Research Clears up How Brain ‘Cleaners’ Fail in ALS

Summary: Findings point to microglial TREM2 as a potential target for the treatment of ALS.

Source: Mayo Clinic

In preclinical studies, Mayo Clinic scientists and collaborators have identified the molecular mechanism used by the brain’s “cleaners” as they remove a problematic protein in the brain.

This work, published in Nature Neuroscience, demonstrates that the cleaners—resident immune cells in the brain called microglia—play a protective role in a mouse model of Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis (ALS). The study may provide a potential therapeutic target for that disease.

The loss of neurons characterizes the neurodegenerative diseases of Alzheimer’s and ALS. In Alzheimer’s, the lost neurons handle memory retrieval, and in ALS, it is the neurons that manage movement that are damaged. In the brain of people diagnosed with either of these diseases, pathologists can see a buildup of specific proteins: beta-amyloid and tau in those with Alzheimer’s, and a protein called TAR-DNA binding protein 43 kDa (TDP-43) in people with ALS.

Microglia are the cells tasked with cleaning up debris in the brain, and they have a unique receptor called TREM2. When this receptor is mutated, evidence suggests risks increase for developing Alzheimer’s disease, the theory being that microglia cannot clean up the brain efficiently. But the evidence for TREM2 and ALS was more tenuous until now.

“The aggregation of TDP-43 in the brain is a hallmark for most ALS patients,” explains Long-Jun Wu, Ph.D., a Mayo Clinic neuroimmunologist and senior author of the paper. “Our study shows for the first time that TDP-43 is a potential ligand for microglial TREM2. Further, we found that this interaction mediates microglial TREM2 sensing and clearance of pathological TDP-43 protein.

This is a diagram from the study
Using samples donated to Mayo Clinic’s Brain Bank for Neurodegenerative Disorders, as well as mouse models, biochemistry, confocal microscopy, and computational simulations, researchers showed that a receptor on microglial cells, called TREM2, can clear a protein that builds up in the brains of patients with ALS. Image created with BioRender. Credit: Mayo Clinic

As a ligand, TDP-43 binds to the TREM2 receptor, which is important for microglia cells to clear up the protein. Using biochemistry, computational simulations, confocal microscopy, mouse models, and samples from the Mayo Clinic Brain Bank for Neurodegenerative Disorders, the researchers were able to decipher the interaction between TREM2 and TDP-43, thereby potentially revealing a target for therapy for ALS.

“The mechanisms underlying ALS initiation and progression are poorly understood,” says Dr. Wu. “Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system. Our current findings point out microglial TREM2 as a potential therapeutic target for ameliorating TDP-43-related neurodegeneration, including ALS.”

The Neuroimmune Interaction in Heath and Disease Laboratory led by Dr. Wu plans to delve into the exact binding sites of human TDP-43 and the TREM2 receptor. They also want to investigate a specific population of microglia that seem to be supercharged to remove TDP-43. And the eventual goal is to explore if TREM2 activators might be a candidate for treatment in mouse models of ALS, which is a first step toward potentially treating human disease.

About this ALS research news

Author: Press Office
Source: Mayo Clinic
Contact: Press Office – Mayo Clinic
Image: The image is credited to Mayo Clinic

Original Research: Closed access.
TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration” by Manling Xie et al. Nature Neuroscience


TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration

Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to risk of neurodegenerative disease. However, the function of TREM2 in neurodegeneration is still not fully understood.

Here, we investigated the role of microglial TREM2 in TAR DNA-binding protein 43 (TDP-43)-related neurodegeneration using virus-mediated and transgenic mouse models.

We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that human TDP-43 (hTDP-43) induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability.

Using mass spectrometry (MS) and surface plasmon resonance (SPR) analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in human tissues from individuals with amyotrophic lateral sclerosis (ALS). We computationally identified regions within hTDP-43 that interact with TREM2.

Our data highlight that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection of microglia in TDP-43-related neurodegeneration.

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