• The role of lipids in the development of

    From ScienceDaily@1:317/3 to All on Tue Mar 1 21:30:36 2022
    The role of lipids in the development of Alzheimer's disease

    Date:
    March 1, 2022
    Source:
    Universite' de Gene`ve
    Summary:
    Neurons in the brain coexist with and rely on many other cell
    types to function properly. Astrocytes, which take their name
    from their star shape, ensure the survival of neurons by feeding
    and detoxifying them with the help of a multifunctional protein,
    APOE. One of three forms of this protein, APOE4, significantly
    increases the risk of developing Alzheimer's disease, but the
    mechanisms at play are unknown.



    FULL STORY ========================================================================== Neurons in the brain coexist with and rely on many other cell types
    to function properly. Astrocytes, which take their name from their star
    shape, ensure the survival of neurons by feeding and detoxifying them with
    the help of a multifunctional protein, APOE. One of three forms of this protein, APOE4, significantly increases the risk of developing Alzheimer's disease, but the mechanisms at play are unknown. A collaboration
    between the University of Geneva (UNIGE), the European Molecular Biology Laboratory (EMBL), the University of Zurich and the pharmaceutical company AbbVie has discovered a potential mechanism: far from ceasing to function, APOE4 is on the contrary more efficient. By triggering astrocytic lipid secretion, it causes the accumulation of potentially toxic lipids that
    are harmful to neurons, and thus might contribute to the development of Alzheimer's disease. These results published in the journal Cell Reports,
    shed new light on the neurodegenerative mechanisms of a disease that
    affects nearly 50 million people worldwide.


    ========================================================================== Astrocytes, present in very large numbers in the brain, have a major
    protective function. These cells secrete apolipoprotein E (or APOE),
    a small protein that forms particles containing lipids and vitamins to
    feed the neurons. It also detoxifies the neurons by getting them rid of
    "lipid waste" that could become harmful if not removed. As the neurons
    are unable to eliminate this waste on their own, APOE comes into play
    to collect it and bring it back to the astrocytes where it is destroyed.

    The gene coding for APOE exists in three frequent variants in humans:
    APOE2, present in 8% of the population, APOE3, the most common, and
    APOE4, which is found in nearly 15% of people and increases the risk of developing Alzheimer's disease by a factor of ten. "The reasons why APOE4 increases the risk of Alzheimer's disease so significantly are not well understood," explains Anne- Claude Gavin, a professor in the Department
    of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine and
    holder of a Louis-Jeantet Foundation Chair, who directed this research
    together with Viktor Lakics, a Research fellow and Biology Area Leader
    in Neuroscience discovery at AbbVie. What are the mechanisms behind
    the dysfunction of APOE4? And above all, could they serve as a basis
    for prevention or therapy? To answer these questions, Anne-Claude Gavin
    and her team joined forces with scientists from the European Molecular
    Biology Laboratory (EMBL), the University of Zurich and AbbVie.

    A protein that is too effective Working on these questions, the research
    team identified novel molecular mechanisms that explain how APOE binds to astrocyte membranes to detect and extract the lipids it needs. Employing
    human cell lines with different APOE variants, in vitro experiments demonstrated that APOE is very efficient at transporting potentially
    harmful lipids produced in neurons. "And to our great surprise, the APOE4 variant proved to be even more efficient than the other forms," reveals Katharina Beckenbauer, a former post-doc in Anne-Claude Gavin's group,
    senior scientist at AbbVie, and one of the first authors of the work.

    "So, contrary to what we thought until now, the problem is not that
    APOE4 stops working, but, in fact, the opposite. And the mechanism
    goes haywire." A hijacked function As astrocytes age, they become less efficient and start to accumulate lipids rather than destroy them. "We
    modelled this process experimentally and observed the molecules
    secreted by the astrocytes," explains Karina Lindner, a PhD student
    in Anne-Claude Gavin's laboratory and one of the first authors of this
    work. "We observed that cellular ageing diverts APOE from its primary
    function -- transporting lipids to neurons and also recovering lipid waste
    from them - - towards the secretion of triglycerides, particular lipid
    species that could become harmful if not removed." And this phenomenon
    is exacerbated with APOE4: it stimulates the secretion of triglycerides, leading to their uncontrolled accumulation. This deleterious accumulation
    of potentially harmful lipids could very well be an important contributor
    to the neuronal death, a hallmark of Alzheimer's disease. "APOE4 would
    thus have the capacity to accelerate the pathological process in the
    disease through the mechanism we have discovered." In order to better understand the details of the action of APOE and especially of the E4
    variant, the scientists at UNIGE want now to determine how secretion of
    these potentially harmful lipids is regulated and whether this secretion
    can be detected in people suffering from Alzheimer's disease.

    special promotion Explore the latest scientific research on sleep and
    dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by Universite'_de_Gene`ve. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Karina Lindner, Katharina Beckenbauer, Larissa C. van Ek, Kevin
    Titeca,
    Sherida M. de Leeuw, Khader Awwad, Franziska Hanke, Alla
    V. Korepanova, Vladimir Rybin, Elizabeth Louise van der
    Kam, Eric G. Mohler, Christian Tackenberg, Viktor Lakics,
    Anne-Claude Gavin. Isoform- and cell-state- specific lipidation
    of ApoE in astrocytes. Cell Reports, 2022; 38 (9): 110435 DOI:
    10.1016/j.celrep.2022.110435 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220301131037.htm

    --- up 1 day, 10 hours, 50 minutes
    * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)