Iyer AK, Vermunt L, Mirfakhar FS, Minaya M, Acquarone M, Koppisetti RK, Renganathan A, You S-F, Danhash E, Verbeck A, Galasso G, Lee SM, Marsh J, Nana AL, Spina S, Seeley WW, Grinberg LT, Temple S, Teunissen CE, Sato C, Karch C. Cell autonomous microglia defects in a stem cell model of frontotemporal dementia. 2024 May 16 10.1101/2024.05.15.24307444 (version 1) medRxiv.

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  1. Microglia in the human brain are not known to develop tau pathology but do play a significant role in propagation of tau pathology in animal models of tauopathy (Asai et al., 2015; Shi et al., 2019; Wang et al., 2022), in corticobasal syndrome (Palleis et al., 2024), and across the FTD spectrum (Bevan-Jones et al., 2020). The functional role of endogenously expressed tau in microglia is underexplored. This study, although limited to one particular FTLD-MAPT mutation, IVS10+16, is a well-controlled investigation of how this mutation impacts iMGL biology in comparison to isogenic iMGL controls.

    Interestingly, the authors detected 3R tau in these MAPT mutant iMGLs, and more 4R tau than in control iMGLs, which is consistant with reports on this mutation (Hutton et al., 1998). MAPT IVS10+16 iMGLs show upregulation of chemokines, downregulation of DAM and LAM genes, reduction of phagocytosis, TREM2 signaling, and energy metabolism.

    These findings were validated by bulk RNA-Seq of human brain tissues isolated from MAPT IVS10+16 mutation carriers and control cases without neuropathological change. Publicly available proteomic datasets from the CSF samples of MAPT carriers and controls show enrichment of protein modules involved in extracellular matrix, complement, adaptive immunity, autophagy, and synapse assembly in symptomatic cases, whereas integrin signaling is more enriched in presymptomatic cases.

    Finally, to determine the biological effect of iMGL on neurons, conditioned media from MAPT IVS10+16 or control iMGLs were applied to iNeurons, which showed reduced synaptic density and increased dendritic length.

    These data support the idea that the MAPT IVS10+16 mutation may alter microglia to be less active and impaired for phagocytosis and energy metabolism. This is consistent with a recent study showing little activation of microglia in FTLD-tau brain (Hartnell et al., 2024). However, the study is inconclusive on whether this is due to the endogenous expression of tau, since they have not tested the effect of silencing MAPT expression on these MAPT IVS10+16 iMGLs.

    It will also be of interest to learn if misfolded tau is found to accumulate in these MAPT mutant microglia. 

    References:

    Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015 Nov;18(11):1584-93. Epub 2015 Oct 5 PubMed.

    Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.

    Wang C, Fan L, Khawaja RR, Liu B, Zhan L, Kodama L, Chin M, Li Y, Le D, Zhou Y, Condello C, Grinberg LT, Seeley WW, Miller BL, Mok SA, Gestwicki JE, Cuervo AM, Luo W, Gan L. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022 Apr 12;13(1):1969. PubMed.

    Palleis C, Franzmeier N, Weidinger E, Bernhardt AM, Katzdobler S, Wall S, Ferschmann C, Harris S, Schmitt J, Schuster S, Gnörich J, Finze A, Biechele G, Lindner S, Albert NL, Bartenstein P, Sabri O, Barthel H, Rupprecht R, Nuscher B, Stephens AW, Rauchmann BS, Perneczky R, Haass C, Brendel M, Levin J, Höglinger GU. Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With β-Amyloid-Negative CBS. Neurology. 2024 Jan 9;102(1):e207901. Epub 2023 Dec 14 PubMed.

    Bevan-Jones WR, Cope TE, Jones PS, Kaalund SS, Passamonti L, Allinson K, Green O, Hong YT, Fryer TD, Arnold R, Coles JP, Aigbirhio FI, Larner AJ, Patterson K, O'Brien JT, Rowe JB. Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain. 2020 Mar 1;143(3):1010-1026. PubMed.

    Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.

    Hartnell IJ, Woodhouse D, Jasper W, Mason L, Marwaha P, Graffeuil M, Lau LC, Norman JL, Chatelet DS, Buee L, Nicoll JA, Blum D, Dorothee G, Boche D. Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology. Brain. 2024 Feb 1;147(2):590-606. PubMed.

    View all comments by Tsuneya Ikezu

  2. Iyer et al. present compelling evidence of MAPT expression and presence of endogenous tau in microglia (iMGLs), utilizing both human brain samples and induced microglia-like cells derived from induced pluripotent stem cells (iPSCs). This finding is significant as it corroborates the limited existing studies that report tau in glial cells.

    Furthermore, this study is notable because most data on the cellular localization of tau and its phagocytosis derive from transgenic mouse models, which exclusively express human tau in neurons. The primary observational results indicate that, in iMGLs derived from iPSCs carrying the MAPT IVS10+16 mutation, TREM2 expression is reduced, resulting in defects in phagocytosis, cytoskeletal organization, endolysosomal function, and metabolic processes in these microglia. Future research should explore the interaction between tau and TREM2 and how MAPT mutations lead to TREM2 downregulation and subsequent cellular phenotypes. 

    View all comments by Kristine Freude

  3. Microtubule-associated protein tau traditionally has been viewed solely as a neuronal protein, pivotal in the progression of neurodegenerative conditions such as Alzheimer’s disease and primary tauopathies. Consequently, our focus has predominantly centered on studying the pathological accumulation of tau in neurons, with any observed changes in microglia being perceived as a downstream response to this neuronal pathology. However, this narrative has never explained why microglial dysregulation often precedes the pathological accumulation of neuronal tau in human disease.

    Here, the research team led by Dr. Celeste Karch at Washington University in St. Louis, Missouri, illuminated a crucial insight into this dilemma: Microglia also express tau protein if its genome carries the MAPT IVS10+16 mutation, which is known to increase 4R tau splice variant expression. The authors show that tau expression in microglia seems to affect normal microglial function and triggers significant transcriptional alterations in important pathways governing microglial function.

    While data from FTD iMGLs show tau expression compared to CRISPR-corrected “control” iMGLs, it is important to consider a few points. First, earlier studies have shown that microglia can cross-seed tau via exosomes, which are known to contain mRNAs (derived from neurons). Therefore, it is important to determine the identity/origin of tau mRNA, especially in microglia isolated for in vivo experiments. Second, we sometimes see that cell confluency may result in the de novo expression of certain neuronal proteins during the maturation steps of deriving iMGLs. Therefore, consideration of aberrant transcription/translational factors driving microglial tau expression may be important. Finally, extensive investigations are warranted to delineate the role of microglia tau “physiological” function (in mutant carriers) thoroughly and to develop a mouse model of (MAPT IVS10+16) FTDs to validate the observed phenotype. It would also be important to determine whether microglial tau expression is specific to this specific splice-site mutation, or whether other intronic/exonic tau mutants/ haplotypes also display such a phenomenon. Nonetheless, this study may have profound implications for the neuroimmune changes in tauopathies.

    View all comments by Karthikeyan Tangavelou

  4. Our current understanding is that tau, encoded by the MAPT gene, is highly enriched in neuronal axons and present at minimal levels in non-neuronal cells. However, in the brains of individuals with FTLD-tau, those inclusions have been detected in glial cells, and they drive glial activation and dysfunction. This underscores the role of tau-inclusion-bearing glia in neurodegenerative diseases (Ezerskiy et al., 2022; Chung et al., 2021).

    Glial cells, especially microglia, are active phagocytes. A critical question is whether glial tau inclusions result from phagocytosed tau released from tau-bearing neurons or from tau expressed intrinsically by glia. By leveraging human iPSC-derived microglia-like cells (iMGLs), the current study demonstrated that microglia express tau mRNA and protein isoforms.

    Furthermore, it reports that if the primary tauopathy MAPT IVS10-16 mutation is expressed by microglia, then it influences their transcriptomic states and alters cell functions in a cell-autonomous manner. Additionally, human iMGLs bearing this mutation regulated neuronal synapses. This pioneering study uncovered cell-autonomous effects of microglia-expressed tau and illuminated the contribution of intrinsically developed tau inclusions in microglia to tau pathogenesis.

    This intriguing research leaves several issues to be addressed by the field:

    1. Tau expression in microglia: Emerging studies support cell-autonomous tau expression in glia, predominantly in astrocytes and oligodendrocytes. Evidence of tau inclusions in microglia is still scarce. However, the current study provides convincing evidence that microglia, whether isolated from the human brain or differentiated from iPSCs (hMGLs), express tau at baseline levels. Does microglial tau expression change with aging or under various tauopathy conditions, including Alzheimer's disease?
    2. The nature of microglial tau: Characterization of microglial tau is needed at the basic cell biology and biochemistry levels, including post-translational modifications, solubility/aggregation, and cellular location. Are these tau species phosphorylated or acetylated at similar sites as neuronal tau? It would be informative to profile the solubility of microglial tau, particularly microglia bearing FTD mutations, compared to neuronal tau. Do these tau species aggregate or form oligomers? Where are these tau species located in microglia, and are they secreted? How do mutations affect these processes? Moreover, Li Gan’s group generated a tau interactome landscape in human iPSC-derived neurons and uncovered tau binding partners involved in diverse cellular processes, including synaptic activity and mitochondrial function (Tracy et al., 2022). It would be intriguing to examine tau interactors in microglia and compare with neuronal tau partners.
    3. Contribution of microglial tau to neuroinflammation: The current study aligns with a recent case report by Richard Bevan-Jones and colleagues, which describes microglial activation in frontotemporal regions lacking tau aggregation or atrophy in a presymptomatic carrier of the IVS10+16 mutation (Bevan-Jones et al. 2019). It is possible that microglial tau with FTD mutations, such as IVS10+16, plays an early role in microglial activation in frontotemporal dementia before neuronal tau inclusions develop. It remains to be investigated how microglia respond to immunogenic tau released from neurons at a more advanced disease stage and how FTD mutations affect this.
    4. Mechanisms of microglial activation: We and others have shown that extracellular tau fibrils activate microglia and induce inflammatory signaling pathways such as TREM2-TYROBP, NFκB, and cGAS-STING, both in vitro and in vivo (Wang et al., 2022; Udeochu et al., 2023; Jin et al., 2021). One underlying mechanism is that, upon entering microglia, neuronal tau triggers the release of mitochondrial DNA, which is sensed by cGAS, leading to the activation of the STING-IFN response. Previous studies have observed diverse cellular and pathological heterogeneity in primary tauopathies, suggesting different mechanisms are involved (Chung et al., 2021). How intrinsically expressed tau activates microglia remains to be determined.

    References:

    Bevan-Jones WR, Cope TE, Jones PS, Passamonti L, Hong YT, Fryer T, Arnold R, Coles JP, Aigbirhio FI, O'Brien JT, Rowe JB. In vivo evidence for pre-symptomatic neuroinflammation in a MAPT mutation carrier. Ann Clin Transl Neurol. 2019 Feb;6(2):373-378. Epub 2019 Jan 2 PubMed.

    Chung DC, Roemer S, Petrucelli L, Dickson DW. Cellular and pathological heterogeneity of primary tauopathies. Mol Neurodegener. 2021 Aug 23;16(1):57. PubMed.

    Ezerskiy LA, Schoch KM, Sato C, Beltcheva M, Horie K, Rigo F, Martynowicz R, Karch CM, Bateman RJ, Miller TM. Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction. JCI Insight. 2022 Jan 11;7(1) PubMed.

    Jin M, Shiwaku H, Tanaka H, Obita T, Ohuchi S, Yoshioka Y, Jin X, Kondo K, Fujita K, Homma H, Nakajima K, Mizuguchi M, Okazawa H. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nat Commun. 2021 Nov 15;12(1):6565. PubMed.

    Tracy TE, Madero-Pérez J, Swaney DL, Chang TS, Moritz M, Konrad C, Ward ME, Stevenson E, Hüttenhain R, Kauwe G, Mercedes M, Sweetland-Martin L, Chen X, Mok SA, Wong MY, Telpoukhovskaia M, Min SW, Wang C, Sohn PD, Martin J, Zhou Y, Luo W, Trojanowski JQ, Lee VM, Gong S, Manfredi G, Coppola G, Krogan NJ, Geschwind DH, Gan L. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell. 2022 Feb 17;185(4):712-728.e14. Epub 2022 Jan 20 PubMed.

    Udeochu JC, Amin S, Huang Y, Fan L, Torres ER, Carling GK, Liu B, McGurran H, Coronas-Samano G, Kauwe G, Mousa GA, Wong MY, Ye P, Nagiri RK, Lo I, Holtzman J, Corona C, Yarahmady A, Gill MT, Raju RM, Mok SA, Gong S, Luo W, Zhao M, Tracy TE, Ratan RR, Tsai LH, Sinha SC, Gan L. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. Nat Neurosci. 2023 May;26(5):737-750. Epub 2023 Apr 24 PubMed.

    Wang C, Fan L, Khawaja RR, Liu B, Zhan L, Kodama L, Chin M, Li Y, Le D, Zhou Y, Condello C, Grinberg LT, Seeley WW, Miller BL, Mok SA, Gestwicki JE, Cuervo AM, Luo W, Gan L. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022 Apr 12;13(1):1969. PubMed.

    View all comments by Wenjie Luo

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