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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.”

    See the full article here .

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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.

    See the full article here .

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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

    See the full article here .

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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.

    See the full article here .

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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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  • 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.

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  • 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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  • richardmitnick 12:58 pm on November 10, 2015 Permalink | Reply
    Tags: Alzheimer’s, , ,   

    From TUM: “Possible Reasons Found for Failure of Alzheimer’s Treatment” 

    Techniche Universitat Munchen

    Techniche Universitat Munchen

    09.11.2015
    Dr. Vera Siegler

    1
    High-resolution two-photon microscopy: Pictures of cells (green) and amyloid-β plaques (blue) in Alzheimer’s brain. (Picture: Marc Aurel Busche / TUM)

    Agglutinated proteins in the brain, known as amyloid-β plaques, are a key characteristic of Alzheimer’s. One treatment option uses special antibodies to break down these plaques. This approach yielded good results in the animal model, but for reasons that are not yet clear, it has so far been unsuccessful in patient studies. Scientists at the Technical University of Munich (TUM) have now discovered one possible cause: they noticed that, in mice that received one antibody treatment, nerve cell disorders did not improve and were even exacerbated.

    Immunotherapies with antibodies that target amyloid-β were long considered promising for treating Alzheimer’s. Experiments with animals showed that they reduced plaques and reversed memory loss. In clinical studies on patients, however, it has not yet been possible to confirm these results. A team of researchers working with Dr. Dr. Marc Aurel Busche, a scientist at the TUM hospital Klinikum rechts der Isar Klinik und Poliklinik für Psychiatrie und Psychotherapie and at the TUM Institute of Neuroscience, and Prof. Arthur Konnerth from the Institute of Neuroscience has now clarified one possible reason for this. The findings were published in Nature Neuroscience.

    Immunotherapy Increases Number of Hyperactive Nerve Cells

    The researchers used Alzheimer’s mice models for their study. These animals carry a transgene for the amyloid-β precursor protein, which, as in humans, leads to the formation of amyloid-β plaques in the brain and causes memory disorders. The scientists treated the animals with immunotherapy antibodies and then analyzed nerve cell activity using high-resolution two-photon microscopy. They found that, while the plaques disappeared, the number of abnormally hyperactive neurons rose sharply.

    “Hyperactive neurons can no longer perform their normal functions and, after some time, wear themselves out. They then fall silent and, later, possibly die off,” says Busche, explaining the significance of their discovery. “This could explain why patients who received the immunotherapy experienced no real improvement in their condition despite the decrease in plaques,” he adds.

    Released Oligomers Potential Reason for Hyperactivity

    Even in young Alzheimer’s mice, when no plaques were yet detectable in the brain, the antibody treatment led to increased development of hyperactive nerve cells. “Looking at these findings, even using the examined immunotherapies at an early stage, before the plaques appear, would offer little chance of success. As the scientist explains, the treatment already exhibits these side effects here, too.

    “We suspect that the mechanism is as follows: The antibodies used in treatment release increasing numbers of soluble oligomers. These are precursors of the plaques and have been considered problematic for some time now. This could cause the increase in hyperactivity,” says Busche.

    The work was funded by an Advanced ERC grant to Prof. Arthur Konnerth, the EU FP7 program (Project Corticonic) and the Deutsche Forschungsgemeinschaft (IRTG 1373 and SFB870). Marc Aurel Busche was supported by the Hans und Klementia Langmatz Stiftung.

    Publication
    Marc Aurel Busche, Christine Grienberger, Aylin D. Keskin, Beomjong Song, Ulf Neumann, Matthias Staufenbiel, Hans Förstl and Arthur Konnerth, Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models, Nature Neuroscience, November 9, 2015.
    DOI: 10.1038/nn.4163

    See the full article here .

    Please help promote STEM in your local schools.

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    Techniche Universitat Munchin Campus

    Technische Universität München (TUM) is one of Europe’s top universities. It is committed to excellence in research and teaching, interdisciplinary education and the active promotion of promising young scientists. The university also forges strong links with companies and scientific institutions across the world. TUM was one of the first universities in Germany to be named a University of Excellence. Moreover, TUM regularly ranks among the best European universities in international rankings.

     
  • richardmitnick 8:45 am on March 21, 2015 Permalink | Reply
    Tags: Alzheimer’s, , ,   

    From Rockefeller: “Changes in a blood-based molecular pathway identified in Alzheimer’s disease” 

    Rockefeller U bloc

    Rockefeller University

    March 20, 2015
    No Writer Credit

    By the time most people receive a diagnosis of Alzheimer’s disease — based on clinical signs of mental decline — their brains have already suffered a decade or more of damage. But although the mechanisms that spur the destruction of neurons in Alzheimer’s disease are not yet fully understood, two well-documented signs of the condition are accumulation of the amyloid-β peptide (the main component of plaques found in Alzheimer’s patient brains) and chronic inflammation. New research from Rockefeller University, published March 16 in the Proceedings of the National Academy of Sciences, identifies a bridge between the two. That bridge, a molecular cascade known as the contact system, may provide opportunities for early diagnosis of the disease through simple blood tests.

    “People have been looking for a long time for markers for Alzheimer’s disease,” says Sidney Strickland, head of the Patricia and John Rosenwald Laboratory of Neurobiology and Genetics. But current diagnostic tests for pre-symptomatic Alzheimer’s leave much to be desired. Evaluating the level of amyloid-β in the cerebral spinal fluid, for instance, requires an invasive spinal tap procedure.

    “Finding a blood biomarker that would let us know through a simple test whether someone is on their way to developing the disease would be a significant advance,” says first author Daria Zamolodchikov, a postdoctoral associate in the Strickland lab.

    The new study grew from the lab’s ongoing work that looks at how the vascular system is involved in Alzheimer’s disease. It has been shown that amyloid-β can activate a protein in plasma called factor XII, the first step in a pathway known as the contact system. When activated, this system leads to the release of a small peptide called bradykinin, a molecule known to promote potentially damaging inflammation. Although some studies have found these molecules in the cerebral spinal fluid and brain tissue of Alzheimer’s patients, no one had studied them in Alzheimer’s patient plasma.

    Using plasma from people with and without diagnosed Alzheimer’s disease, the researchers measured the activation levels of the contact system. They found increased activation of this system in the plasma of Alzheimer’s patients, potentially implicating it in the inflammatory pathology of the disease. Moreover, in a subset of patients whose amyloid-β levels in the cerebral spinal fluid were known, the researchers demonstrated a positive correlation between activation of the contact system and changes in cerebral spinal fluid amyloid-β levels, which as mentioned above are correlated with the development of Alzheimer’s.

    The researchers found similar activation of the contact system in mouse models of Alzheimer’s, which are genetically modified to overproduce amyloid-β. They then conducted a follow-up experiment with healthy mice. “We went one step further and took completely normal wild-type mice and injected them with amyloid-β. We found that on its own, injection with amyloid-β can activate this system. It’s a proof of principle in a complex environment,” says Zamolodchikov.

    These findings will need to be supported by studies in larger patient populations and longitudinal studies, but they could eventually open the door to diagnosis of pre-symptomatic Alzheimer’s based on blood levels of these molecules.

    The contact system may also offer a new approach to therapies for Alzheimer’s disease, since inhibition of the pathway could blunt some of the inflammatory aspects of the disease. One concern is that the contact system is also involved in blood clotting and inhibition might carry a risk of bleeding. However, people with a defect in this system do not have hemophilia. Thus, inhibition of this pathway might slow progression of the disease without increasing the risk of hemorrhage.

    Proceedings of the National Academy of Sciences online: March 16, 2015
    Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma
    Daria Zamolodchikov, Zu-Lin Chen, Brooke A. Conti, Thomas Renné, and Sidney Strickland

    See the full article here.

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
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