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Three-dimensional real time imaging of amyloid ? aggregation on living cells.

ABSTRACT: Alzheimer's disease (AD) is a progressive disorder of the brain that gradually decreases thinking, memory, and language abilities. The aggregation process of amyloid ? (A?) is a key step in the expression of its neurocytotoxicity and development of AD because A? aggregation and accumulation around neuronal cells induces cell death. However, the molecular mechanism underlying the neurocytotoxicity and cell death by A? aggregation has not been clearly elucidated. In this study, we successfully visualized real-time process of A?₄₂ aggregation around living cells by applying our established QD imaging method. 3D observations using confocal laser microscopy revealed that A?₄₂ preferentially started to aggregate at the region where membrane protrusions frequently formed. Furthermore, we found that inhibition of actin polymerization using cytochalasin D reduced aggregation of A?₄₂ on the cell surface. These results indicate that actin polymerization-dependent cell motility is responsible for the promotion of A?₄₂ aggregation at the cell periphery. 3D observation also revealed that the aggregates around the cell remained in that location even if cell death occurred, implying that amyloid plaques found in the AD brain grew from the debris of dead cells that accumulated A?₄₂ aggregates.

SUBMITTER: Kuragano M

PROVIDER: S-EPMC7297742 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Three-dimensional real time imaging of amyloid β aggregation on living cells.

Kuragano Masahiro M Yamashita Ryota R Chikai Yusaku Y Kitamura Ryota R Tokuraku Kiyotaka K

Scientific reports 20200616 1

Alzheimer's disease (AD) is a progressive disorder of the brain that gradually decreases thinking, memory, and language abilities. The aggregation process of amyloid β (Aβ) is a key step in the expression of its neurocytotoxicity and development of AD because Aβ aggregation and accumulation around neuronal cells induces cell death. However, the molecular mechanism underlying the neurocytotoxicity and cell death by Aβ aggregation has not been clearly elucidated. In this study, we successfully vis ...[more]

PMID: 32546691

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Project description:Three-dimensional (3D) cell cultivation is a powerful technique for monitoring and understanding diverse cellular mechanisms in developmental cancer and neuronal biology, tissue engineering, and drug development. 3D systems could relate better to in vivo models than two-dimensional (2D) cultures. Several factors, such as cell type, survival rate, proliferation rate, and gene and protein expression patterns, determine whether a particular cell line can be adapted to a 3D system. The 3D system may overcome some of the limitations of 2D cultures in terms of cell-cell communication and cell networks, which are essential for understanding differentiation, structural organization, shape, and extended connections with other cells or organs. Here, the effect of the anticancer drug cisplatin, also known as cis-diamminedichloroplatinum (II) or CDDP, on adenosine triphosphate (ATP) generation was investigated using 3D spheroid-forming cells and real-time monitoring for 7 days. First, 12 cell lines were screened for their ability to form 3D spheroids: prostate (DU145), testis (F9), embryonic fibroblast (NIH-3T3), muscle (C2C12), embryonic kidney (293T), neuroblastoma (SH-SY5Y), adenocarcinomic alveolar basal epithelial cell (A549), cervical cancer (HeLa), HeLa contaminant (HEp2), pituitary epithelial-like cell (GH3), embryonic cell (PA317), and osteosarcoma (U-2OS) cells. Of these, eight cell lines were selected: NIH-3T3, C2C12, 293T, SH-SY5Y, A549, HeLa, PA317, and U-2OS; and five underwent real-time monitoring of CDDP cytotoxicity: HeLa, A549, 293T, SH-SY5Y, and U-2OS. ATP generation was blocked 1 day after addition of 50 μM CDDP, but cytotoxicity in HeLa, A549, SH-SY5Y, and U-2OS cells could be visualized only 4 days after treatment. In 293T cells, CDDP failed to kill entirely the culture and ATP generation was only partially blocked after 1 day. This suggests potential CDDP resistance of 293T cells or metabolic clearance of the drug. Real-time monitoring and ATP measurements directly confirmed the cytotoxicity of CDDP, indicating that CDDP may interfere with mitochondrial activity.

Dataset Information

Three-dimensional real time imaging of amyloid ? aggregation on living cells.

Publications

Three-dimensional real time imaging of amyloid β aggregation on living cells.

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