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  • richardmitnick 10:49 am on July 12, 2017 Permalink | Reply
    Tags: Alzheimer’s, , Tau can in a complex with RNA condense into a highly compact “droplet” while retaining its liquid properties, Tau protein,   

    From UCSB: “A Biophysical ‘Smoking Gun’ “ 

    UC Santa Barbara Name bloc
    UC Santa Barbara

    July 6, 2017
    Julie Cohen

    1
    Tau was found to belong to proteins that undergo liquid-liquid phase separation upon association with RNAs that establishes a new phase state. Photo Credit: Peter Allen.

    While much about Alzheimer’s disease remains a mystery, scientists do know that part of the disease’s progression involves a normal protein called tau, aggregating to form ropelike inclusions within brain cells that eventually strangle the neurons. Yet how this protein transitions from its soluble liquid state to solid fibers has remained unknown — until now.

    Discovering an unsuspected property of tau, UC Santa Barbara physical chemist Song-I Han and neurobiologist Kenneth S. Kosik have shed new light on the protein’s ability to morph from one state to another.

    Remarkably, tau can, in a complex with RNA, condense into a highly compact “droplet” while retaining its liquid properties. In a phenomenon called phase separation, tau and RNA hold together, without the benefit of a membrane, but remain separate from the surrounding milieu. This novel state highly concentrates tau and creates a set of conditions in which it becomes vulnerable to aggregation. Kosik and Han outline their discoveries in the journal PLOS Biology.

    “Our findings, along with related research in neurodegeneration, posit a biophysical ‘smoking gun’ on the path to tau pathology,” said Kosik, UCSB’s Harriman Professor of Neuroscience and co-director of the campus’s Neuroscience Research Institute. “The signposts on this path are the intrinsic ability of tau to fold into myriad shapes, to bind to RNA and to form compact reversible structures under physiologic conditions, such as the concentration, the temperature and the salinity.”

    The researchers found that, depending on the length and shape of the RNA, up to eight tau molecules bind to the RNA to form an extended fluidic assembly. Several other proteins like tau are known to irreversibly aggregate in other neurodegenerative diseases such as amyotrophic lateral sclerosis, more commonly known as Lou Gehrig’s disease.

    “There is an interesting relationship between intrinsically disordered proteins that are predisposed to become neurodegenerative — in this case tau — and this phase separation state,” said Han, a professor in UCSB’s Department of Chemistry and Biochemistry. “Is this droplet stage a reservoir that protects tau or an intermediate stage that helps transform tau into a disease state with fibrils or both at the same time? Figuring out the exact physiological role of these droplets is the next challenge.”

    Subsequent analysis will consist of an intensive search for the counterpart of tau droplets in living cells. In future work, the researchers also want to explore how and why a cell regulates the formation and dissolution of these droplets and whether this represents a potential inroad toward therapy.

    See the full article here .

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    The University of California, Santa Barbara (commonly referred to as UC Santa Barbara or UCSB) is a public research university and one of the 10 general campuses of the University of California system. Founded in 1891 as an independent teachers’ college, UCSB joined the University of California system in 1944 and is the third-oldest general-education campus in the system. The university is a comprehensive doctoral university and is organized into five colleges offering 87 undergraduate degrees and 55 graduate degrees. In 2012, UCSB was ranked 41st among “National Universities” and 10th among public universities by U.S. News & World Report. UCSB houses twelve national research centers, including the renowned Kavli Institute for Theoretical Physics.

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  • richardmitnick 3:30 pm on June 29, 2017 Permalink | Reply
    Tags: Alzheimer’s, , , , , , neutral sphingomyelinase (nSMase2) allow cancer cells to pass DNA and proteins to other cells to change their behavior, Stony Brook U   

    From Stony Brook: “Researchers Define Structure of Key Enzyme Implicated in Cancer, Neurological Disease” 

    Stoney Brook bloc

    Stoney Brook

    Jun 29, 2017
    No writer credit found

    1
    Stony Brook-led research into the structure of a key enzyme involved with cell growth regulation could offer important clues to understanding cancer and neurodegenerative diseases, including Alzheimer’s disease. The finding, published in PNAS, reveals the first visualization of the enzyme and could provide insight into how the enzyme is activated.

    The enzyme, neutral sphingomyelinase (nSMase2), is one of the major enzymes that produces ceramide in the body. Ceramides are oil-like lipids that are produced in response to chemotherapy and other cell stresses. The ceramides that nSMase2 produces allow cancer cells to pass DNA and proteins to other cells to change their behavior. This plays a significant role in aiding the cancerous cells to spread into other regions as ceramides are produced. With this first visual of the structure of the enzyme, the researchers hope to understand how to de-activate the enzyme. Information on de-activating the enzyme could lead to a way to design cancer drugs that inhibit nSMase2.

    The different colors of this structural visualization of nSMase2 indicate parts of the enzyme that may change their shape when the protein is switched ‘on,’ encouraging cancer cells to spread.

    “Our finding is promising because the way in which we determined the structure reveals an unexpected mechanism for how nSMase2 is activated to generate ceramide,” said Mike Airola, PhD, Assistant Professor of Biochemistry and Cell Biology and lead author. To obtain this structure, the researchers screened thousands of different samples to have this protein form very small crystals that could be captured visually via X-rays. These X-rays bounce off the protein, and based on the angle of movements they calculated what structure looks like.

    Once they defined structure in this way, the research team made hypotheses as to how the shape of this important enzyme changes in order to be activated and then tested these hypotheses. Their findings suggested the same region that kept nSMase2 off was crucial for turning it on.

    The researchers determined the enzyme consists of two parts: one that partitions inside the oil-like membrane and one that soluble in water. Their work with the structure revealed that to turn nSMase2 ‘on,’ these two parts come together to switch the enzyme from off to on. They found that by removing some of these parts, they were able to obtain a picture of the enzyme trapped in its ‘off’ state. Using the structure, Dr. Airola and colleagues added back different parts of the enzyme, and then they were able to turn it back on to its on, or activated state.

    Dr. Airola explained that while much is known about the cellular functions of nSMase2, there is limited scientific knowledge into the molecular mechanisms regulating its activity. This latest research presents the crystal structure of the enzyme and enabled the researchers to understand its molecular mechanism to a level not known before.

    The next step in their research is to get a picture of the enzyme in its activated ‘on’ state. They are also working to identify new scaffolds that could be used as drugs to inhibit this enzyme. Their long-term goal is to understand how this enzyme is turned on and stop it from working as potential therapeutic strategy.

    Co-authors on the paper include Stony Brook University researchers Lina M. Obeid, Yusuf A. Hannun and Can E. Senkal of the Stony Brook University Cancer Center; Miguel Garcia-Diaz and Kip Guja of the Department of Pharmacological Sciences; Prajna Shanbhogue and Rohan Maini of the Department of Biochemistry and Cell Biology; Achraf Shamseddine of the Department of Medicine; and Nana Bartke and Bill X. Wu of the Medical University of South Carolina.

    The research was supported in part by the National institutes of Health. Some of the research was completed with access to the facilities at the Synchrotron Light Source and Brookhaven National Laboratory.

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    Stony Brook’s reach extends from its 1,039-acre campus on Long Island’s North Shore–encompassing the main academic areas, an 8,300-seat stadium and sports complex and Stony Brook Medicine–to Stony Brook Manhattan, a Research and Development Park, four business incubators including one at Calverton, New York, and the Stony Brook Southampton campus on Long Island’s East End. Stony Brook also co-manages Brookhaven National Laboratory, joining Princeton, the University of Chicago, Stanford, and the University of California on the list of major institutions involved in a research collaboration with a national lab.

    And Stony Brook is still growing. To the students, the scholars, the health professionals, the entrepreneurs and all the valued members who make up the vibrant Stony Brook community, this is a not only a great local and national university, but one that is making an impact on a global scale.

     
  • richardmitnick 4:27 pm on June 20, 2017 Permalink | Reply
    Tags: Alzheimer’s, , Drynaria Rhizome, , Naringenin and two naringenin metabolites   

    From MedicalXpress: “Plant reveals anti-Alzheimer’s compounds” 

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    MedicalXpress

    June 20, 2017
    No writer credit found

    1
    Diagram of the brain of a person with Alzheimer’s Disease. Credit: Wikipedia/public domain.

    Japanese scientists have developed a method to isolate and identify active compounds in plant medicines, which accurately accounts for drug behavior in the body. Using the technique, they have identified several active compounds from Drynaria Rhizome, a traditional plant medicine, which improve memory and reduce disease characteristics in a mouse model of Alzheimer’s disease.

    Traditional plant medicines have been used by humans for a long time, and these therapies are still popular in many countries. Plants typically contain a huge variety of compounds, many of which have no effect in the body, and some which can have significant effects. If a plant medicine shows a therapeutic effect, scientists are interested in isolating and identifying the compounds that cause the effect to see if they can be used as new drugs.

    In many cases, scientists repeatedly screen crude plant medicines in lab experiments to see if any compounds show a particular effect in cells grown in a dish or in cell-free assays. If a compound shows a positive effect in cells or test tubes, it could potentially be used as a drug, and the scientists go on to test it in animals. However, this process is a lot of work and doesn’t account for changes that can happen to drugs when they enter the body – enzymes in the blood and liver can metabolize drugs into various forms called metabolites. In addition, some areas of the body, such as the brain, are difficult to access for many drugs, and only certain drugs or their metabolites will enter these tissues.

    “The candidate compounds identified in traditional benchtop drug screens of plant medicines are not always true active compounds, because these assays ignore bio-metabolism and tissue distribution,” explains Chihiro Tohda, senior author on the recent study published in Frontiers in Pharmacology. “So, we aimed to develop more efficient methods to identify authentic active compounds that take these factors into account.”

    The scientists were interested in finding active compounds for Alzheimer’s disease in Drynaria Rhizome, a traditional plant medicine. They used mice with a genetic mutation as a model for Alzheimer’s disease. This mutation gives the mice some characteristics of Alzheimer’s disease, including reduced memory and a buildup of specific proteins in the brain, called amyloid and tau proteins. This means that the mice are a useful tool to test potential Alzheimer’s disease treatments.

    Initially, the researchers mashed the plant up and treated the mice orally using this crude plant extract. They found that the plant treatment reduced memory impairments and levels of amyloid and tau proteins in their brains. In a key step, the team then examined the mouse brain tissue, where the treatment is needed, 5 hours after they treated the mice with the extract. They found that three compounds from the plant had made it into the brain – these were a compound called naringenin and two naringenin metabolites.

    The researchers then treated the mice with pure naringenin and noticed the same improvements in memory deficits and reductions in amyloid and tau proteins, meaning that naringenin and its metabolites were likely the active compounds in the plant. They found a protein called CRMP2 that naringenin binds to in neurons, which causes them to grow, suggesting that this could be the mechanism by which naringenin can improve Alzheimer’s disease symptoms.

    The team hope that the technique can be used to identify other treatments. “We are applying this method to discover new drugs for other diseases such as spinal cord injury, depression and sarcopenia,” explains Tohda.

    See the full article here .

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  • richardmitnick 3:54 pm on January 20, 2017 Permalink | Reply
    Tags: Alzheimer’s, , Grid cells, Tau tangle   

    From COSMOS: “Tau tangles damage brain GPS in Alzheimer’s disease” 

    Cosmos Magazine bloc

    COSMOS

    20 January 2017
    Elizabeth Finkel

    1
    A coloured transmission electron micrograph of a tau tangle in a nerve cell from the brain of a patient with Alzheimers disease. The tangle (dark blue) lies in the cytoplasm (green) of the cell body. Such tangles in the brain’s GPS cells may explain why wandering is an early symptom of the disease.
    THOMAS NCMIR / SPL / Getty Images

    Grandad got lost driving home, again. It’s often the first hint of Alzheimer’s disease.

    Now a US team has pinpointed why this might happen. The brain’s so-called grid cells, which map your location like a personal GPS, are poisoned by abnormal clumps of a protein called tau.

    The finding, published in Neuron today, offers a specific new test for the early stages of the disease and could be useful for testing new drugs. “It adds an interesting piece of the puzzle,” says Kevin Barnham, a neuroscientist at Australia’s Florey Institute of Neuroscience and Mental Health.

    Alzheimer’s disease is like an unsolved murder mystery. For decades, researchers have been fingering two shady suspects: both of them disfigured proteins.

    One is called beta amyloid. Normally soluble, the abnormal variety clumps between cells. The other potential culprit, tau, is also normally soluble; the disfigured form creates tangles inside cells.

    Despite decades of research – and many failed drug trials – proving that either suspect was the cause of the disease, or figuring out just how they wreak their damage, has remained frustratingly difficult. “After 40 years, we have to rethink the disease in its entirety,” says Bryce Vissel, a neuroscientist at the University of Technology Sydney, Australia.

    While beta amyloid has been the main suspect, most drugs aimed at clearing it away have had little effect in trials. The shift, now, is to anti-tau drugs.

    In that context, the recent paper links early Alzheimer’s symptoms to tau’s actions in the brain. “We came from two ends and filled in the middle,” says study co-author Karen Duff from Columbia University. “It’s very satisfying.”

    Post-mortem studies of Alzheimer’s patients show tau tangles appear in the brain sequentially. The first form in a region called the entorhinal cortex, a part of the brain involved in navigation.

    2
    A grid cell from the entorhinal cortex of the mouse brain, firing repeatedly and uniformly in a grid-like pattern. When a mouse moves through its environment, grid cells are activated, with each cell representing a specific location. Karen Duff / Columbia University Medical Centre

    Next affected is the hippocampus, crucial for making new memories, and finally the neocortex, associated with reasoning and language.

    The abnormal tau protein can travel between cells, seeding new tangles.

    The researchers tried to model the sequence seen in humans by genetically engineering mice to produce an abnormal form of human tau in their entorhinal cortex.

    The entorhinal cortex tissue contains various types of cells but those most affected by tau were the grid cells.

    Co-author Abid Hussaini, also at Columbia University, inserted electrodes into those brain cells to measure their electrical characteristics.

    Normally grid cells are highly excitable, but once the mice developed tau tangles at around 30 months of age, these cells became less active and eventually died.

    At the same time, the mice began getting lost in their mazes.

    It’s the first finding to highlight how grid cells are especially susceptible to the effects of tau, an effect “that may be unique to Alzheimer’s disease”, Duff says.

    And that may offer a new model to test for drugs that target tau. “We’re always looking for a model that is relatable to the disease,” Barnham says, “and this effect on [grid cells] is potentially relatable.”

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  • richardmitnick 12:17 pm on January 19, 2017 Permalink | Reply
    Tags: Alzheimer’s, , , TREM2,   

    From Wash U: “Study details molecular roots of Alzheimer’s” 

    Wash U Bloc

    Washington University in St.Louis

    December 20, 2016 [Don’t know where this was hiding.]
    Julia Evangelou Strait
    straitj@wustl.edu

    1

    A new study at Washington University School of Medicine in St. Louis details the structure of TREM2, a protein involved in Alzheimer’s disease and other neurodegenerative disorders. Researchers found that mutations associated with Alzheimer’s alter the surface of the protein, while mutations linked to another brain disorder disrupt the protein’s interior. Such alterations may impair TREM2’s normal role in cleaning up cellular waste via a process called phagocytosis. (Image: Daniel L. Kober)

    Scientists at Washington University School of Medicine in St. Louis have detailed the structure of a molecule that has been implicated in Alzheimer’s disease. Knowing the shape of the molecule — and how that shape may be disrupted by certain genetic mutations — can help in understanding how Alzheimer’s and other neurodegenerative diseases develop and how to prevent and treat them.

    The study is published Dec. 20 in the journal eLife.

    The idea that the molecule TREM2 is involved in cognitive decline — the hallmark of neurodegenerative diseases, including Alzheimer’s — has gained considerable support in recent years. Past studies have demonstrated that certain mutations that alter the structure of TREM2 are associated with an increased risk of developing late-onset Alzheimer’s, frontal temporal dementia, Parkinson’s disease and sporadic amyotrophic lateral sclerosis (ALS). Other TREM2 mutations are linked to Nasu-Hakola disease, a rare inherited condition that causes progressive dementia and death in most patients by age 50.

    “We don’t know exactly what dysfunctional TREM2 does to contribute to neurodegeneration, but we know inflammation is the common thread in all these conditions,” said senior author Thomas J. Brett, PhD, an assistant professor of medicine. “Our study looked at these mutations in TREM2 and asked what they do to the structure of the protein itself, and how that might impact its function. If we can understand that, we can begin to look for ways to correct it.”

    The analysis of TREM2 structure, completed by first author, Daniel L. Kober, a doctoral student in Brett’s lab, revealed that the mutations associated with Alzheimer’s alter the surface of the protein, while those linked to Nasu-Hakola influence the “guts” of the protein. The difference in location could explain the severity of Nasu-Hakula, in which signs of dementia begin in young adulthood. The internal mutations totally disrupt the structure of TREM2, resulting in fewer TREM2 molecules. The surface mutations, in contrast, leave TREM2 intact but likely make it harder for the molecule to connect to proteins or send signals as normal TREM2 molecules would.

    TREM2 lies on the surface of immune cells called microglia, which are thought to be important “housekeeping” cells. Via a process called phagocytosis, such cells are responsible for engulfing and cleaning up cellular waste, including the amyloid beta that is known to accumulate in Alzheimer’s disease. If the microglia lack TREM2, or the TREM2 that is present doesn’t function properly, the cellular housekeepers can’t perform their cleanup tasks.

    “Exactly what TREM2 does is still an open question,” Brett said. “We know mice without TREM2 have defects in microglia, which are important in maintaining healthy brain biology. Now that we have these structures, we can study how TREM2 works, or doesn’t work, in these neurodegenerative diseases.”

    TREM2 also has been implicated in other inflammatory conditions, including chronic obstructive pulmonary disease and stroke, making the structure of TREM2 important for understanding chronic and degenerative diseases throughout the body, he added.

    This work was supported by the National Institutes of Health (NIH), grant numbers R01-HL119813, R01-AG044546, R01-AG051485, R01-HL120153, R01-HL121791, K01-AG046374, T32-GM007067, K08-HL121168, and P50-AG005681-30.1; the Burroughs-Wellcome Fund; the Alzheimer’s Association, grant number AARG-16-441560; and the American Heart Association, grant number PRE22110004. Results were derived from work performed at Argonne National Laboratory (ANL) Structural Biology Center. ANL is operated by U. Chicago Argonne, LLC, for the U.S. DOE, Office of Biological and Environmental Research, supported by grant number DE-AC02-06CH11357.

    Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. Dec. 20, 2016.

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  • richardmitnick 4:09 pm on May 26, 2016 Permalink | Reply
    Tags: Alzheimer’s, Alzheimer’s Disease May Be Caused By Brain Infections, ,   

    From NOVA: “Alzheimer’s Disease May Be Caused By Brain Infections” 

    PBS NOVA

    NOVA

    26 May 2016
    Allison Eck

    Silent infections earlier in life could be at the root of Alzheimer’s disease.

    Alzheimer’s researchers have long presumed that amyloid beta proteins are the brain’s garbage, accumulating over time but serving no obvious purpose. These plaques trigger the formation of tau proteins (or “tangles”), which proceed to destroy nerve cells.

    Robert D. Moir of Harvard Medical School and Massachusetts General Hospital thought something was missing in this picture—and looked to proteins that live on our innate immune system for answers. Moir and his colleague Rudolph E. Tanzi noticed that amyloid proteins look like these immune system proteins, which trap and then purge harmful viruses, yeast, fungi, and bacteria. The two scientists wanted to see if amyloid plaques serve a similar function in the brain.

    1
    Salmonella bacteria, trapped in amyloid beta plaques.

    In one experiment, Moir and Tanzi subjected young mice’s brains to Salmonella bacteria. They noticed that plaques began to form around single Salmonella bacterium and that in mice without amyloid beta, bacterial infections arose more quickly. The team’s work, published* Wednesday in the journal Science Translational Medicine, suggests that silent, often symptomless infections in the brain could be the precursor to the development of Alzheimer’s disease later in life.

    Here’s Gina Kolata, reporting for The New York Times:

    “The Harvard researchers report a scenario seemingly out of science fiction. A virus, fungus or bacterium gets into the brain, passing through a membrane—the blood-brain barrier—that becomes leaky as people age. The brain’s defense system rushes in to stop the invader by making a sticky cage out of proteins, called beta amyloid. The microbe, like a fly in a spider web, becomes trapped in the cage and dies. What is left behind is the cage—a plaque that is the hallmark of Alzheimer’s.

    So far, the group has confirmed this hypothesis in neurons growing in petri dishes as well as in yeast, roundworms, fruit flies and mice. There is much more work to be done to determine if a similar sequence happens in humans, but plans—and funding—are in place to start those studies, involving a multicenter project that will examine human brains.

    The finding may help explain why some people with Alzheimer’s have exhibited higher levels of herpes antibodies, a sign of previous infection, than others who didn’t have Alzheimer’s.”

    Of course, infection is likely not the only contributing factor. People with the ApoE4 gene aren’t as effective in breaking down beta amyloid, so any potential immune-like response by amyloid proteins could lead to an unhealthy buildup.

    Whatever the complex set of circumstances may be, this finding may fill in some of missing links in Alzheimer’s research.

    *Science paper:
    Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease

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  • richardmitnick 10:40 am on April 1, 2016 Permalink | Reply
    Tags: , Alzheimer’s, ,   

    From AAAS: “Alzheimer’s may be caused by haywire immune system eating brain connections” 

    AAAS

    AAAS

    Mar. 31, 2016
    Emily Underwood

    1
    Over-pruning synapses may drive early-stage Alzheimer’s disease. Eraxion/iStockphoto

    More than 99% of clinical trials for Alzheimer’s drugs have failed, leading many to wonder whether pharmaceutical companies have gone after the wrong targets. Now, research in mice points to a potential new target: a developmental process gone awry, which causes some immune cells to feast on the connections between neurons.

    “It is beautiful new work,” which “brings into light what’s happening in the early stage of the disease,” says Jonathan Kipnis, a neuroscientist at the University of Virginia School of Medicine in Charlottesville.

    Most new Alzheimer’s drugs aim to eliminate β amyloid, a protein that forms telltale sticky plaques around neurons in people with the disease. Those with Alzheimer’s tend to have more of these deposits in their brains than do healthy people, yet more plaques don’t always mean more severe symptoms such as memory loss or poor attention, says Beth Stevens of Boston Children’s Hospital, who led the new work.

    What does track well with the cognitive decline seen in Alzheimer’s disease—at least in mice that carry genes that confer high risk for the condition in people—is a marked loss of synapses, particularly in brain regions key to memory, Stevens says. These junctions between nerve cells are where neurotransmitters are released to spark the brain’s electrical activity.

    Stevens has spent much of her career studying a normal immune mechanism that prunes weak or unnecessary synapses as the brain matures from the womb through adolescence, allowing more important connections to become stronger. In this process, a protein called C1q sets off a series of chemical reactions that ultimately mark a synapse for destruction. After a synapse has been “tagged,” immune cells called microglia—the brain’s trash disposal service—know to “eat” it, Stevens says. When this system goes awry during the brain’s development, whether in the womb or later during childhood and into the teen years, it may lead to psychiatric disorders such as schizophrenia, she says.

    Stevens hypothesized that the same mechanism goes awry in early Alzheimer’s disease, leading to the destruction of good synapses and ultimately to cognitive impairment. Using two Alzheimer’s mouse models—each of which produces excess amounts of the β amyloid protein, and develops memory and learning impairments as they age—she and her team found that both strains had elevated levels of C1q in brain tissue. When they used an antibody to block C1q from setting off the microglial feast, however, synapse loss did not occur, the team reports today in Science.

    To Stevens, that suggests that the normal mechanism for pruning synapses during development somehow gets turned back on again in the adult brain in Alzheimer’s, with dangerous consequences. “Instead of nicely whittling away [at synapses], microglia are eating when they’re not supposed to,” she says.

    The group is now tracking these mice to see whether a drug that blocks C1q slows their cognitive decline. To determine whether elevated β amyloid can cause the C1q system to go haywire, Stevens and colleagues also injected a form of the protein which is known to generate plaques into the brains of normal mice and so-called knockouts that could not produce C1q because of a genetic mutation. Although normal mice exposed to the protein lost many synapses, knockouts were largely unaffected, Stevens says. In addition, microglia only went after synapses when β amyloid was present, suggesting that the combination of protein and C1q is what destroys synapses, rather than either element alone, she says, adding that other triggers, such as inflammatory molecules called cytokines, might also set the system off.

    The findings contradict earlier theories which held that increased microglia and C1q activity were merely part of an inflammatory reaction to β amyloid plaques. Instead, microglia seem to start gorging on synapses long before plaques form, Stevens says. She and several co-authors are shareholders in Annexon Biosciences, a biotechnology company that will soon start testing the safety of a human form of the antibody the team used to block C1q, known as ANX-005, in people.

    Such a central role for microglia in Alzheimer’s disease is “still on the controversial side,” says Edward Ruthazer, a neuroscientist at the Montreal Neurological Institute and Hospital in Canada. One “really compelling” sign that the mechanism is important in people would be if high levels of C1q in cerebrospinal fluid early on predicted developing full-blown Alzheimer’s later in life, he says. Still, he says, “it’s difficult to argue with the strength of the study’s evidence.”

    The science team:
    Soyon Hong1, Victoria F. Beja-Glasser1,*, Bianca M. Nfonoyim1,*, Arnaud Frouin1, Shaomin Li2, Saranya Ramakrishnan1, Katherine M. Merry1, Qiaoqiao Shi2, Arnon Rosenthal3,4,5, Ben A. Barres6, Cynthia A. Lemere,2, Dennis J. Selkoe2,7, Beth Stevens1,8,†

    Author Affiliations

    1F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
    2Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
    3Alector Inc., 953 Indiana Street, San Francisco, CA 94107, USA.
    4Annexon Biosciences, 280 Utah Avenue Suite 110, South San Francisco, CA 94080, USA.
    5Department of Anatomy, University of California San Francisco, CA 94143, USA.
    6Department of Neurobiology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
    7Prothena Biosciences, Dublin, Ireland.
    8Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

    ↵†Corresponding author. E-mail: beth.stevens@childrens.harvard.edu

    ↵* These authors contributed equally to this work.

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  • richardmitnick 10:54 am on January 26, 2016 Permalink | Reply
    Tags: Alzheimer’s, ,   

    From Nature: “More evidence emerges for ‘transmissible Alzheimer’s’ theory” 

    Nature Mag
    Nature

    26 January 2016
    Alison Abbott

    Alzheimers amyloid-β protein brown in the frontal cortex
    Deposits of amyloid-β protein (brown) in the frontal cortex of patients who developed CJD after surgery. Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H.

    For the second time in four months, researchers have reported autopsy results that suggest Alzheimer’s disease might occasionally be transmitted to people during certain medical treatments — although scientists say that neither set of findings is conclusive.

    The latest autopsies, described in the Swiss Medical Weekly (1) on 26 January, were conducted on the brains of seven people who died of the rare, brain-wasting Creutzfeldt–Jakob disease (CJD). Decades before their deaths, the individuals had all received surgical grafts of dura mater — the membrane that covers the brain and spinal cord. These grafts had been prepared from human cadavers and were contaminated with the prion protein that causes CJD.

    But in addition to the damage caused by the prions, five of the brains displayed some of the pathological signs that are associated with Alzheimer’s disease, researchers from Switzerland and Austria report. Plaques formed from amyloid-β protein were discovered in the grey matter and blood vessels. The individuals, aged between 28 and 63, were unusually young to have developed such plaques. A set of 21 controls, who had not had surgical grafts of dura mater but died of sporadic CJD at similar ages, did not have this amyloid signature.

    Transplant trouble

    According to the authors, it is possible that the transplanted dura mater was contaminated with small ‘seeds’ of amyloid-β protein — which some scientists think could be a trigger for Alzheimer’s — along with the prion protein that gave the recipients CJD.

    Both diseases have long incubation periods. But whereas CJD progresses quickly once initiated, age-related Alzheimer’s develops slowly. None of the individuals had displayed obvious Alzheimer’s symptoms before their deaths.

    The results follow a study published in Nature (2) last September in which scientists from University College London reported that four of eight relatively young people, all of whom died of CJD decades after receiving contaminated batches of growth hormone prepared from cadavers, also displayed amyloid plaques in the blood vessels and grey matter of their brains.

    “Our results are all consistent,” says neurologist John Collinge, a co-author on the Nature paper. “The fact that the new study shows the same pathology emerging after a completely different procedure increases our concern.”

    Not infectious

    Neither study implies that Alzheimer’s disease could ever be transmitted through normal contact with caretakers or family members, the scientists emphasize. And no one uses cadaver-derived preparations in the clinic anymore. Synthetic growth hormone is used for growth disorders, and synthetic membranes are used for patching up in brain surgery.

    But the scientists say that if the theory of amyloid seeding turns out to be true, it would have important clinical implications. In general surgery, for example, any amyloid-β proteins, which are very sticky, would not be routinely removed from surgical instruments; standard sterilization procedures cannot shift them.

    “It is our job as doctors to see in advance what might become a problem in the clinic,” says neuropathologist Herbert Budka of the University Hospital Zurich, Switzerland, who is a co-author of the latest paper.

    “Nothing is proven yet,” cautions Pierluigi Nicotera, head of the German Centre for Neurodegenerative Diseases in Bonn. He points out that amyloid-β has not been identified in the preparations that were transplanted in either the growth hormone or dura mater studies. Nor can researchers rule out the possibility that the underlying condition that led to the need for neurosurgery could have contributed to the observed amyloid pathology, as the authors of the latest paper note.

    “We need more systematic studies in model organisms to work out if the seeding hypothesis of Alzheimer’s is correct,” Nicotera says.

    Nature doi:10.1038/nature.2016.19229

    See the full article here .

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    Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public.

     
  • richardmitnick 8:20 am on January 20, 2016 Permalink | Reply
    Tags: Alzheimer’s, , ,   

    From UCLA: “UCLA Nursing research finds possible answer to why some develop Alzheimer’s — and others don’t” 

    UCLA bloc

    UCLA

    January 19, 2016
    Laura Perry

    Temp 1
    The researchers viewed synapses using a technology called flow cytometry.UCLA School of Nursing

    Alzheimer’s disease affects millions, but there is no cure and no real test for the diagnosis until death, when an examination of the brain can reveal the amyloid plaques that are a telltale characteristic of the disease.

    Interestingly, the same plaque deposits have also been found in the brains of people who had no cognitive impairment, which has led scientists to wonder: Why do some develop Alzheimer’s and some do not?

    Researchers at the UCLA School of Nursing, led by Professor Karen Gylys, may have just uncovered the answer. Their study, published in the January issue of the American Journal of Pathology, is the first to look at disease progression in the synapses — where brain cells transmit impulses.

    The researchers analyzed autopsy tissue samples from different locations of the brains of patients who were considered cognitively normal and those who met the criteria for dementia. Using flow cytometry — a laser-based technology that suspends cells in a stream of fluid and passes them through an electronic detection apparatus — they measured the concentration of two of the known biochemical hallmarks of Alzheimer’s: amyloid beta and p-tau, proteins that when found in high levels in brain fluid are indicative of Alzheimer’s. This allowed the scientists to see large populations of individual synapses — more than 5,000 at a time — versus just two under a microscope.

    They found that people with Alzheimer’s had elevated concentrations of synaptic soluble amyloid-beta oligomers – smaller clusters of amyloid-beta that are toxic to brain cells. These oligomers are believed to affect the synapses, making it harder for the brain to form new memories and recall old ones.

    Temp 2
    Karen Gylys. UCLA School of Nursing

    “Being able to look at human synapses has almost been impossible,” Gylys said. “They are difficult to get a hold of and a challenge to look at under an electron microscope.”

    To overcome that challenge, the UCLA researchers cryogenically froze the tissue samples — which prevented the formation of ice crystals that would have otherwise occluded the synapses had the samples been conventionally frozen. Researchers also did a special biochemical assay for oligomers, and found that the concentration of oligomers in patients who had dementia was much higher than in patients who had the amyloid plaque buildup but no dementia.

    Researchers also studied the timing of the biochemical changes in the brain. They found that the accumulation of amyloid beta in the synapses occurred in the earliest stages of the amyloid plaques, and much earlier than the appearance of synaptic p-tau, which did not occur until late-stage Alzheimer’s set in. This result supports the currently accepted “amyloid cascade hypothesis” of Alzheimer’s, which says that the accumulation of amyloid-beta in the brain is one of the first steps in the development of the disease.

    The researchers now plan to examine exactly how soluble amyloid-beta oligomers lead to tau pathology and whether therapies that slow the accumulation of amyloid-beta oligomers in the synapses might delay or even prevent the onset of Alzheimer’s-related dementia.

    “The study indicates there is a threshold between the oligomer buildup and the development of Alzheimer’s,” Gylys said. “If we can develop effective therapies that target these synaptic amyloid beta oligomers, even a little bit, it might be possible to keep the disease from progressing.”

    Gylys said people can reduce their risk for Alzheimer’s through lifestyle and diet choices, but added that one solution is not going to be enough. “Alzheimer’s disease, like heart disease or cancer, is a lot of things going wrong,” she said. “But understanding this threshold effect is very encouraging.”

    Other investigators involved in the study were Tina Bilousova, Harry Vinters, Eric Hayden, David Teplow, Gregory Cole and Edmond Teng of UCLA; Carol Miller of the University of Southern California; and Wayne Poon, Maria Corrada, Claudia Kawas, Charles Glabe and Ricardo Albay III of UC Irvine.

    The research was supported by grants from the National Institutes of Health and National Institute of Aging.

    See the full article here .

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    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

     
  • richardmitnick 5:49 pm on January 12, 2016 Permalink | Reply
    Tags: Alzheimer’s, , Atherosclerosis Alzheimer’s and Parkinson's diseases related, ,   

    From Wash U: “Atherosclerosis is Alzheimer’s disease of blood vessels, study suggests” 

    Wash U Bloc

    Washington University in St.Louis

    January 11, 2016
    Julia Evangelou Strait

    1
    A new study suggests that plaque forming in arteries has much in common with the progression of Alzheimer’s disease. The image shows a cross section of a mouse aorta, the main artery in the body, with a large plaque. Red lines near the top are the wall of the aorta. The plaque contains a dysfunctional buildup of immune cells called macrophages (pink) and protein waste (green). I. Sergin

    In atherosclerosis, plaque builds up on the inner walls of arteries that deliver blood to the body. Studying mice and tissue samples from the arteries of patients, researchers at Washington University School of Medicine​ in St. Louis suggest this accumulation is driven, at least in part, by processes similar to the plaque formation implicated in brain diseases such as Alzheimer’s and Parkinson’s.

    The study is published in the journal Science Signaling.

    A look behind the scenes in the process of plaque accumulating in arteries, the new study is the first to show that another buildup is taking place. Immune cells attempting to counteract plaque formation begin to accumulate misshapen proteins. This buildup of protein junk inside the cells interferes with their ability to do their jobs.

    Protein buildup is widely studied in the brain — accumulation of proteins such as amyloid beta and tau are hallmarks of Alzheimer’s, Parkinson’s and other degenerative neurological disorders. But until now, the process of misshapen protein buildup within cells has not been implicated in atherosclerosis.

    “In an attempt to fix the damage characteristic of atherosclerosis, immune cells called macrophages go into the lining of the arteries,” said senior author Babak Razani, MD, PhD, assistant professor of medicine. “The macrophage is like a firefighter going into a burning building. But in this case, the firefighter is overcome by the conditions. So another firefighter goes in to save the first and is likewise overcome. And another goes in, and the process continues to build on itself and worsen.”

    The researchers showed that this protein buildup inside macrophages results from problems with the waste-disposal functions of the cell. They identified a protein called p62 that is responsible for sequestering waste and delivering it to cellular incinerators called lysosomes. To mimic atherosclerosis, the researchers exposed the cells to types of fats known to lead to the condition. The researchers noted that during atherosclerosis, the macrophages’ incinerators become dysfunctional. And when cells stop being able to dispose of waste, p62 builds up. In a surprise finding, when p62 is missing and no longer gathers the waste in one place, atherosclerosis in mice becomes even worse.

    Razani and his colleagues, including the study’s first author, Ismail Sergin, PhD, a postdoctoral research fellow, also found these protein aggregates and high amounts of p62 in atherosclerotic plaque samples taken from patients, suggesting these processes are at work in people with plaque building up in the arteries.

    “That p62 sequesters waste in brain cells was known, and its buildup is a marker for a dysfunctional waste-disposal system,” Razani said. “But this is the first evidence that its function in macrophages is playing a role in atherosclerosis.”

    The study demonstrates that p62’s role in gathering up the misfolded proteins is protective against atherosclerosis, even if the cell can’t actually dispose of the waste it gathers.

    “If p62 is missing, the proteins don’t aggregate,” Razani said. “It’s tempting to think this might be good for the cell, but we showed this is actually worse. It causes more damage than if the waste were corralled into a large ‘trash bin.’ You can imagine a situation where lots of trash is being generated and see that it would be better to keep it all in one place, rather than have it strewn across the floor. You might have difficulty removing the trash to the dumpster, but at least it’s contained.”

    In atherosclerosis, and perhaps in the brain disorders characterized by protein accumulation, such evidence suggests it would be better to focus on ways to fix the cells’ waste-disposal system for getting rid of the large protein aggregates, rather than on ways to stop the aggregates from forming.

    This work was supported by the National Institutes of Health (NIH), grant numbers 5K08HL098559, 1R01HL125838 and 1R01AG037120; the Foundation for Barnes-Jewish Hospital; and the Washington University Diabetic Cardiovascular Disease Center.

    Sergin I, Bhattacharya S, Emanuel R, Esen E, Stokes CJ, Evans TD, Arif B, Curci JA, Razani B. Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis. Science Signaling. Jan. 5, 2016.

    See the full article here .

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    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

     
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