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    Home > Active Ingredient News > Study of Nervous System > Nat Neurosci TREM2 new ligand!

    Nat Neurosci TREM2 new ligand!

    • Last Update: 2021-12-31
    • Source: Internet
    • Author: User
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    Editor | Amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis, ALS), also commonly known as gradual freezing disease, is a progressive and fatal neurodegenerative disease

    ALS is one of the five most common motor neuron diseases.
    It is caused by the degeneration of motor neurons that control skeletal muscles in the central nervous system

    Because of the degeneration and death of upper and lower motor neurons, the muscles gradually weaken and shrink, causing obstacles in pronunciation, swallowing, and breathing.
    Eventually, the brain completely loses the ability to control voluntary movement

    This disease does not necessarily affect the patient's advanced cognitive neurological activities like Alzheimer's disease.
    On the contrary, patients with advanced disease can always maintain clear thinking and retain the memory, personality and intelligence before the onset

    However, because its pathological mechanism is not yet fully understood, there is no effective drug clinically

    Clinical pathology showed that 97% of the brains of ALS patients showed ectopic aggregation of TDP-43 (transferred from the nucleus to the cytoplasm and formed protein aggregation).
    Cell and animal studies have also confirmed this pathological TDP-43 nerve Metatoxicity

    Therefore, studying the mechanisms related to pathological TDP-43 has become an important direction to overcome ALS

    On December 16, 2021, the team of Professor Long-Jun Wu from the Department of Neurology of Mayo Clinic, USA, cooperated with many units and published an article entitled TREM2 interacts with TDP-43 and mediates microglial neuroprotection in Nature Neuroscience.
    An article against TDP-43 related neurodegeneration found a new mechanism in TDP-43-related neurodegeneration.
    "TREM2 directly binds to the key pathological protein TDP-43 to mediate the recognition and clearance of pathological TDP by microglia.
    -43, Protecting Neurons", is expected to provide a new basis and therapeutic target for clinically conquering ALS

    Myeloid cell trigger receptor 2 (TREM2) belongs to the immunoglobulin transmembrane receptor superfamily and is mainly expressed in myeloid cells

    TREM2 is only expressed in microglia in the central nervous system, and its related mutations are high-risk factors for a variety of neurodegenerative diseases

    Clinical data and animal experiments have confirmed that TREM2 mutations can significantly increase the risk of Alzheimer's disease (AD) [1,2]

    There are also clinical reports suggesting that TREM2 mutations also increase the incidence of ALS [3], but the function and mechanism of TREM2 in ALS have not been confirmed

    In this study, a TDP-43 (key pathological protein of ALS) related neurodegenerative disease model was established on TREM2 knockout mice through viruses and transgenic mice, which confirmed that microglia TREM2 is involved in TDP-43-related neurodegeneration.
    It plays a neuroprotective role in sexual diseases

    Behaviorally, TREM2 knockout mice showed higher mortality and more severe motor dysfunction

    To further explore the mechanism, the team's research members found that the lack of TREM2 reduced the ability of mouse microglia to engulf and clear pathological TDP-43 (Figure 1), which in turn exacerbated motor neuron death

    In addition, single-cell mass spectrometry flow cytometry (CyTOF) experiments found that pathological TDP-43 can induce a type of TREM2-dependent CD11c high expression microglia subpopulation, which has a strong presence in the motor cortex of mice.
    The phagocytic capacity of TDP-43

    Figure 1.
    Loss of TREM2 leads to a decrease in the ability of microglia to phagocytose and clear pathological TDP-43.
    To further explore the molecular mechanism of pathological TDP-43 clearance mediated by TREM2, the team’s research members combined immunoprecipitation and Mass spectrometry and other research methods have proved that TREM2 can directly bind to TDP-43 in the in vitro environment, in vivo mice, and brain samples of ALS patients

    In collaboration with Mayo Clinic Computer-Aided Molecular Design Laboratory, the research team used simulation calculations to infer the possible binding regions of TREM2 and TDP-43, and used surface plasmon resonance to confirm the potential binding regions

    In summary, this study not only provides solid evidence to confirm the protective effect of microglia TREM2 in TDP-43-related neurodegenerative diseases (not limited to ALS), but also reports that TDP-43 is a microglia for the first time.
    The ligand of TREM2 is expected to provide a new theoretical basis for clinically conquering TDP-43-related neurodegenerative diseases (such as ALS, FTD and AD, etc.

    Mayo Clinic Department of Neurology, Professor Wu Longjun's research group, Ph.
    candidate Xie Manling is the first author of the article, and Professor Wu Longjun is the corresponding author

    The former postdoctoral postdoctoral fellow of Professor Wu Longjun's research group Liu Yong is the co-first author and the co-corresponding author.
    He currently works at the First People's Hospital of Guangzhou (South China University of Technology)

    In addition, Professor Guojun Bu and Professor Dennis W.
    Dickson, Department of Neuroscience, Mayo Clinic, Professor Yuan-Ping Pang and Professor Liewei Wang, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, and Mark P.
    Mattson, Department of Neuroscience, Johns Hopkins University The professor also made important contributions to this research

    Original link: https:// Plate maker: XI Reference 1 Wang, Y.
    et al.
    TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model .
    Cell 160, 1061-1071, doi:10.
    049 (2015).
    2 Jonsson, T.
    et al.
    Variant of TREM2 associated with the risk of Alzheimer's disease.
    N Engl J Med 368, 107- 116, doi:10.
    1056/NEJMoa1211103 (2013).
    3 Cady, J.
    et al.
    TREM2 variant p.
    R47H as a risk factor for sporadic amyotrophic lateral sclerosis.
    JAMA Neurol 71, 449-453, doi:10.
    6237 ( 2014).
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