1. 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.


  2. 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.”


  3. 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.”


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

    November 18, 2017 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.”


  5. 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.”

     


  6. 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.


  7. 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.


  8. 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.”


  9. 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.


  10. 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.