• Alzheimer's: Protective immune cells act

    From ScienceDaily@1:317/3 to All on Thursday, March 17, 2022 22:30:44
    Alzheimer's: Protective immune cells active decades before symptom onset
    Boosting the brain's defenses could help combat the disease

    Date:
    March 17, 2022
    Source:
    DZNE - German Center for Neurodegenerative Diseases
    Summary:
    In individuals with a genetic predisposition to Alzheimer's disease,
    the immune cells of the brain -- the 'microglia' -- start exerting
    a protective effect up to two decades before the first symptoms
    appear. A team draws this conclusion based on a study of more than
    200 volunteers.

    In light of their study data, the scientists consider modulating
    the activity of microglia to be a promising therapeutic approach. To
    this end, they aim to develop drugs that target a cellular receptor
    called TREM2.



    FULL STORY ==========================================================================
    In individuals with a genetic predisposition to Alzheimer's disease,
    the immune cells of the brain -- the "microglia" -- start exerting a
    protective effect up to two decades before the first symptoms appear. A
    team from Deutsches Zentrum fu"r Neurodegenerative Erkrankungen
    (DZNE) and Ludwig-Maximilians-Universita"t (LMU) Mu"nchen draws this
    conclusion based on a study of more than 200 volunteers, which they
    report in the journal The Lancet Neurology. In light of their study data,
    the scientists consider modulating the activity of microglia to be a
    promising therapeutic approach. To this end, they aim to develop drugs
    that target a cellular receptor called TREM2.


    ========================================================================== About one percent of all people with Alzheimer's develop the disease
    as a result of gene mutations that can be passed on from generation
    to generation.

    As part of the international DIAN (Dominantly Inherited Alzheimer Network) observational study, DZNE and LMU Mu"nchen are participating in research
    into this genetic form of Alzheimer's disease. The DIAN study cohort
    includes adults who carry gene mutations that cause Alzheimer's as well
    as their close relatives without mutations.

    Measurements Over Several Years For the current research, the team led by molecular biologist Prof. Christian Haass and neurologist Dr. Estrella Morenas-Rodri'guez analyzed how signatures of microglial activation
    were related to the development of certain biomarkers of Alzheimer's
    disease. To this end, cerebrospinal fluid and cognition were assessed
    over a period of several years in 248 participants of the DIAN study
    comprising the different stages of Alzheimer's disease. The volunteers
    were also examined by magnetic resonance imaging (MRI) and positron
    emission tomography (PET) to visualize brain shrinkage and amyloid
    pathology -- both are hallmarks of Alzheimer's disease.

    The starting point for the research team was a protein called TREM2. "This
    is a receptor on the surface of microglia, but parts of it can detach
    and are then detectable in the cerebrospinal fluid. It is known from
    laboratory studies, particularly in mice but also from our earlier
    human studies, that levels of TREM2 in the cerebrospinal fluid are a
    good indicator of microglial activity.

    TREM2 is a kind of activity switch. As TREM2 levels increase, so do
    microglial protective activities," explains Christian Haass, research
    group leader at DZNE and professor of biochemistry at LMU Mu"nchen. "For
    a long time, it was assumed that microglia mainly cause damage in the
    course of Alzheimer's disease, as they can fuel chronic inflammatory
    processes. However, there is growing evidence from my laboratory and
    many others that microglia have a protective effect at least at the
    beginning of the disease. This hypothesis is supported by our current
    data." Estrella Morenas-Rodri'guez, postdoctoral researcher in the
    Haass team at the time of the investigation and now junior group leader
    at Hospital Universitario 12 de Octubre in Madrid, Spain adds: "One of
    the determinant points which allowed us to make our observations, and
    that was also a challenge, was to be able to study for the first time
    the increase of the TREM2 marker longitudinally. That is, we measured
    the marker in several samples taken from the same individuals every
    one or two years. With that we could better capture the development of
    the different processes occurring in Alzheimer's disease than studying
    samples at just one time point." Conspicuous Long in Advance People
    with a genetic predisposition to Alzheimer's usually develop the disease
    at a similar age as their relatives with the same mutation who already experience symptoms of dementia. Based on this experience, the researchers
    were able to estimate the time until the onset of symptoms for all study participants individually. In doing so, they came across early signs
    of the disease. "We found that TREM2 levels in the cerebrospinal fluid
    rise as early as 21 years before the estimated onset of the disease,"
    Haass says. "We also observed that the faster TREM2 increases over the
    years, the slower pathological events progress in the brain that are
    typical of Alzheimer's. We can infer this from biomarkers for so-called
    amyloid proteins and tau proteins." The brain examinations using MRI and
    PET pointed in a similar direction: In study participants in whom TREM2
    levels rose rapidly, deposits of amyloid proteins that are characteristic
    of Alzheimer's developed more slowly and brain volume declined more
    slowly. "Besides the relationship with a slower pathological process, one
    of our most important and promising findings was to see how strikingly
    the faster TREM2 increase correlated with a slower cognitive decline in
    an early stage of Alzheimer's disease. This has important implications
    for treatment," Morenas-Rodri'guez notes.

    "We see our findings as evidence that TREM2-mediated microglial activity
    has a protective effect," Haass says. "In our view, microglia become
    active as soon as the first amyloid proteins are deposited in the
    brain, a process, which we call seeding. In other words, at a very
    early stage of Alzheimer's and that is what we and our colleagues at the DZNE-Tu"bingen also observe in animal models." Approach for New Therapies
    For some time now, Haass and his team have been researching drugs that specifically reinforce the protective effect of microglia. Their target
    is the TREM2 receptor anchored on the cell surface. "We are still in
    the laboratory phase. However, the current results in humans show that modulating TREM2 is a promising strategy to develop new options against Alzheimer's. Although in this particular case we studied the genetic form
    of the disease, we consider that our findings also apply to the so-called sporadic variant of the disease, which is far more common. Certainly, it
    is crucial that treatment starts as early as possible. Today's therapies
    all come far too late to be really effective," says Haass.


    ========================================================================== Story Source: Materials provided by DZNE_-_German_Center_for_Neurodegenerative_Diseases.

    Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Estrella Morenas-Rodri'guez, Yan Li, Brigitte Nuscher, Nicolai
    Franzmeier, Chengjie Xiong, Marc Sua'rez-Calvet, Anne M Fagan,
    Stephanie Schultz, Brian A Gordon, Tammie L S Benzinger, Jason
    Hassenstab, Eric McDade, Regina Feederle, Celeste M Karch, Kai
    Schlepckow, John C Morris, Gernot Kleinberger, Bengt Nellgard,
    Jonathan Vo"glein, Kaj Blennow, Henrik Zetterberg, Michael Ewers,
    Mathias Jucker, Johannes Levin, Randall J Bateman, Christian Haass,
    Sarah Adams, Ricardo Allegri, Aki Araki, Nicolas Barthelemy,
    Jacob Bechara, Sarah Berman, Courtney Bodge, Susan Brandon,
    William (Bill) Brooks, Jared Brosch, Jill Buck, Virginia Buckles,
    Kathleen Carter, Lisa Cash, Charlie Chen, Jasmeer Chhatwal, Patricio
    Chrem, Jasmin Chua, Helena Chui, Carlos Cruchaga, Gregory S Day,
    Chrismary De La Cruz, Darcy Denner, Anna Diffenbacher, Aylin
    Dincer, Tamara Donahue, Jane Douglas, Duc Duong, Noelia Egido,
    Bianca Esposito, Marty Farlow, Becca Feldman, Colleen Fitzpatrick,
    Shaney Flores, Nick Fox, Erin Franklin, Nelly Friedrichsen, Hisako
    Fujii, Samantha Gardener, Bernardino Ghetti, Alison Goate, Sarah
    Goldberg, Jill Goldman, Alyssa Gonzalez, Susanne Gra"ber-Sultan,
    Neill Graff-Radford, Morgan Graham, Julia Gray, Emily Gremminger,
    Miguel Grilo, Alex Groves, Lisa Ha"sler, Cortaiga Hellm, Elizabeth
    Herries, Laura Hoechst-Swisher, Anna Hofmann, David Holtzman,
    Russ Hornbeck, Yakushev Igor, Ryoko Ihara, Takeshi Ikeuchi,
    Snezana Ikonomovic, Kenji Ishii, Clifford Jack, Gina Jerome, Erik
    Johnson, Stephan Ka"ser, Kensaku Kasuga, Sarah Keefe, William (Bill)
    Klunk, Robert Koeppe, Deb Koudelis, Elke Kuder-Buletta, Christoph
    Laske, Allan Levey, Oscar Lopez, Jacob Marsh, Rita Martinez,
    Ralph Martins, Neal Scott Mason, Colin Masters, Kwasi Mawuenyega,
    Austin McCullough, Arlene Mejia, James MountzMD, Cath Mummery,
    Neelesh Nadkarni, Akemi Nagamatsu, Katie Neimeyer, Yoshiki Niimi,
    James Noble, Joanne Norton, Brigitte Nuscher, Antoinette O'Connor,
    Ulricke Obermu"ller, Riddhi Patira, Richard Perrin, Lingyan Ping,
    Oliver Preische, Alan Renton, John Ringman, Stephen Salloway,
    Peter Schofield, Michio Senda, Nick Seyfried, Kristine Shady,
    Hiroyuki Shimada, Wendy Sigurdson, Jennifer Smith, Lori Smith,
    Beth Snitz, Hamid Sohrabi, Sochenda Stephens, Kevin Taddei,
    Sarah Thompson, Peter Wang, Qing Wang, Elise Weamer, Jinbin Xu,
    Xiong Xu. Soluble TREM2 in CSF and its association with other
    biomarkers and cognition in autosomal-dominant Alzheimer's disease:
    a longitudinal observational study. The Lancet Neurology, 2022;
    21 (4): 329 DOI: 10.1016/S1474-4422 (22)00027-8 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220317094758.htm

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