. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017 Aug 10;170(4):649-663.e13. PubMed.


Please login to recommend the paper.


  1. In this extremely exciting paper, the Colonna lab shows that TREM2-deficient, dysfunctional microglia can be therapeutically modulated to regain their original defense mechanisms. Ulland and colleagues show this by restoring energy supply via stimulation of an alternative signaling pathway similar to TREM2. Apparently this also allows the microglia to switch at least partially from a locked homoeostatic state (Mazaheri et al., 2017) to a biologically active defense state.

    This even reduces neuritic dystrophies around amyloid plaques, although plaque load itself remains unchanged. The function of TREM2 in amyloid plaque clearance therefore still remains unclear, and may have to be resolved in more physiological animal models with less aggressive amyloid plaque pathology.  

    Excitingly, TREM2 seems to be located in a central signaling pathway for microglial energy metabolism. The latter is consistent with our recent findings demonstrating reduced FDG-µPET signals in TREM2 p.T66M mice (Figure 1; Kleinberger et al., 2017; see also May 2017 news). 

    Figure 1. Reduced FDG signal in several brain areas in TREM2 p.T66M knock-in mice at 12 months of age when compared to age- and sex-matched wild-type controls. [Courtesy of Kleinberger et al., 2017.]

    All together, these data suggest a major defense function of microglia during disease development. This is also supported by the finding that microglia become activated during healthy aging (Kleinberger et al., 2017); and by the fact that TREM2 is upregulated around amyloid plaques.

    This is in line with the finding of increased levels of sTREM2 in CSF of aging people, which are even further enhanced during disease progression (Suárez-Calvet et al., 2016; Suárez-Calvet et al., 2016). 


    . TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 2017 Jul;18(7):1186-1198. Epub 2017 May 8 PubMed.

    . The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017 Jul 3;36(13):1837-1853. Epub 2017 May 30 PubMed.

    . Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. Sci Transl Med. 2016 Dec 14;8(369):369ra178. PubMed.

    View all comments by Gernot Kleinberger
  2. This is an exciting paper showing a novel molecular mechanism by which TREM2 alters microglial metabolism. Although we know that TREM2 mutations associated with AD change microglial proliferation and survival, and contribute to plaque build-up and neuron injury, we have limited understanding of the cellular signaling responses in normal or TREM2-deficient microglial to fully explain the increase in AD.

    This study shows microglia expressing TREM2 successfully increase mTOR signaling in response to a variety of cellular stresses, thus allowing cells to have metabolic flexibility during times of stress. In the absence of TREM2, the microglia fail to upregulate mTOR and instead have activation of dysregulated autophagy, leading to decreased ability to have glycolytic capacity.

    Interestingly, the data supports a tonic TREM2 signal needed for basal mTOR activation, and during cellular stress there appears to be an increased requirement for TREM2-induced mTOR to allow microglial proliferation and survival. Thus, the stressed microglial cells become increasingly dysfunctional because of the loss of metabolic flexibility.

    Dysregulated mTOR is already known to play a role in AD, Down’s syndrome, Huntington’s chorea, and other neurological disorders, but has not previously been linked to TREM2.

    Interestingly, the authors show that bypassing TREM2 by providing a direct energy analog, cyclocreatine, can rescue the abnormal TREM2-deficient microglial dysfunction in vitro and limit neuronal dystrophy in response to Aβ plaques in an AD mouse model. This is exciting data, but as the authors correctly point out, additional studies are needed before cyclocreatine is used in patients with AD as patients may experience a variety of health problems, including changes in blood glucose, muscle cramping, and weight gain. Additionally, cyclocreatine may interact with commonly used medications.  However, these results will may pave the way for new treatment options to prevent or treat AD. 

    View all comments by Mary Beth Humphrey
  3. This is an interesting paper that uncovers an unexpected molecular mechanism linking TREM2 deficiency to microglia metabolic state through the mTOR pathway. It is interesting that the metabolic-deficient phenotype is mostly seen in microglia that are clustering around amyloid plaques but less so in those not engaged with plaques. This suggests that the state of activation of microglia (associated with upregulation of TREM2) and their polarization toward plaques may be energetically demanding and renders these cells more susceptible to homeostatic disruptions.

    We have recently reported that the polarization of microglial processes toward plaques, leading to their encapsulation, is a very important function independent of phagocytosis. Plaque encapsulation modifies the degree of plaque compaction (and thus their toxicity), and by insulating plaques from adjacent neuronal processes acts as a neuroprotective barrier (Condello et al., 2015; Yuan et al., 2016; Wang et. al. 2016). 

    We found that TREM2 deficiency in mice or the R47H variant in humans lead to reduced plaque encapsulation, which changes amyloid fiber conformation to a less compact and potentially more toxic one. Indeed, we found that this was associated with a marked increase in axonal dystrophy and tau hyperphosphorylation around plaques that have deficient microglia encapsulation, suggesting that the loss of microglia’s protective function led to increased neuronal process injury.

    Consistent with this view, Ulland et al. found that the reduced clustering of microglia around plaques is associated with increased axonal dystrophy and that the administration of cyclocreatine to ameliorate the metabolic deficit in microglia improves clustering and reduces axonal dystrophy.

    Overall, this study provides a novel mechanism explaining the failure of microglia plaque engagement in TREM2 mutants. A similar metabolic deficit could occur in aging, where we have shown that microglia plaque encapsulation becomes deficient and axonal dystrophy is increased (Condello et al., 2015). Thus, this paper could have implications beyond TREM2 mutants, for the highly prevalent late-onset AD. 


    . Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat Commun. 2015 Jan 29;6:6176. PubMed.

    . TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron. 2016 May 18;90(4):724-39. PubMed.

    . TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016 May 2;213(5):667-75. Epub 2016 Apr 18 PubMed.

    View all comments by Jaime Grutzendler

Make a Comment

To make a comment you must login or register.

This paper appears in the following:


  1. Without TREM2, Microglia Run Out of Gas


  1. TREM2 R62H
  2. TREM2 R47H

Research Models

  1. Trem2 KO (Colonna) x 5XFAD