RRC ID 73990
著者 Takata M, Nishimura K, Harada K, Iwasaki R, Ando M, Yamada S, Ginhoux F, Takata K.
タイトル Analysis of Aβ-induced neurotoxicity and microglial responses in simple two- and three-dimensional human iPSC-derived cortical culture systems.
ジャーナル Tissue Cell
Abstract The extracellular accumulation of amyloid-β (Aβ) in plaques and associated neurodegeneration are the pathological hallmarks of Alzheimer's disease (AD). These plaques are surrounded by microglia-the resident tissue macrophages of the brain parenchyma that originate from primitive macrophages from the embryonic yolk sac. Microglia, including a unique subpopulation called "disease-associated microglia" (DAM), are strongly implicated in AD pathology; however, their exact function and physiology remain largely unknown. Notably, simple cell and tissue culture systems that adequately recreate the brain microenvironment and can simulate critical aspects of AD pathology could fundamentally contribute to elucidating microglial function in disease development and progression. Thus, we added human-induced pluripotent stem cell (hiPSC)-induced primitive macrophages (hiMacs) to hiPSC-induced cortical neurons (cell model) and cortical organoids (tissue model). The treatment of these culture systems with the O-acyl isopeptide of Aβ1-42, which reverts to natural extracellular Aβ1-42 at neutral pH and starts self-aggregation, caused the degeneration of hiPSC-induced cortical neurons in 2D culture and within cortical organoid cultures. Notably, the hiMacs phagocytosed extracellular Aβ and exhibited a DAM-like phenotype. In both cell and tissue organoid culture systems, neurodegeneration was attenuated by the addition of hiMacs. Moreover, in cortical organoids, Aβ plaques formed more circular and fewer hotspot-like morphological structures in the vicinity of hiMacs. These findings demonstrate the utility of simple hiPSC-induced cortical cell and tissue culture systems supplemented with hiMacs for elucidating critical aspects of AD pathology, such as microglial function and physiology. Adopting such systems in routine research practice may lead to the development of novel therapeutic strategies for AD.
巻・号 81
ページ 102023
公開日 2023-4-1
DOI 10.1016/j.tice.2023.102023
PII S0040-8166(23)00011-3
PMID 36709697
MeSH Alzheimer Disease* / pathology Amyloid beta-Peptides / metabolism Amyloid beta-Peptides / toxicity Animals Brain / metabolism Humans Induced Pluripotent Stem Cells* / metabolism Mice Mice, Transgenic Microglia / pathology
IF 1.837
リソース情報
ヒト・動物細胞 1231A3(HPS0381)