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Modeling Neurodegenerative Microenvironment Using Cortical Organoids Derived from Human Stem Cells.


ABSTRACT: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, mini-brain tissues called organoids have been derived from human induced pluripotent stem cells (hiPSCs) for modeling human brain development and neurological diseases. Thus, the objective of this research is to model and characterize neural degeneration microenvironment using three-dimensional (3D) forebrain cortical organoids derived from hiPSCs and study the response to the drug treatment. It is hypothesized that the 3D forebrain organoids derived from hiPSCs with AD-associated genetic background may partially recapitulate the extracellular microenvironment in neural degeneration. To test this hypothesis, AD-patient derived hiPSCs with presenilin-1 mutation were used for cortical organoid generation. AD-related inflammatory responses, matrix remodeling and the responses to DAPT, heparin (completes with heparan sulfate proteoglycans [HSPGs] to bind A?42), and heparinase (digests HSPGs) treatments were investigated. The results indicate that the cortical organoids derived from AD-associated hiPSCs exhibit a high level of A?42 comparing with healthy control. In addition, the AD-derived organoids result in an elevated gene expression of proinflammatory cytokines interleukin-6 and tumor necrosis factor-?, upregulate syndecan-3, and alter matrix remodeling protein expression. Our study demonstrates the capacity of hiPSC-derived organoids for modeling the changes of extracellular microenvironment and provides a potential approach for AD-related drug screening.

SUBMITTER: Yan Y 

PROVIDER: S-EPMC6033307 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Modeling Neurodegenerative Microenvironment Using Cortical Organoids Derived from Human Stem Cells.

Yan Yuanwei Y   Song Liqing L   Bejoy Julie J   Zhao Jing J   Kanekiyo Takahisa T   Bu Guojun G   Zhou Yi Y   Li Yan Y  

Tissue engineering. Part A 20180227 13-14


Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, mini-brain tissues called organoids have been derived from human induced pluripotent stem cells (hiPSCs) for modeling human brain development and neurological diseases. Thus, the objective of this research is to model and characterize neural degeneration microenvironm  ...[more]

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