Simple modeling of familial Alzheimer’s disease using human pluripotent stem cell-derived cerebral organoid technology

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Abstract

Background

Cerebral organoids (COs) are the most advanced in vitro models that resemble the human brain. The use of COs as a model for Alzheimer’s disease (AD), as well as other brain diseases, has recently gained attention. This study aimed to develop a human AD CO model using normal human pluripotent stem cells (hPSCs) that recapitulates the pathological phenotypes of AD and to determine the usefulness of this model for drug screening.

Methods

We established AD hPSC lines from normal hPSCs by introducing genes that harbor familial AD mutations, and the COs were generated using these hPSC lines. The pathological features of AD, including extensive amyloid-β (Aβ) accumulation, tauopathy, and neurodegeneration, were analyzed using enzyme-linked immunosorbent assay, Amylo-Glo staining, thioflavin-S staining, immunohistochemistry, Bielschowsky’s staining, and western blot analysis.

Results

The AD COs exhibited extensive Aβ accumulation. The levels of paired helical filament tau and neurofibrillary tangle-like silver deposits were highly increased in the AD COs. The number of cells immunoreactive for cleaved caspase-3 was significantly increased in the AD COs. In addition, treatment of AD COs with BACE1 inhibitor IV, a β-secretase inhibitor, and compound E, a γ-secretase inhibitor, significantly attenuated the AD pathological features.

Conclusion

Our model effectively recapitulates AD pathology. Hence, it is a valuable platform for understanding the mechanisms underlying AD pathogenesis and can be used to test the efficacy of anti-AD drugs.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-024-03732-1.

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Most cited references 54

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Cerebral organoids model human brain development and microcephaly

Madeline Lancaster, Magdalena Renner, Carol-Anne Martin … (2013)

The complexity of the human brain has made it difficult to study many brain disorders in model organisms, and highlights the need for an in vitro model of human brain development. We have developed a human pluripotent stem cell-derived 3D organoid culture system, termed cerebral organoid, which develops various discrete though interdependent brain regions. These include cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNAi and patient-specific iPS cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could explain the disease phenotype. Our data demonstrate that 3D organoids can recapitulate development and disease of even this most complex human tissue.

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The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

Jeff Sevigny, Ping Chiao, Thierry Bussière … (2016)

Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

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Generation of cerebral organoids from human pluripotent stem cells.

Madeline Lancaster, Juergen A. Knoblich (2014)

Human brain development exhibits several unique aspects, such as increased complexity and expansion of neuronal output, that have proven difficult to study in model organisms. As a result, in vitro approaches to model human brain development and disease are an intense area of research. Here we describe a recently established protocol for generating 3D brain tissue, so-called cerebral organoids, which closely mimics the endogenous developmental program. This method can easily be implemented in a standard tissue culture room and can give rise to developing cerebral cortex, ventral telencephalon, choroid plexus and retinal identities, among others, within 1-2 months. This straightforward protocol can be applied to developmental studies, as well as to the study of a variety of human brain diseases. Furthermore, as organoids can be maintained for more than 1 year in long-term culture, they also have the potential to model later events such as neuronal maturation and survival.

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Author and article information

Contributors

Murim Choi: murimchoi@snu.ac.kr

Min Young Lee:

ORCID: http://orcid.org/0000-0003-0067-2803

vetmedic@knu.ac.kr

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 24 April 2024

Publication date PMC-release: 24 April 2024

Publication date Collection: 2024

Volume: 15

Electronic Location Identifier: 118

Affiliations

[1 ]Department of Molecular Physiology, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, ( https://ror.org/040c17130) 41566 Daegu, Republic of Korea

[2 ]Department of Veterinary Anatomy, College of Veterinary Medicine, Chonnam National University, ( https://ror.org/05kzjxq56) 61186 Gwangju, Republic of Korea

[3 ]Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, ( https://ror.org/04h9pn542) 03080 Seoul, Republic of Korea

[4 ]Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), ( https://ror.org/00a8tg325) 01812 Seoul, Republic of Korea

[5 ]Department of Pharmacology, College of Dentistry, Jeonbuk National University, ( https://ror.org/05q92br09) 54896 Jeonju, Republic of Korea

[6 ]Department of Cardiovascular and Neurologic Disease, College of Oriental Medicine, Daegu Haany University, ( https://ror.org/045wr3278) 42158 Daegu, Republic of Korea

[7 ]GRID grid.262229.f, ISNI 0000 0001 0719 8572, Department of Neurology, Pusan National University Yangsan Hospital, , Pusan National University School of Medicine, ; 50612 Yangsan, Republic of Korea

Author information

Min Young Lee http://orcid.org/0000-0003-0067-2803

Article

Publisher ID: 3732

DOI: 10.1186/s13287-024-03732-1

PMC ID: 11040922

PubMed ID: 38659053

SO-VID: e8f93b05-e669-44f6-9322-b1cb246975b3

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 8 May 2023

Date accepted : 12 April 2024

Funding

Funded by: National Research Fund (KR)

Award ID: 2018R1D1A1A02044017

Award ID: 2020R1A5A2017323

Award ID: 2021R1F1A1047379

Award ID: RS-2023-00223069

Award ID: 2023R1A2C2003446

Award ID: RS-2023-00225239

Award Recipient : Hyung-Ryong Kim Min Young Lee

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ScienceOpen disciplines: Molecular medicine

Keywords: cerebral organoids,human pluripotent stem cells,alzheimer’s disease,disease modeling,drug screening

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ScienceOpen disciplines: Molecular medicine

Keywords: cerebral organoids, human pluripotent stem cells, alzheimer’s disease, disease modeling, drug screening

Simple modeling of familial Alzheimer’s disease using human pluripotent stem cell-derived cerebral organoid technology

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Abstract

Background

Methods

Results

Conclusion

Supplementary Information

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Most cited references 54

Cerebral organoids model human brain development and microcephaly

The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

Generation of cerebral organoids from human pluripotent stem cells.

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