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PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia

Journal Article


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Abstract


  • Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.

Authors


  •   Konttinen, Henna (external author)
  •   Castro Cabral-da-Silva, Mauricio
  •   Ohtonen, Sohvi (external author)
  •   Wojciechowski, Sara (external author)
  •   Shakirzyanova, Anastasia (external author)
  •   Caligola, Simone (external author)
  •   Giugno, Rosalba (external author)
  •   Ishchenko, Yevheniia (external author)
  •   Hernandez, Damian (external author)
  •   Fazaludeen, Mohammad (external author)
  •   Eamen, Shaila (external author)
  •   Budia, Mireia (external author)
  •   Fagerlund, Ilkka (external author)
  •   Scoyni, Flavia (external author)
  •   Korhonen, Paula (external author)
  •   Huber, Nadine (external author)
  •   Haapasalo, Annakaisa (external author)
  •   Hewitt, Alex W. (external author)
  •   Vickers, James (external author)
  •   Smith, Grady (external author)
  •   Oksanen, Minna (external author)
  •   Graff, Caroline (external author)
  •   Kanninen, Katja (external author)
  •   Lehtonen, Sarka (external author)
  •   Propson, Nicholas (external author)
  •   Schwartz, Michael (external author)
  •   Pebay, Alice (external author)
  •   Koistinaho, Jari (external author)
  •   Ooi, Lezanne
  •   Malm, Tarja (external author)

Publication Date


  • 2019

Citation


  • Konttinen, H., e Castro Cabral-Da-Silva, M., Ohtonen, S., Wojciechowski, S., Shakirzyanova, A., Caligola, S., Giugno, R., Ishchenko, Y., Hernandez, D., Fazaludeen, M., Eamen, S., Budia, M. Gomez., Fagerlund, I., Scoyni, F., Korhonen, P., Huber, N., Haapasalo, A., Hewitt, A. W., Vickers, J., Smith, G. C., Oksanen, M., Graff, C., Kanninen, K. M., Lehtonen, S., Propson, N., Schwartz, M. P., Pebay, A., Koistinaho, J., Ooi, L. & Malm, T. (2019). PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia. Stem Cell Reports, 13 (4), 669-683.

Scopus Eid


  • 2-s2.0-85072708982

Ro Full-text Url


  • https://ro.uow.edu.au/cgi/viewcontent.cgi?article=1946&context=smhpapers1

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/932

Number Of Pages


  • 14

Start Page


  • 669

End Page


  • 683

Volume


  • 13

Issue


  • 4

Place Of Publication


  • United States

Abstract


  • Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.

Authors


  •   Konttinen, Henna (external author)
  •   Castro Cabral-da-Silva, Mauricio
  •   Ohtonen, Sohvi (external author)
  •   Wojciechowski, Sara (external author)
  •   Shakirzyanova, Anastasia (external author)
  •   Caligola, Simone (external author)
  •   Giugno, Rosalba (external author)
  •   Ishchenko, Yevheniia (external author)
  •   Hernandez, Damian (external author)
  •   Fazaludeen, Mohammad (external author)
  •   Eamen, Shaila (external author)
  •   Budia, Mireia (external author)
  •   Fagerlund, Ilkka (external author)
  •   Scoyni, Flavia (external author)
  •   Korhonen, Paula (external author)
  •   Huber, Nadine (external author)
  •   Haapasalo, Annakaisa (external author)
  •   Hewitt, Alex W. (external author)
  •   Vickers, James (external author)
  •   Smith, Grady (external author)
  •   Oksanen, Minna (external author)
  •   Graff, Caroline (external author)
  •   Kanninen, Katja (external author)
  •   Lehtonen, Sarka (external author)
  •   Propson, Nicholas (external author)
  •   Schwartz, Michael (external author)
  •   Pebay, Alice (external author)
  •   Koistinaho, Jari (external author)
  •   Ooi, Lezanne
  •   Malm, Tarja (external author)

Publication Date


  • 2019

Citation


  • Konttinen, H., e Castro Cabral-Da-Silva, M., Ohtonen, S., Wojciechowski, S., Shakirzyanova, A., Caligola, S., Giugno, R., Ishchenko, Y., Hernandez, D., Fazaludeen, M., Eamen, S., Budia, M. Gomez., Fagerlund, I., Scoyni, F., Korhonen, P., Huber, N., Haapasalo, A., Hewitt, A. W., Vickers, J., Smith, G. C., Oksanen, M., Graff, C., Kanninen, K. M., Lehtonen, S., Propson, N., Schwartz, M. P., Pebay, A., Koistinaho, J., Ooi, L. & Malm, T. (2019). PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia. Stem Cell Reports, 13 (4), 669-683.

Scopus Eid


  • 2-s2.0-85072708982

Ro Full-text Url


  • https://ro.uow.edu.au/cgi/viewcontent.cgi?article=1946&context=smhpapers1

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/932

Number Of Pages


  • 14

Start Page


  • 669

End Page


  • 683

Volume


  • 13

Issue


  • 4

Place Of Publication


  • United States