive, or we’ll simply have to educate people to cope with the uncertainty,” Karlawish said.

    He emphasized that for now, disclosing amyloid PET result to cognitively normal adults is something that occurs only in experimental contexts such as the A4 trial. Amyloid PET scans are available for people who already have cognitive problems, to help distinguish Alzheimer’s from other forms of dementia.

    Alzheimer’s researchers hope, however, that trials such as the A4 trial, which is testing an anti-amyloid drug, will lead eventually to preventive therapies to cognitively normal adults, particularly those considered to have high Alzheimer’s risk based on PET amyloid levels and other biomarkers.

    “In the future, learning this kind of information will be a normal part of going to the doctor, like finding out you have a high cholesterol level,” Karlawish said. “The challenge is to anticipate what it will be like for seniors to learn this, and to develop effective strategies to help them cope with problems that may result, such as being stigmatized socially or losing their usual sense of well-being.”