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

被引：133

作者：

Konttinen, Henna ^{[1
]}

Cabral-da-Silva, Mauricio e Castro ^{[2
]}

Ohtonen, Sohvi ^{[1
]}

Wojciechowski, Sara ^{[1
]}

Shakirzyanova, Anastasia ^{[1
]}

Caligola, Simone ^{[3
]}

Giugno, Rosalba ^{[3
]}

Ishchenko, Yevheniia ^{[1
]}

Hernandez, Damian ^{[4
,5
,6
]}

Fazaludeen, Mohammad Feroze ^{[1
]}

Eamen, Shaila ^{[1
]}

Budia, Mireia Gomez ^{[1
]}

Fagerlund, Ilkka ^{[1
]}

Scoyni, Flavia ^{[1
]}

Korhonen, Paula ^{[1
]}

Huber, Nadine ^{[1
]}

Haapasalo, Annakaisa ^{[1
]}

Hewitt, Alex W. ^{[4
,5
,7
]}

Vickers, James ^{[8
]}

Smith, Grady C. ^{[2
]}

Oksanen, Minna ^{[1
]}

Graff, Caroline ^{[9
,10
]}

Kanninen, Katja M. ^{[1
]}

Lehtonen, Sarka ^{[1
]}

Propson, Nicholas ^{[11
,12
]}

Schwartz, Michael P. ^{[13
]}

Pebay, Alice ^{[4
,5
,6
]}

Koistinaho, Jari ^{[1
,14
]}

Ooi, Lezanne ^{[2
]}

Malm, Tarja ^{[1
]}

机构：

[1] Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio 70211, Finland

[2] Univ Wollongong, Illawarra Hlth & Med Res Inst, Sch Chem & Mol Biosci, Wollongong, NSW 2522, Australia

[3] Univ Verona, Dept Comp Sci, I-37134 Verona, Italy

[4] Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic 3002, Australia

[5] Univ Melbourne, Dept Surg, Melbourne, Vic 3002, Australia

[6] Univ Melbourne, Dept Anat & Neurosci, Melbourne, Vic 3002, Australia

[7] Univ Tasmania, Sch Med, Menzies Inst Med Res, Hobart, Vic 7005, Australia

[8] Univ Tasmania, Wicking Dementia Res & Educ Ctr, Hobart, Tas 7000, Australia

[9] Karolinka Inst, Dept NVS, Div Neurogeriatr, S-17176 Stockholm, Sweden

[10] Karolinska Univ Hosp Solna, Theme Aging Genet Unit, S-17176 Stockholm, Sweden

[11] Baylor Coll Med, Dept Mol & Cell Biol, Houston, TX 77030 USA

[12] Baylor Coll Med, Huffington Ctr, Houston, TX 77030 USA

[13] Univ Wisconsin Madison, Dept Chem, Madison, WI 53706 USA

[14] Univ Helsinki, Neurosci Ctr, FIN-00014 Helsinki, Finland

来源：

STEM CELL REPORTS | 2019年 / 13卷 / 04期

基金：

欧盟地平线“2020”; 英国医学研究理事会; 芬兰科学院; 澳大利亚国家健康与医学研究理事会; 澳大利亚研究理事会;

关键词：

PLURIPOTENT STEM-CELLS; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; BETA; DIFFERENTIATION; MODEL; HEMATOPOIESIS; PRESENILIN-1; MACROPHAGES; ACTIVATION;

D O I：

10.1016/j.stemcr.2019.08.004

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1 Delta E9, 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 PSEN1 Delta E9 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.

引用

页码：669 / 683

页数：15

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