• Key signaling pathway in immune cells co

    From ScienceDaily@1:317/3 to All on Thu Apr 14 22:30:46 2022
    Key signaling pathway in immune cells could be new Alzheimer's target


    Date:
    April 14, 2022
    Source:
    Weill Cornell Medicine
    Summary:
    Inhibiting an important signaling pathway in brain-resident immune
    cells may calm brain inflammation and thereby slow the disease
    process in Alzheimer's and some other neurodegenerative diseases,
    suggests a new study. The findings point to the possibility of
    new therapeutic strategies against neurodegenerative diseases,
    which are relatively common in older adults and so far have no
    effective, disease-modifying treatments.



    FULL STORY ========================================================================== Inhibiting an important signaling pathway in brain-resident immune
    cells may calm brain inflammation and thereby slow the disease process
    in Alzheimer's and some other neurodegenerative diseases, suggests a
    study by Weill Cornell Medicine investigators. The findings point to
    the possibility of new therapeutic strategies against neurodegenerative diseases, which are relatively common in older adults and so far have
    no effective, disease-modifying treatments.


    ========================================================================== Brain inflammation, especially via the activation of immune cells in
    the brain called microglia, has long been noted as a common feature
    of neurodegenerative diseases. The spread of abnormal, thread-like
    aggregates -- "tangles" -- of a neuronal protein called tau is another
    frequent feature of these disorders.

    In the study, which appeared April 12 in Nature Communications, the
    researchers showed that the tau tangles help trigger the inflammatory activation of microglia, via a multifunctional signaling pathway called
    the NF-kB pathway.

    Inhibiting microglial NF-kB signaling in a tau-based Alzheimer's mouse
    model largely pulled the immune cells out of their inflammatory state
    and reversed the animals' learning and memory problems.

    "Our findings suggest restraining overactive NF-kB may be a
    good therapeutic strategy in Alzheimer's and other tau-mediated neurodegenerative diseases," said senior author Dr. Li Gan, director of
    the Helen and Robert Appel Alzheimer's Disease Research Institute and
    the Burton P. and the Judith B.

    Resnick Distinguished Professor in Neurodegenerative Diseases in the
    Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

    Tau tangles are found inside neurons in affected brain areas in
    Alzheimer's, Parkinson's, Pick disease, progressive supranuclear palsy, frontotemporal dementia and other neurodegenerative diseases. Experiments
    have shown that tangles, when injected into animal brains, can seed the formation of new tangles, creating a chain-reaction in which the tangles
    spread to other brain regions. Autopsy studies in Alzheimer's and other "tauopathies" indicate that this spread of tangles often tracks closely
    the progress of disease.

    The tangles' precise role in harming brain cells has never been fully understood. However, prior studies have suggested that tau tangles
    can interact with microglia, in a way that drives the microglia into
    an inflammatory, disease-associated state. In this inflamed state,
    the microglia, which normally try to consume the tau tangles, become
    relatively inefficient at doing so. Much of the tau ends up being not
    digested but, rather, disgorged from the microglia, in forms that tend
    to seed new tangles.

    In the new study, Dr. Gan and her team found evidence from cell
    culture and mouse experiments that tau tangles push microglia into this disease-linked inflammatory state mainly by activating the NF-kB signaling pathway within them. In a Alzheimer's mouse model with tau-tangle
    mainly driven by seeded tau, they showed that keeping the NF-kB pathway overactive in microglia enhanced the seeding and spread of tangles, which propel further NF-kB activation. By contrast, shutting off NF-kB blocked
    this vicious cycle, and markedly lessened the spread of the tangles.

    In another tau mouse model, with tau tangle formed in aged neurons, the researchers showed that the inactivation of microglial NF-kB shifted the microglia almost entirely out of their inflammatory, disease-associated
    state, restoring a much more normal cell appearance and pattern of gene activity. This shift, which suppresses microglia from disgorging toxic
    tau seeds, strikingly, prevented key cognitive/memory deficits the mice normally develop in this model.

    "Taken together, our experiments suggest that tau's toxic effects on
    cognition require microglial NF-kB signaling," said co-senior author
    Dr. Wenjie Luo, associate professor of research in neuroscience in the
    Appel Alzheimer's Disease Research Institute and the Feil Family Brain
    and Mind Research Institute at Weill Cornell.

    Over the past two decades, many experimental Alzheimer's treatments have
    aimed to slow or stop the disease process by targeting amyloid plaques
    and more recently tau tangles. So far, all these efforts have failed
    in large-scale clinical trials. The new findings suggest that future
    drugs taming overactive microglial NF-kB signaling might fare better,
    Dr. Gan said.

    Her lab is now following up with further research to detail more
    precisely how microglial NF-kB signaling, which affects the activities
    of at least hundreds of other microglial genes, impairs neurons and leads
    to cognitive and memory deficits. The researchers will investigate how to restrain specific aspects of overactive NF-kB signaling without affecting
    the normal function of brain's immune cells.


    ========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Chao Wang, Li Fan, Rabia R. Khawaja, Bangyan Liu, Lihong Zhan, Lay
    Kodama, Marcus Chin, Yaqiao Li, David Le, Yungui Zhou, Carlo
    Condello, Lea T. Grinberg, William W. Seeley, Bruce L. Miller,
    Sue-Ann Mok, Jason E. Gestwicki, Ana Maria Cuervo, Wenjie Luo,
    Li Gan. Microglial NF-kB drives tau spreading and toxicity in
    a mouse model of tauopathy. Nature Communications, 2022; 13 (1)
    DOI: 10.1038/s41467-022-29552-6 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220414135250.htm

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