Known as a keen sensor of mischief, TREM2 sets off microglial responses to Aβ, tau, and other markers of neuronal distress. A new study now adds pathological TDP-43 to that list. In a paper published December 16 in Nature Neuroscience, researchers led by Long-Jun Wu of the Mayo Clinic in Jacksonville, Florida, report that TREM2 facilitates microglial responses to TDP-43 pathology. Without the receptor, microglia fail to ramp up phagocytosis, exacerbating TDP-43 aggregation, motor impairment, and ultimately death. What’s more, the researchers found that in cell culture, in mouse models, and even in people who died with ALS, TREM2 appeared to bind extracellular TDP-43. The researchers propose that microglia use TREM2 to sense TDP-43 pathology, and that mutations in the microglial receptor could compromise this function and the neuroprotective responses.

  • Without TREM2, TDP-43 strikes a greater neurodegenerative blow in mice.
  • TREM2 facilitates microglial clean-up of TDP-43 aggregates.
  • The two proteins bind.

“Overall, this interesting publication proposes a novel role for TREM2 and TREM2-mediated microglia activation in ALS pathology,” wrote Yun Chen and Marco Colonna of Washington University in St. Louis. “Importantly, the physical interaction between TREM2 and TDP-43 potentially points to a new therapeutic application for anti-TREM2 antibodies currently tested for Alzheimer’s disease.” TREM2-directed antibodies currently in development aim to enhance signaling through the receptor, ramping up phagocytosis and other microglial functions.  

The R47H variant in TREM2 increases a person’s risk for AD, casting microglial function as a central player in AD pathogenesis. Microglia are also intimately involved—for better or worse—in other neurodegenerative diseases, including ALS and FTD (Oct 2008 news; Maniatis et al., 2019). However, whether TREM2—and the R47H variant in particular—sways risk for those diseases is still unsettled (Cady et al., 2014; Rayaprolu et al., 2013). 

First authors Manling Xie and Yong Liu and colleagues wanted to investigate whether TREM2 influences the way microglia respond to TDP-43 pathology, the predominant neuropathological culprit in ALS, and in about half of FTD cases. The RNA binding protein also accumulates in some people with AD, as well as in limbic-predominant, age-related TDP-43 encephalopathy (LATE).

As a model, the researchers injected newborn mice with an adeno-associated virus expressing wild-type human TDP-43. The resulting overexpression of the human protein quickly drove formation of nuclear and cytoplasmic inclusions of TDP-43. By the time these mice were 2 weeks old, they clasped their hindlimbs when suspended upside down, a hallmark of ongoing motor neuron degeneration. At 5 weeks of age, they had lost about a quarter of the neurons in their motor cortices and, at 10 weeks, found it hard to balance. About 70 percent survived their first 2 months, and many of the survivors at least partially recovered motor function. While the mechanisms governing this recovery are unclear, Wu told Alzforum that it may be facilitated by how microglia handle the TDP-43 pathology. In support of this idea, in mice lacking TREM2, the degenerative phenotypes were all faster and worse. Knockouts had more TDP-43 pathology, developed motor impairments at a younger age, and lost more neurons. Only about 25 percent survived their first 2 months, and they remained impaired. Wu noted that without overexpression of TDP-43, TREM2 knockouts suffered no behavioral or motor impairments, or any health issues, relative to wild-type mice.

Suspecting subpar microglial responses were to blame for the more severe disease in TREM2 knockouts, the scientists took a closer look at how microglia responded to TDP-43 pathology. In wild-type mice, it triggered a microglia response, characterized by elevated expression of IBA1, CD206, CD11c, F4-80, and transforming growth factor-β (TGFβ), and by decreased CX3CR1 expression. In TREM2 knockouts, the cells remained in a homeostatic state. What’s more, the researchers found that while microglia in wild-type mice readily gobbled up TDP-43 aggregates, in TREM2 knockouts they appeared to have no appetite for it. In turn, TDP-43 accumulated to a much greater degree. The researchers observed similar trends when they waited until mice reached adulthood before injecting the AAV TDP-43 overexpression vector.

Got No Appetite. In wild-type mice (left) overexpressing human TDP-43, microglia express Iba1 (red) and internalize TDP-43 (green). In TREM2 knockouts (right), microglia express less Iba1 and do not ingest the protein. [Courtesy of Xie et al., Nature Neuroscience, 2021.]

What rouses microglia to respond to TDP-43 pathology, and how is TREM2 involved in the process? Previous studies have found that neurons riddled with TDP-43 inclusions offload the dysfunctional protein in extracellular vesicles, and these can be detected in the cerebrospinal fluid of people with ALS and FTD (Steinacker et al., 2008). The researchers hypothesized that microglia might somehow sense this extracellular TDP-43 via TREM2.

To investigate, they first asked whether TREM2 even interacts with TDP-43. Indeed, they found the two proteins bound together in several scenarios: in human iPSC-derived neurons; in mice overexpressing human TDP-43; and in a transgenic mouse model of ALS expressing a mutant form of TDP-43. Not only did the two proteins cling together in brain extracts, they were also spotted together within the motor cortices of mice overexpressing TDP-43.

Notably, the researchers also detected complexes of TDP-43 and TREM2 in spinal-cord lysates from people who had died with ALS.

Using computational simulations based on the structural characteristics of each protein, researchers predicted how they likely interact: The TREM2 extracellular domain latches onto residues 333-402 in the low-complexity domain of TDP-43.

In all, the findings raise the possibility that via TREM2, microglia sense extracellular forms of TDP43 spewed out by sick neurons. Once activated, TREM2 signals microglia to transform into a state reminiscent of disease-associated microglia found in other neurodegenerative models. It remains to be seen how different mutations in TREM2, including those tied to neurodegenerative disease, may influence TDP-43 binding.

“The study opens a new exciting area of investigation, which will be important to follow up and expand,” Chen and Colonna wrote. However, they offered some notes of caution, pointing out that it is still up for debate whether TREM2 is a risk gene for ALS, and in the study that did find a link, it was the R47H variant that boosted ALS risk. However, none of the findings in the current study implicate the R47 residue in the interaction between TREM2 and TDP-43. “Future studies to verify this interaction with crystal structure analysis will be important,” they wrote.—Jessica Shugart


  1. In this new study, Xie et al. report a novel role for TREM2 in microglial responses in an AAV-expressed, human TDP-43 model of amyotrophic lateral sclerosis (ALS), and they provide evidence of physical interactions between TREM2 and TDP-43. The authors propose that this interaction occurs during phagocytosis and show supporting biochemical evidence with various techniques. Overall, this interesting publication proposes a novel role for TREM2 and TREM2-mediated microglia activation in ALS pathology. Importantly, the physical interaction between TREM2 and TDP-43 potentially points to a new therapeutic application for anti-TREM2 antibodies currently being tested for Alzheimer’s disease.

    The study opens an exciting area of investigation that will be important to follow up and expand upon. Some notes of caution should be considered. It is important to note that whether TREM2 is a risk factor for ALS is still under debate (Lill et al., 2015; Cady et al., 2014). In the study that reported TREM2 as a risk factor, ALS was associated with the loss-of-function mutation R47H (Cady et al., 2014). However, neither the mass-spectra results, nor the molecular dynamics simulation in silico in this publication suggest the involvement of R47 residue in the interaction between TREM2 and TDP-43. Nevertheless, the surface plasmon resonance and co-immunoprecipitation data support the idea that TREM2 can bind to TDP-43 directly. Future studies to verify this interaction with crystal structure analysis will be important to resolve the discrepancy between binding and genetic risk.

    The authors also show that TDP-43 GFP+ puncta engulfed in the Iba1+ microglia co-localize with TREM2 puncta. This experiment provides suggestive in vivo evidence of physical interactions between TREM2 and TDP-43 that should be validated in the future with other independent approaches, as well as in other ALS models.


    . The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease. Alzheimers Dement. 2015 Dec;11(12):1407-1416. Epub 2015 Apr 30 PubMed.

    . TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 2014 Apr;71(4):449-53. PubMed.

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News Citations

  1. Microglia in ALS: Helpful, Harmful, or Neutral?

Paper Citations

  1. . Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis. Science. 2019 Apr 5;364(6435):89-93. PubMed.
  2. . TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 2014 Apr;71(4):449-53. PubMed.
  3. . TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Mol Neurodegener. 2013 Jun 21;8:19. PubMed.
  4. . TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol. 2008 Nov;65(11):1481-7. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat Neurosci. 2022 Jan;25(1):26-38. Epub 2021 Dec 16 PubMed.