. TREM2 function impedes tau seeding in neuritic plaques. Nat Neurosci. 2019 Aug;22(8):1217-1222. Epub 2019 Jun 24 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is an intriguing study highlighting the importance of TREM2 and microglia in curtailing tau pathology. There have been few studies examining TREM2 function in the context of tau pathology, despite numerous findings suggesting a link between tau pathology and TREM2.

    Prior studies examining TREM2 function in tau pathology have reported conflicting results. Bemiller et al. have shown that absence of TREM2 in hTau mice leads to increased tau pathology (Bemiller et al., 2017). However, Leyns et al. showed that absence of TREM2 in PS19 mice ameliorated tau pathology (Leyns et al., 2017). Further complicating the role of TREM2 function in tauopathy, Sayed et al. found that only TREM2 haplo-insufficiency, not complete deficiency, led to increased tau pathology in P301S mice (Sayed et al., 2018). 

    Similar to studies in murine amyloid models, the question of whether TREM2 function promotes or deters progression of AD pathology is complex. In recent years, the variable effect of TREM2 function during different stages of pathology has begun to be elaborated. It is seemingly detrimental during early stages of amyloid deposition and late stages of tau aggregation, while beneficial during late stages of amyloid pathology and early stages of tau aggregation.

    Unique to this study is its examining the contextual and disease progression-dependent effect of TREM2 function with input from both tau and amyloid pathology. This study argues TREM2 is essential in mitigating tau seeding and spreading. The authors suggest this is due to the ability of TREM2 to direct microglia to contain amyloid plaques. This is supported by analysis of plaques in TREM2 AD risk variant carriers showing increased AT8 staining within the plaque microenvironment.

    This brief communication does not distinguish whether tau spreading in the context of reduced TREM2 function is TREM2-dependent or mediated by microglia or other cells. To ascertain regional specificity, future examination of tau spreading to other brain regions and/or injection of pathological tau into other brain regions will further bolster the findings of this report. In-depth analysis of these regions will help tackle whether global changes such as inflammatory profiles induce mouse tau aggregation or if microenvironment changes induce tau spreading.

    It will also be interesting to determine how soluble tau is impacted in this model since soluble tau has also been reported to have detrimental effects on neurons (Bolos et al., 2017). The effect on other tau epitopes should also further highlight the important role of microglia and TREM2 in limiting amyloid and tau pathology.

    —Stephanie Bissel and Tyler McCray also contributed to this comment.

    References:

    . TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener. 2017 Oct 16;12(1):74. PubMed.

    . TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11524-11529. Epub 2017 Oct 9 PubMed.

    . Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10172-10177. Epub 2018 Sep 19 PubMed.

    . Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons. Transl Psychiatry. 2017 Dec 8;7(12):1267. PubMed.

  2. This is a very exciting study because these data demonstrated a crucial role of TREM2 in modulating the interplay between amyloid plaques and tau pathology. Since the identification of Alzheimer’s disease (AD) associated TREM2 variants in 2013, major progress has been made in understanding the function of TREM2 in response to amyloid pathology. We now know that TREM2 signaling is critical in modulating microglia survival and activation (Wang et al., 2015; Ulland et al., 2017). TREM2 deficiency leads to impaired microglia response to amyloid plaques (Ulrich et al., 2014Wang et al, 2015; Jay et al., 2015), leading to reduced compaction of Aβ and increased formation of dystrophic neurites (DNs) (Wang et al., 2016; Yuan et al., 2016). However, the downstream effect of this altered amyloid pathology remains elusive.

    It has been recently demonstrated that DNs are one of the major sites of tau pathology when human AD seeds were injected into APP transgenic mice (He et al., 2018). In this study, the Holtzman laboratory investigated whether microglia can regulate this process. Leyns et al. injected AD tau seeds into APPPS1 mice that are deficient in TREM2 or APPPS1 mice that only express human R47H TREM2, a loss-of-function variant associated with AD (Song et al., 2018). Both TREM2 deficiency and TREM2 R47H significantly increased levels of hyperphosphorylated AT8+ neuritic tau around amyloid plaques. A strong correlation between AT8+ neurites and BACE1+ DNs were also observed, confirming DNs as favorable sites for tau seeding. Importantly, these data indicate that TREM2 plays a protective role in limiting amyloid plaque-mediated tau seeding. Consistently, Leyns et al. also demonstrated that peri-plaque tau pathology is also increased in the postmortem AD brains of individuals with TREM2 mutations.

    While these data illustrate a critical function of microglia in limiting the formation of neuritic tau pathology, it is unclear if the development of other forms of tau pathologies besides neuritic tau are affected by TREM2 deficiency, particularly the formation of neurofibrillary tangles (NFTs) as a result of secondary seeding events (He et al., 2018). It would be helpful to understand if TREM2 deficiency will also increase NFTs in different brain regions at later time points. In addition, tau seeding in older animals could be explored to understand whether TREM2 has an impact on the development of other axonal-related tau pathology, such as the neuropil threads (NTs) in this model. This would be interesting given that TREM2 modulates microglia response in axonal-rich regions, such as corpus callosum, in the context of aging and white matter insults  (Poliani et al., 2015). 

    This study further stresses the complexity of microglia response during tau pathogenesis. In an earlier study, the Holtzman laboratory demonstrated TREM2 deficiency protects against neurodegeneration without affecting tau pathology in PS19 tau transgenic mice (Leyns et al., 2017), suggesting excessive TREM2 activation could be potentially damaging as tau pathology progresses. Further studies are required to understand the overall impact of microglia on tauopathy and neurodegeneration.

    References:

    . TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015 Mar 12;160(6):1061-71. Epub 2015 Feb 26 PubMed.

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

    . Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener. 2014 Jun 3;9:20. PubMed.

    . TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med. 2015 Mar 9;212(3):287-95. Epub 2015 Mar 2 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.

    . 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.

    . Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018 Jan;24(1):29-38. Epub 2017 Dec 4 PubMed.

    . Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med. 2018 Mar 5;215(3):745-760. Epub 2018 Jan 10 PubMed.

    . TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest. 2015 May;125(5):2161-70. Epub 2015 Apr 20 PubMed.

    . TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11524-11529. Epub 2017 Oct 9 PubMed.

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. TREM2, Microglia Dampen Dangerous Liaisons Between Aβ and Tau