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Sayed FA, Kodama L, Fan L, Carling GK, Udeochu JC, Le D, Li Q, Zhou L, Wong MY, Horowitz R, Ye P, Mathys H, Wang M, Niu X, Mazutis L, Jiang X, Wang X, Gao F, Brendel M, Telpoukhovskaia M, Tracy TE, Frost G, Zhou Y, Li Y, Qiu Y, Cheng Z, Yu G, Hardy J, Coppola G, Wang F, DeTure MA, Zhang B, Xie L, Trajnowski JQ, Lee VM, Gong S, Sinha SC, Dickson DW, Luo W, Gan L. AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation. Sci Transl Med. 2021 Dec;13(622):eabe3947. PubMed.
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Washington University
Previous observations from our lab and others that TREM2 KO, or TREM2 R47H Tg expression on a TREM2 KO background, attenuates neurodegeneration in the P301S model of tauopathy that can be puzzling given that the R47H variant increases the risk of AD. This study identifies an enrichment of “DAM”-like microglia using hTREM2R47H/mTREM2 mice that may more closely model the extent of TREM2 function in human AD TREM2 variant carriers.
As the authors note, several of the genes upregulated and pathways identified by GSEA were related to interferon signaling, which may be distinct from the DAM state that is generally linked with upregulation of things like cathepsins, ApoE, and tetraspanins such as Cd9 and Cd63. Distinctions in interferon states and so-called “activated response microglia (ARMs)” were elegantly demonstrated by Bart DeStrooper’s group and collaborators and by David Hansen’s group among others. Whether dysfunctional TREM2 favors one subdivision of microglial activation that corresponds with tissue damage over another that may limit or respond to damage will be interesting to investigate.
References:
Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee SH, Haddick PC, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP, Hansen DV. Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models. Cell Rep. 2018 Jan 16;22(3):832-847. PubMed.
Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I, Schmidt I, Mancuso R, Chen WT, Woodbury ME, Srivastava G, Möller T, Hudry E, Das S, Saido T, Karran E, Hyman B, Perry VH, Fiers M, De Strooper B. The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques. Cell Rep. 2019 Apr 23;27(4):1293-1306.e6. PubMed.
View all comments by Jason UlrichUniversity of Washington
The effect of sex on AD susceptibility is well established, but the molecular basis for it is not understood. This paper addressed whether an AD risk factor, the R47H allele of the immune receptor TREM2 expressed by microglia, manifests sex-specific molecular phenotypes. Single-nuclei RNA-Seq of R47H carriers with AD identified profound differences in affected gene networks between males and females. Using an elegant mouse model with engineered knock-ins of human TREM2, the common allele and the R47H variant, on the background of an established PS19 model of tauopathy, the study showed an exacerbated immune response in female mice, which was accompanied by memory and spatial learning deficits.
The study corroborates our previous finding of the exaggerated immune response in the brains of AD patients with R47H, particularly an upregulation of pro-inflammatory cytokines and interferon response signatures (Korvatska et al., 2020). Importantly, the exaggerated immune response in the microglia was abolished by pharmacological inhibition of AKT kinase, a downstream effector of TREM2 signaling.
Overall, the paper highlights the importance of analysis of both sexes when performing patient studies or modeling human neurodegenerative pathology in mice.
References:
Korvatska O, Kiianitsa K, Ratushny A, Matsushita M, Beeman N, Chien WM, Satoh JI, Dorschner MO, Keene CD, Bammler TK, Bird TD, Raskind WH. Triggering Receptor Expressed on Myeloid Cell 2 R47H Exacerbates Immune Response in Alzheimer's Disease Brain. Front Immunol. 2020;11:559342. Epub 2020 Sep 25 PubMed.
View all comments by Olena KorvatskaPicower Institute of MIT
MIT
A large number of genetic risk factors have now been identified that alter risk for developing Alzheimer’s disease, however the mechanisms underlying their effects remain elusive in most cases. Cell-type contributions and sex-specific differences add additional layers of complexity. Heterozygous point mutations affecting TREM2 are well established to increase Alzheimer’s risk, and as TREM2 exhibits microglia-specific expression in the brain, provide a clear genetic and cell-type specific source of dysfunction. A large majority of the studies examining TREM2 functions in neurodegeneration, however, have utilized homozygous TREM2 loss-of-function mutations, which in humans cause distinct forms of neurodegeneration (Yeh et al., 2017).
To further our understanding of TREM2-based Alzheimer’s disease, Sayed and colleagues performed a comprehensive examination of both human Alzheimer’s disease tissue and model mice carrying heterozygous TREM2 R47H mutations. They perform the first large-scale, single-nucleus RNA-Seq experiment from TREM2 R47H Alzheimer’s disease patients, identifying sex-specific transcriptional changes and a pro-inflammatory microglia signature.
To complement these postmortem transcriptional studies, the authors also generate heterozygous, humanized TREM2 R47H mice, which they combine with the well-characterized tau P301S model. Surprisingly, Sayed and colleagues find that in contrast to homozygous TREM2 R47H or knockout mutations (Leyns et al., 2017; Gratuze et al., 2020), heterozygous TREM2 R47H mutations exacerbate cognitive deficits and neuron loss in P301S. Moreover, these disease-enhancing effects were observed specifically in female mice, highlighting both sex-specific differences and important differences between heterozygous and homozygous mutations in TREM2.
These latter findings are consistent with an earlier study by the Gan group, showing stronger effects due to heterozygous versus homozygous TREM2 knockout mutations, also in the P301S background (Sayed et al., 2018). Sayed and colleagues further find that heterozygous TREM2 R47H, P301S mice, and microglia isolated from them, exhibit a pro-inflammatory phenotype consistent with their human and mouse sequencing datasets.
The authors also identified a gene-expression signature in human and mouse samples consistent with activation of AKT signaling, which they validated at the protein level in mouse brain tissue. Importantly, they find that inhibition of AKT signaling is capable of reducing inflammation in tau-treated microglia in culture, as well as largely preventing TREM2 R47H-dependent cognitive deficits, synapse loss and gene-expression changes in P301S mice.
Thus, this work suggests a possible node for therapeutic intervention in TREM2 R47H-mediated Alzheimer’s disease, as well as adding further support to the conclusion that TREM2 R47H mutations have unique effects. Indeed, these and other findings suggest that differences likely exist between TREM2 knockout and R47H mutations, between heterozygous and homozygous TREM2 mutations, and between the effects that these mutations have on male versus female mice and humans.
References:
Gratuze M, Leyns CE, Sauerbeck AD, St-Pierre MK, Xiong M, Kim N, Serrano JR, Tremblay MÈ, Kummer TT, Colonna M, Ulrich JD, Holtzman DM. Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration. J Clin Invest. 2020 Sep 1;130(9):4954-4968. PubMed.
Leyns CE, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, Robinson GO, Anderson E, Colonna M, Holtzman DM. 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.
Sayed FA, Telpoukhovskaia M, Kodama L, Li Y, Zhou Y, Le D, Hauduc A, Ludwig C, Gao F, Clelland C, Zhan L, Cooper YA, Davalos D, Akassoglou K, Coppola G, Gan L. 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.
Yeh FL, Hansen DV, Sheng M. TREM2, Microglia, and Neurodegenerative Diseases. Trends Mol Med. 2017 Jun;23(6):512-533. Epub 2017 Apr 22 PubMed.
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