Konttinen H, Cabral-da-Silva ME, Ohtonen S, Wojciechowski S, Shakirzyanova A, Caligola S, Giugno R, Ishchenko Y, Hernández D, Fazaludeen MF, Eamen S, Budia MG, Fagerlund I, Scoyni F, Korhonen P, Huber N, Haapasalo A, Hewitt AW, Vickers J, Smith GC, Oksanen M, Graff C, Kanninen KM, Lehtonen S, Propson N, Schwartz MP, Pébay A, Koistinaho J, Ooi L, Malm T. PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia. Stem Cell Reports. 2019 Oct 8;13(4):669-683. Epub 2019 Sep 12 PubMed.

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  1. Konttinen et al. have developed another microglia protocol based on human iPSC-derived primitive (but not definitive) erythromyeloid progenitors induced by hypoxia. The protocol is similar to but slightly simpler than that described by Abud and colleagues (Abud et al., 2017), resulting in a similar transcriptomic profile of microglia. Konttinen et al. have differentiated 16 lines, indicating the method is robust.

    As it’s known from primary human brain transcriptomic data (Zhang et al., 2016), APP and PSEN1 are not specifically expressed in microglia but are in neurons and oligodendrocytes. Thus, it is expected that those genotypes would not affect many microglial assays. However, APOE shows glial-specific expression and its protein levels differ by APOE genotype both in astrocytes and microglia (TCW et al., 2019). Therefore, it could influence multiple glial functions including phagocytosis.

    I would like to emphasize that human and mouse microglia may behave quite differently based on the authors’ finding that the APOE4 genotype in human microglia impairs migration and phagocytosis, while expressing the human APOE4 gene in mouse microglia increases migration (the opposite result for the same scratch assay/wound density measurement) and enhances phagocytosis (Muth et al., 2019). We would further need to compare human and mouse microglia side by side to figure out what causes these differences.

    An interesting functional finding of this paper in terms of APOE4 in human microglia is that APOE4 did not affect calcium transients but did lower oxygen consumption rate similar to LPS stimulation. On the assumption that there is no uptake on external APOE-lipids, it will be interesting to investigate what causes mitochondrial dysfunction by APOE4 genotype.

    References:

    Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CH, Newman SA, Yeromin AV, Scarfone VM, Marsh SE, Fimbres C, Caraway CA, Fote GM, Madany AM, Agrawal A, Kayed R, Gylys KH, Cahalan MD, Cummings BJ, Antel JP, Mortazavi A, Carson MJ, Poon WW, Blurton-Jones M. iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron. 2017 Apr 19;94(2):278-293.e9. PubMed.

    Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, Vogel H, Steinberg GK, Edwards MS, Li G, Duncan JA 3rd, Cheshier SH, Shuer LM, Chang EF, Grant GA, Gephart MG, Barres BA. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron. 2016 Jan 6;89(1):37-53. Epub 2015 Dec 10 PubMed.

    Tcw J, Qian L, Pipalia NH, Chao MJ, Liang SA, Shi Y, Jain BR, Bertelsen SE, Kapoor M, Marcora E, Sikora E, Andrews EJ, Martini AC, Karch CM, Head E, Holtzman DM, Zhang B, Wang M, Maxfield FR, Poon WW, Goate AM. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. 2022 Jun 23;185(13):2213-2233.e25. PubMed. BioRxiv.

    Muth C, Hartmann A, Sepulveda-Falla D, Glatzel M, Krasemann S. Phagocytosis of Apoptotic Cells Is Specifically Upregulated in ApoE4 Expressing Microglia in vitro. Front Cell Neurosci. 2019;13:181. Epub 2019 May 3 PubMed.

    View all comments by Julia TCW

  2. Konttinen and coworkers add to the rapidly growing body of work examining the effect of AD risk factors using induced human microglia derived from iPSCs. The observed reductions in phagocytosis and increased inflammatory cytokine production in APOE4 microglia echo the recent report from Lin, Seo, and colleagues that found APOE4 reduced Aβ42 uptake and increased inflammatory gene expression pathways (Lin et al., 2018). Similar enhancements of inflammatory signaling by APOE4 have also previously been described using primary microglia obtained from APOE3 or APOE4 targeted replacement mice (Vitek et al., 2009). 

    The effect of APOE isoform on microglial metabolism is an interesting aspect of this study. Ulland, Song and colleagues reported TREM2 knockout reduced glycolysis and mitochondrial mass in microglia in 5xFAD mice, indicating that glycolytic activation of microglia could play an important role in the microglial response to AD pathology (Ulland et al., 2017). It would be interesting to know how APOE genotype would influence the microglial metabolism in response to stimuli more associated with neurodegenerative disease, such as myelin debris or dead/dying neurons.

    References:

    Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018 Jun 27;98(6):1141-1154.e7. Epub 2018 May 31 PubMed.

    Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. 2009 Sep;30(9):1350-60. PubMed.

    Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Zhou Y, Cairns NJ, Kambal A, Loginicheva E, Gilfillan S, Cella M, Virgin HW, Unanue ER, Wang Y, Artyomov MN, Holtzman DM, Colonna M. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017 Aug 10;170(4):649-663.e13. PubMed.

    View all comments by Jason Ulrich

  3. In their article, Konttinen et al. write: "[E]xact mechanisms underlying human APOE4-induced inflammatory phenotype in AD microglia remain incompletely defined." Their study and several other recent publications suggest a strong possibility of a cell-autonomous—potentially intracellular—mechanism. Here is one worth considering: Parcon et al., 2018, "Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs."

    References:

    Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Liu L, Shmookler Reis RJ, Barger SW, Mrak RE, Griffin WS. Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimers Dement. 2018 Feb;14(2):230-242. Epub 2017 Sep 22 PubMed.

    View all comments by Steve Barger

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