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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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    Wash U campus

    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.

     
  • 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 .

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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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