1. Protein involved in Alzheimer’s disease may also be implicated in cognitive abilities

    August 17, 2017 by Ashley

    From the IOS Press press release:

    Rare mutations in the amyloid precursor protein (APP) have previously been shown to be strongly associated with Alzheimer’s disease (AD). Common genetic variants in this protein may also be linked to intelligence (IQ) in children, according to recent research performed at the University of Bergen, Norway.

    Results of the research were published online in the Journal of Alzheimer’s Disease. Senior author Dr. Tetyana Zayats is a researcher at the KGJebsen Centre for Neuropsychiatric Disorders at the University of Bergen.

    The study analyzed genetic markers and IQ collected from 5,165 children in the Avon Longitudinal Study of Parents and Children. The genetic findings were followed up in the genetic data from two adult datasets (1) 17,008 cases with AD and 37,154 controls, and (2) 112,151 individuals assessed for general cognitive functioning. The function of the genetic markers was analysed using reporter assays in cells.

    Brain cells communicate via synapses containing hundreds of specialized proteins. Mutations in some of these proteins lead to dysfunctional synapses and brain diseases such as epilepsy, intellectual disability, autism or AD. Dr. Zayats and co-workers at the University of Bergen examined a subgroup of these proteins that have been implicated in synaptic plasticity and learning (the ARC complex). They found that a variation in DNA sequence within the gene encoding a member of this group of proteins, amyloid beta precursor protein (APP) was associated with non-verbal (fluid) intelligence in children, which reflects our capacity to reason and solve problems. In adults, this variation revealed association with AD, while the overall genetic variation within the APP gene itself appeared to be correlated with the efficiency of information processing (reaction time).

    “This study has potential implications for our understanding of the normal function of these synaptic proteins as well as their involvement in disease” said Dr. Zayats.

    APP encodes the amyloid-? precursor protein that forms amyloid-? — containing neuritic plaques, the accumulation of which is one of the key pathological hallmarks in AD brains. However, it is unclear how these plaques affect brain functions and whether they lead to AD.

    “Our understanding of biological processes underlying synaptic functioning could be expanded by examining human genetics throughout the lifespan as genetic influences may be the driving force behind the stability of our cognitive functioning,” Dr. Zayats commented.

    Genetic correlation between intelligence and AD has also been found in large-scale genome-wide analyses on general cognitive ability in adults. Several genes involved in general intelligence have previously reported to be associated with AD or related dementias. Such overlap has also been noted for the APP gene, where a coding variant was shown to be protective against both AD and cognitive decline in elderly.

    “While this is only an exploratory study, in-depth functional and association follow up examinations are needed,” Dr. Zayats noted. “Examining genetic overlap between cognitive functioning and AD in children — not only adults — presents us with a new avenue to further our understanding of the role of synaptic plasticity in cognitive functioning and disease.”


  2. Novel perspectives on anti-amyloid treatment for the prevention of Alzheimer’s disease

    August 13, 2017 by Ashley

    From the VIB (the Flanders Institute for Biotechnology) press release:

    For decades researchers have been investigating the underlying foundations of Alzheimer’s disease to provide clues for the design of a successful therapy. This week, VIB/KU Leuven scientists have published breakthrough insights in the journal Cell. A collaboration between Prof. Lucía Chávez-Gutiérrez and Prof. Bart De Strooper (both VIB-KU Leuven) revealed the molecular basis of the hereditary form of Alzheimer’s disease that strikes early in life. These new findings provide powerful insights for the design of novel therapeutic strategies to tackle the disease. The hereditary form of Alzheimer’s disease is caused by mutations in the Gamma Secretase enzyme and the APP protein. Gamma Secretase cuts APP several times in a progressive manner, with each cleavage generating a shorter fragment, called amyloid beta, which gets released into the brain.

    The VIB-KU Leuven team discovered that disease-causing mutations in Gamma secretase and APP disrupt the cleavage process leading to the generation of longer amyloid beta fragments that are only partially digested. These longer amyloid fragments are thought to cause widespread neuronal death, resulting in memory problems and other symptoms of Alzheimer’s disease, before aggregating into amyloid plaques (a hallmark of the disease). The researchers uncovered that the disease-causing mutations disrupt this process by weakening the interactions of Gamma Secretase and APP during the progressive cleavages. In that way they promote the premature release of longer amyloid beta fragments. The more the Gamma Secretase-APP interaction is undermined, the sooner Alzheimer’s disease develops. The report also suggests that changes in the cellular environment could modulate the interaction between Gamma secretase and APP, and could therefore also affect someone’s risk to develop the non-hereditary form of Alzheimer’s disease.

    These findings have important implications for the prevention or treatment of the disease. Previous attempts to tackle the toxic effects of amyloid beta have mostly focused on blocking its production or removing the amyloid plaques from the brain. However, the new insights suggest that stabilizing the interaction between Gamma secretase and APP might be sufficient to avoid the release of longer and toxic amyloid beta fragments and in that way prevent or delay the disease. Prof. Lucía Chávez-Gutiérrez (VIB-KU Leuven): “The mutations causing familial Alzheimer’s disease show the clinical relevance of drugs that strengthen the interaction between Gamma secretase and APP. The more stable the complexes are, the further APP can be processed, resulting in shorter, non-toxic forms of amyloid beta.”


  3. Risk for bipolar disorder associated with faster aging

    August 10, 2017 by Ashley

    From the King’s College London press release:

    New King’s College London research suggests that people with a family history of bipolar disorder may ‘age’ more rapidly than those without a history of the disease.

    The study, published in Neuropsychopharmacology, also shows that bipolar patients treated with lithium — the main medication for the illness — have longer telomeres (a sign of slower biological aging) compared to bipolar disorder patients not treated with lithium. This suggests that the drug may mask the aging effects associated with bipolar disorder, or even help to reverse it.

    Faster aging at the biological level could explain why rates of aging-related diseases such as cardiovascular disease, type-2 diabetes and obesity are higher amongst bipolar disorder patients. However, more research is needed in the relatives of bipolar disorder patients to better understand if they are also at a higher risk for aging-related diseases.

    Unaffected first-degree relatives represent a group of individuals at risk for bipolar disorder who have not been treated with medications, so studying them may represent a truer reflection of the relationship between aging and bipolar disorder. To measure biological aging, the researchers studied a feature of chromosomes called telomeres in 63 patients with bipolar disorder, 74 first-degree relatives and 80 unrelated healthy people.

    Telomeres sit on the end of our chromosomes and act like ‘caps’, protecting the strands of DNA stored inside each of our cells as we age. Telomeres shorten each time a cell divides to make new cells, until they are so short that they are totally degraded and cells are no longer able to replicate. Telomere length therefore acts as a marker of biological age, with shortened telomeres representing older cells, and commonly older individuals.

    The rate at which telomeres shorten across our lifespan can vary, based on a range of environmental and genetic factors. This means that two unrelated people of the same chronological age may not be the same age biologically.

    The researchers from King’s College London and the Icahn School of Medicine at Mount Sinai found that healthy relatives of bipolar patients had shorter telomeres compared to healthy controls (who had no risk for the disorder running in their family). This suggests that genetic or environmental factors associated with family risk for bipolar disorder are also linked to faster biological aging.

    They also conducted MRI (magnetic resonance imaging) scans to explore the relationship between telomere length and brain structure, particularly in the hippocampus, an area of the brain involved in the regulation of mood. They discovered that higher rates of biological aging (i.e. shorter telomeres) were associated with having a smaller hippocampus.

    The study authors suggest that a reduction in telomere length may be associated with a reduced ability of new brain cells to grow in the hippocampus, which can reduce the size of the hippocampus and consequently increase risk for mood disorders such as bipolar disorder.

    Dr Timothy Powell, first author of the study, from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, said: ‘Our study provides the first evidence that familial risk for bipolar disorder is associated with shorter telomeres, which may explain why bipolar disorder patients are also at a greater risk for aging-related diseases.

    ‘We still need to dissect the environmental and genetic contributions to shortened telomeres in those at high risk for bipolar disorder. For instance, do those at risk for bipolar disorder carry genes predisposing them to faster biological aging, or are they more likely to partake in environmental factors which promote aging (e.g. smoking, poor diet)? Identifying modifiable risk factors to prevent advanced aging would be a really important next step.’

    Dr Sophia Frangou, co-senior author of the study, from the Icahn School of Medicine at Mount Sinai, said: ‘Our study shows that telomere length is a promising biomarker of biological aging and susceptibility to disease in the context of bipolar disorder. Moreover, it suggests that proteins which protect against telomere shortening may provide novel treatment targets for people with bipolar disorder and those predisposed to it.’

    Dr Gerome Breen, co-senior author, also at IoPPN, said: ‘Up to now it has been unclear whether or not bipolar disorder patients are at risk of accelerated aging. This study shows that they are at greater risk of faster aging and drugs commonly used to treat the disorder may actually mask or reverse this effect.’


  4. ‘Residual echo’ of ancient humans in scans may hold clues to mental disorders

    by Ashley

    From the NIH/National Institute of Mental Health press release:

    Researchers at the National Institute of Mental Health (NIMH) have produced the first direct evidence that parts of our brains implicated in mental disorders may be shaped by a “residual echo” from our ancient past. The more a person’s genome carries genetic vestiges of Neanderthals, the more certain parts of his or her brain and skull resemble those of humans’ evolutionary cousins that went extinct 40,000 years ago, says NIMH’s Karen Berman, M.D. NIMH is part of the National Institutes of Health.

    In particular, the parts of our brains that enable us to use tools and visualize and locate objects owe some of their lineage to Neanderthal-derived gene variants that are part of our genomes and affect the shape of those structures — to the extent that an individual harbors the ancient variants. But this may involve trade-offs with our social brain. The evidence from MRI scans suggests that such Neanderthal-derived genetic variation may affect the way our brains work today — and may hold clues to understanding deficits seen in schizophrenia and autism-related disorders, say the researchers.

    Dr. Berman, Michael Gregory, M.D., of the NIMH Section on Integrative Neuroimaging, and colleagues, report on their magnetic resonance imaging (MRI) study published online, July 24, 2017 in the journal Scientific Reports.

    During their primordial migration out of Africa, ancestors of present-day humans are thought to have interbred with Neanderthals, whose brain characteristics can be inferred from their fossilized skulls. For example, these indicate that Neanderthals had more prominent visual systems than modern humans.

    “It’s been proposed that Neanderthals depended on visual-spatial abilities and toolmaking, for survival, more so than on the social affiliation and group activities that typify the success of modern humans — and that Neanderthal brains evolved to preferentially support these visuospatial functions,” Berman explained. “Now we have direct neuroimaging evidence that such trade-offs may still be operative in our brains.”

    Might some of us, more than others, harbor Neanderthal-derived gene variants that may bias our brains toward trading sociability for visuospatial prowess — or vice versa? The new study adds support to this possibility by showing how these gene variants influence the structure of brain regions underlying those abilities.

    To test this possibility, Gregory and Berman measured the impact of Neanderthal variants on MRI measures of brain structure in a sample of 221 participants of European ancestry, drawn from the NIMH Genetic Study of Schizophrenia.

    The new MRI evidence points to a a gene variant shared by modern-day humans and Neanderthals that is likely involved in development of the brain’s visual system. Similarly, Neanderthal variants impacting development of a particular suspect brain area may help to inform cognitive disability seen in certain brain disorders, say the researchers.

    For example, in 2012, Berman and colleagues reported on how genetic variation shapes the structure and function of a brain area called the Insula in the autism-related disorder Williams Syndrome. People with this rare genetic disorder are overly sociable and visuo-spatially impaired — conspicuously opposite to the hypothesized Neanderthal propensities and more typical cases on the autism spectrum. Mice in which a gene affected by Williams syndrome is experimentally deleted show increased separation anxiety. And just last week, researchers showed that the same genetic variability also appears to explain why dogs are friendlier than wolves.


  5. Sleep disorders may increase cognitive problems particularly in those at risk for Alzheimer’s

    August 8, 2017 by Ashley

    From the American Thoracic Society press release:

    People who carry a genetic susceptibility to Alzheimer’s disease appear to be at greater risk of diminished cognition from sleep-disordered breathing than those without the susceptibility, according to new research published online, ahead of print in the Annals of the American Thoracic Society.

    In “Greater Cognitive Deficits with Sleep-Disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer’s Disease: The Multi-Ethnic Study of Atherosclerosis,” researchers report that study participants carrying the apolipoprotein ?-4 (APOE-?4) allele showed greater cognitive deficits with the various indices of sleep-disordered breathing compared to those without the allele.

    APOE is a major cholesterol carrier that supports injury repair in the brain. Other studies have shown that those carrying the alternate form of the gene, ?4 allele, are at increased risk of Alzheimer’s disease. Estimates are that 20 percent of the population carries the ?4 allele.

    “Previous studies have shown inconsistent findings between sleep-disordered breathing and cognition, which may be due to the different tests used,” said lead study author Dayna A. Johnson, PhD, MPH, MS, MSW, instructor of medicine at Brigham and Women’s Hospital and Harvard Medical School.

    Dr. Johnson and colleagues investigated the association in a diverse sample using several indicators of sleep-disordered breathing and cognition. They also evaluated whether the presence of the APOE-?4 allele, which is known to increase risk of Alzheimer’s disease, influenced the link between sleep-disordered breathing and cognition.

    The authors analyzed data from 1,752 participants (average age 68) in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent an in-home polysomnography (sleep) study, completed standardized sleep questions, and a battery of tests to measure their cognition. The authors defined sleep-disordered breathing as an apnea-hypopnea index (AHI), which measures the number of stopped or shallow breaths per hour, as AHI > 15, and sleep apnea syndrome as AHI > 5 (below 5 is normal) plus self-reported sleepiness (based on a standardized scale).

    The study found:

    • Increased overnight hypoxemia (oxygen saturation below 90 percent) or increased daytime sleepiness was associated with poorer attention and memory.
    • More daytime sleepiness was also associated with slower cognitive processing speed.
    • Sleep apnea syndrome was associated with poorer attention and processing speed.
    • These associations were strongest in APOE-?4 carriers.

    The researchers adjusted for race, age, body mass index, education level, smoking status, hypertension, diabetes, benzodiazepine use, and depressive symptoms.

    Dr. Johnson said that, overall, the effects of the various sleep factors they measured on cognition were small, but in the range previously reported for several other lifestyle and health risk factors for dementia. Screening and treating sleep-disordered breathing, she added, may help reduce a person’s risk of dementia, especially if that individual carries APOE-?4.

    “Our study provides further evidence that sleep-disordered breathing negatively affects attention, processing speed and memory, which are robust predictors of cognitive decline,” said senior study author Susan Redline, MD, MPH, Peter C. Farrell Professor of Sleep Medicine, Harvard Medical School.

    “Given the lack of effective treatment for Alzheimer’s disease, our results support the potential for sleep-disordered breathing screening and treatment as part of a strategy to reduce dementia risk.”

    Find the report online at: http://www.thoracic.org/about/newsroom/press-releases/resources/sleep-disordered-breathing-ad-cognition.pdf


  6. Gene variant increases risk for depression

    by Ashley

    From the University of Central Florida press release:

    A University of Central Florida study has found that a gene variant, thought to be carried by nearly 25 percent of the population, increases the odds of developing depression.

    People with apolipoprotein-E4, called ApoE4 for short, have a 20 percent greater chance of developing clinically significant depressive symptoms later in life compared to those who don’t have the gene variant, said Rosanna Scott, lead author of the study published in The Journal of Clinical Psychiatry. She will present her work at the International Association of Gerontology and Geriatrics conference in San Francisco next week. Scott, a Ph.D. candidate in clinical psychology, found the link while working on her thesis.

    “Some genes are deterministic, like the one that causes Huntington’s disease — where if you’ve got it, you’ll get the disease. This isn’t one of those genes,” said Daniel Paulson, Scott’s faculty advisor and an assistant professor of psychology who co-authored the study.

    Scott used health and well-being data of 3,203 participants as they aged from 53 to 71 years old. The data came from the Wisconsin Longitudinal Study, a long-term study of health, relationships, mortality and more of people who graduated from Wisconsin high schools in 1957. Those who have ApoE4 reported more symptoms of depression as they aged.

    “Her thesis addressed a critical gap in the theoretical framework of this area of study,” Paulson said. “Now we can more systematically move forward with research on causes and treatments for late-life depression.”

    Scott wanted to study ApoE4 and its potential links to depression because this variant of the ApoE gene is also known to negatively impact how a body handles cholesterol. Previous research — and Scott confirmed in the first paper of her thesis published in the International Journal of Geriatric Psychiatry — found that vascular-system risk factors such as high cholesterol, hypertension and high blood sugar also increase risk for depression. Vascular burden impacts how blood and nutrients are delivered throughout the body and to the brain, therefore impacting mood. Scott wondered if adults with ApoE4 and high vascular burden are at a compounded risk for depression.

    Her research concluded that ApoE4 and poor vascular health do not create a compounded risk, but both independently increase the likelihood of depression.

    Scott’s findings add clarity to the literature that’s already out in the scientific community on this topic, Paulson said. Prior research findings were inconsistent regarding ApoE4 and its risks for depression, and were done with small sample groups, too young a sample, or with data that wasn’t collected during a long period of time, she said.

    Scott aspires to specialize in neuropsychology after completing her Ph.D. She’d like to work in academia to help guide student researchers like herself, and she’d also like to provide neuropsychological assessment and therapy services to the community. She’s particularly interested in chronic health conditions and how they impact mood in older adults.

    “Bottom line, you do statistically have a higher risk of developing depression if you have ApoE4, but it’s not deterministic. You can’t change your genes, but you do have some control over improving your health,” she said. “That should be encouraging.”


  7. At the cellular level, a child’s loss of a father is associated with increased stress

    August 3, 2017 by Ashley

    From the Princeton University press release:

    The absence of a father — due to incarceration, death, separation or divorce — has adverse physical and behavioral consequences for a growing child. But little is known about the biological processes that underlie this link between father loss and child well-being.

    In a study published July 18 in the journal Pediatrics, a team of researchers, including those from Princeton University, report that the loss of a father has a significant adverse effect on telomeres, the protective nucleoprotein end caps of chromosomes. At 9 years of age, children who had lost their father had significantly shorter telomeres — 14 percent shorter on average — than children who had not. Death had the largest association, and the effects were greater for boys than girls.

    Telomeres are thought to reflect cell aging and overall health — their role is to help maintain the DNA ends of chromosomes following cell division. Each time a cell divides, its telomeres shorten; once telomeres are too short, cell replication stops. Previous research has suggested that shortened telomeres are associated with a wide range of diseases in adults, including cardiovascular disease and cancer.

    To determine whether the stress of losing a male parent had an effect on telomere length, Princeton researcher and pediatrician Daniel Notterman, the study’s corresponding author, and his colleagues measured telomere length and analyzed other data collected through the Fragile Families and Child Wellbeing Study. The Fragile Families Study — based at Princeton and Columbia University — has been following a cohort of about 5,000 children born in large U.S. cities at the turn of the 21st century. The study has gathered information on the children’s physical and mental health, cognitive function, social-emotional skills, schooling and living conditions, as well as the makeup, stability and financial resources of their families.

    The researchers then examined whether the type of father loss — incarceration, death, separation or divorce — and the timing of the loss — in early childhood or middle childhood — mattered, and whether telomere length was influenced by other factors, such as income, from information gathered in interviews with mothers at 1, 3, 5 and 9 years after birth.

    They determined that father loss is clearly associated with cellular function as estimated by telomere length: any father loss between birth and 9 years of age leads to a reduction in telomere length, and the effect is greatest for children whose fathers die, about 16 percent shorter. The researchers speculated that there are many reasons why father loss might be a major stressor for a child, such as the loss of family income following a separation or divorce. “The father is being removed from the life of the child and that is plausibly associated with an increase in stress, for both economic and emotional reasons,” said Notterman, a senior research scholar and lecturer with the rank of professor of molecular biology.

    Although the researchers found no significant evidence that the association between telomere length and child wellbeing differs by race or ethnicity, they did find some evidence that boys respond more negatively, as measured by telomere length, to the loss of or separation from a father than girls. This association is especially strong for boys who lost or were separated from their fathers before the age of 5.

    The most striking finding, according to Notterman, is that the effect of father loss on telomere length was mediated by certain alleles, or genetic variants, in cells’ serotonin transporter system. The effects of the loss of a father was 90 percent less for children with the least reactive alleles when compared with those with the most reactive alleles. In other words, a child’s genotype may lessen the association between a child’s social environment and telomere length, and serve as a protective factor.

    These results have far-reaching consequences for the development of public policy. “The fact that there is an actual measurable biological outcome that is related to the absence of a father makes more credible the urgency of public policy efforts to maintain contact between children and fathers,” Notterman said. “If you understand that, for example, punishing a father by incarceration may have an indelible effect not only on the psyche and development of the child, but also on the ability of the child’s chromosomes to maintain their integrity, then perhaps you had better understand the importance of measures to mitigate the effects of incarceration” such as educational initiatives or psychological interventions for children, according to Notterman.

    “The importance of these findings for research on the social sources of health — and health disparities — in the United States can hardly be overstated,” said Christopher Wildeman, an associate professor of policy analysis and management in the College of Human Ecology at Cornell University and the co-director of the National Data Archive on Child Abuse and Neglect, who earned his Ph.D. in sociology at Princeton. Wildeman is familiar with the research but had no role in it.

    “By showing that three causes of paternal absence decrease telomere length, a core biological indicator of health, the authors are able to provide insight into a direct biological channel through which paternal absence could affect the health of their children,” Wildeman added. “Moreover, because each of these causes of paternal absence are unequally distributed in the population, these findings have important implications for how we think about health disparities in the United States.”

    “We all know that resources are limited and are becoming more limited,” Notterman said. “But by understanding that a social and familial phenomenon — the loss of a father — has biological effects which are plausibly linked with the future well-being of a child, we now have a rationale for prioritizing resource allocations to the children who are most vulnerable.”


  8. Study identifies gene that could play key role in depression

    July 25, 2017 by Ashley

    From the University of Maryland School of Medicine press release:

    Globally, depression affects more than 300 million people annually. Nearly 800,000 die from suicide every year — it is the second-leading cause of death among people between the ages of 15 to 29. Beyond that, depression destroys quality for life for tens of millions of patients and their families. Although environmental factors play a role in many cases of depression, genetics are also crucially important.

    Now, a new study by researchers at the University of Maryland School of Medicine (UM SOM) has pinpointed how one particular gene plays a central role — either protecting from stress or triggering a downward spiral, depending on its level of activity.

    The study, published in the Journal of Neuroscience, is the first to illuminate in detail how this particular gene, which is known as Slc6a15, works in a kind of neuron that plays a key role in depression. The study found the link in both animals and humans.

    “This study really shines a light on how levels of this gene in these neurons affects mood,” said the senior author of the study, Mary Kay Lobo, an assistant professor in the Department of Anatomy and Neurobiology. “It suggests that people with altered levels of this gene in certain brain regions may have a much higher risk for depression and other emotional disorders related to stress.”

    In 2006, Dr. Lobo and her colleagues found that the Slc6a15 gene was more common among specific neurons in the brain. They recently demonstrated that these neurons were important in depression. Since this gene was recently implicated in depression by other researchers, her lab decided to investigate its role in these specific neurons. In this latest study, she and her team focused on a part of the brain called the nucleus accumbens. This region plays a central role in the brain’s “reward circuit.” When you eat a delicious meal, have sex, drink alcohol, or have any other kind of enjoyable experience, neurons in the nucleus accumbens are activated, letting you know that the experience is pushing the proper buttons. In depression, any kind of enjoyment becomes difficult or impossible; this symptom is known as anhedonia, which in Latin means the inability to experience pleasure.

    The researchers focused on a subset of neurons in the nucleus accumbens called D2 neurons. These neurons respond to the neurotransmitter dopamine, which plays a central role in the reward circuit.

    They studied mice susceptible to depression; when subjected to social stress — exposure to larger, more aggressive mice — they tend to withdraw and exhibit behavior that indicates depression, such as social withdrawal and lack of interest in food that they normally enjoy. Dr. Lobo found that when these animals were subjected to chronic social stress, levels of the Slc6a15 gene in the D2 neurons of the nucleus accumbens was markedly reduced.

    The researchers also studied mice in which the gene had been reduced in D2 neurons. When those mice were subjected to stress, they also exhibited signs of depression. Conversely, when the researchers enhanced Slc6a15 levels in D2 neurons, the mice showed a resilient response to stress.

    Next, Dr. Lobo looked at the brains of humans who had a history of major depression and who had committed suicide. In the nucleus accumbens of these brains, the gene was reduced. This indicates that the link between gene and behavior extends from mice to humans.

    It is not clear exactly how Slc6a15 works in the brain. Dr. Lobo says it may work by altering neurotransmitter levels in the brain, a theory that has some evidence from other studies. She says her research could eventually lead to targeted therapies focused on Slc6a15 as a new way to treat depression.


  9. Alzheimer’s disease risk linked to a network of genes associated with myeloid cells

    July 16, 2017 by Ashley

    From The Mount Sinai Hospital / Mount Sinai School of Medicine press release:

    Many genes linked to late-onset Alzheimer’s disease (AD) are expressed in myeloid cells and regulated by a single protein, according to research conducted at the Icahn School of Medicine at Mount Sinai and published June 19 in the journal Nature Neuroscience.

    Mount Sinai researchers led an international, genome-wide study of more than 40,000 people with and without the disease and found that innate immune cells of the myeloid lineage play an even more central role in Alzheimer’s disease pathogenesis than previously thought.

    Specifically, the research team identified a network of genes that are implicated in AD and expressed by myeloid cells, innate immune cells that include microglia and macrophages. Furthermore, researchers identified the transcription factor PU.1, a protein that regulates gene expression and, thus, cell identity and function, as a master regulator of this gene network.

    “Our findings show that a large proportion of the genetic risk for late-onset AD is explained by genes that are expressed in myeloid cells, and not other cell types,” says Alison Goate, DPhil, Professor of Neuroscience and Director of The Ronald M. Loeb Center for Alzheimer’s Disease at the Icahn School of Medicine at Mount Sinai and principal author of the study. “Dysregulation of this network is certainly a cause of Alzheimer’s, but we have more work to do to better understand this network and regulation by PU.1, to reveal promising therapeutic targets.”

    Using a combination of genetic approaches to analyze the genomes of 14,406 AD patients, and 25,849 control patients who do not have the disease, researchers found that many genes which are known to influence the age at which AD sets in, are expressed in myeloid cells. This work pinpointed SPI1, a gene that encodes the transcription factor PU.1, as a major regulator of this network of AD risk genes and demonstrated that lower levels of SPI1/PU.1 are associated with later age at onset of AD.

    To test the hypothesis that SPI1 expression levels influence expression of other AD risk genes and microglial function, the researchers used a mouse microglial cell line, BV2 cells that can be cultured in a dish. When researchers knocked down expression of SPI1, the gene that produces PU.1 in cells, they found that the cells showed lower phagocytic activity (engulfment of particles), while overexpression of SPI1 led to increased phagocytic activity. Many other AD genes expressed in microglia also showed altered expression in response to this manipulation of SPI1 expression.

    “Experimentally altering PU.1 levels correlated with phagocytic activity of mouse microglial cells and the expression of multiple AD genes involved in diverse biological processes of myeloid cells,” says Dr. Goate. “SPI1/PU.1 expression may be a master regulator capable of tipping the balance toward a neuroprotective or a neurotoxic microglial function.”

    The researchers stress that because the PU.1 transcription factor regulates many genes in myeloid cells, the protein itself may not be a good therapeutic target. Instead, further studies of PU.1’s role in microglia and AD pathogenesis are necessary, as they may reveal promising downstream targets that may be more effective in modulating AD risk without broad effects on microglial function. Increased understanding is crucial to facilitating the development of novel therapeutic targets for a disease that currently has no cure.


  10. Mice provide insight into genetics of autism spectrum disorders

    July 15, 2017 by Ashley

    From the University of California – Davis press release:

    While the definitive causes remain unclear, several genetic and environmental factors increase the likelihood of autism spectrum disorder, or ASD, a group of conditions covering a “spectrum” of symptoms, skills and levels of disability.

    Taking advantage of advances in genetic technologies, researchers led by Alex Nord, assistant professor of neurobiology, physiology and behavior with the Center for Neuroscience at the University of California, Davis, are gaining a better understanding of the role played by a specific gene involved in autism. The collaborative work appears June 26 in the journal Nature Neuroscience.

    “For years, the targets of drug discovery and treatment have been based on an unknown black box of what’s happening in the brain,” said Nord. “Now, using genetic approaches to study the impact of specific mutations found in cases, we’re trying to build a cohesive model that links genetic control of brain development with behavior and brain function.”

    The Nord laboratory studies how the genome encodes brain development and function, with a particular interest in understanding the genetic basis of neurological disorders.

    Mouse brain models

    There is no known specific genetic cause for most cases of autism, but many different genes have been linked to the disorder. In rare, specific cases of people with ASD, one copy of a gene called CHD8 is mutated and loses function. The CHD8 gene encodes a protein responsible for packaging DNA in cells throughout the body. Packaging of DNA controls how genes are turned on and off in cells during development.

    Because mice and humans share on average 85 percent of similarly coded genes, mice can be used as a model to study how genetic mutations impact brain development. Changes in mouse DNA mimic changes in human DNA and vice-versa. In addition, mice exhibit behaviors that can be used as models for exploring human behavior.

    Nord’s laboratory at UC Davis and his collaborators have been working to characterize changes in brain development and behavior of mice carrying a mutated copy of CHD8.

    “Behavioral tests with mice give us information about sociability, anxiety and cognition. From there, we can examine changes at the anatomical and cellular level to find links across dimensions,” said Nord. “This is critical to understanding the biology of disorders like autism.”

    By inducing mutation of the CHD8 gene in mice and studying their brain development, Nord and his team have established that the mice experience cognitive impairment and have increased brain volume. Both conditions are also present in individuals with a mutated CHD8 gene.

    New implications for early and lifelong brain development

    Analysis of data from mouse brains reveals that CHD8 gene expression peaks during the early stages of brain development. Mutations in CHD8 lead to excessive production of dividing cells in the brain, as well as megalencephaly, an enlarged brain condition common in individuals with ASD. These findings suggest the developmental causes of increased brain size.

    More surprisingly, Nord also discovered that the pathological changes in gene expression in the brains of mice with a mutated CHD8 continued through the lifetime of the mice. Genes involved in critical biological processes like synapse function were impacted by the CHD8 mutation. This suggests that CHD8 plays a role in brain function throughout life and may affect more than early brain development in autistic individuals.

    While Nord’s research centers on severe ASD conditions, the lessons learned may eventually help explain many cases along the autism spectrum.

    Collaborating to improve understanding

    Nord’s work bridges disciplines and has incorporated diverse collaborators. The genetic mouse model was developed at Lawrence Berkeley National Laboratory using CRISPR editing technology, and co-authors Jacqueline Crawley and Jill Silverman of the UC Davis MIND Institute evaluated mouse behavior to characterize social interactions and cognitive impairments.

    Nord also partnered with co-author Konstantinos Zarbalis of the Institute for Pediatric Regenerative Medicine at UC Davis to examine changes in cell proliferation in the brains of mice with the CHD8 mutation, and with Jason Lerch from the Mouse Imaging Centre at the Hospital for Sick Children in Toronto, Canada, to conduct magnetic resonance imaging on mouse brains.

    “It’s the act of collaboration that I find really satisfying,” Nord said. “The science gets a lot more interesting and powerful when we combine different approaches. Together we were able to show that mutation to CHD8 causes changes to brain development, which in turn alters brain anatomy, function and behavior.”

    In the future, Nord hopes to identify how CHD8 packages DNA in neural cells and to determine the specific impacts to early brain development and synaptic function. Nord hopes that deep exploration of CHD8 mutations will ultimately yield greater knowledge of the general factors contributing to ASD and intellectual disability.