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Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure
Open accessAbstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti‐AD drugs in the past decades. However, all drug development programs for disease‐modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)‐derived 3D brain organoids. Because the blood–brain barrier (BBB) leakage is a well‐known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum‐exposed brain organoids are able to recapitulate AD‐like pathologies, including increased amyloid beta (A β ) aggregates and phosphorylated microtubule‐associated tau protein (p‐Tau) level, synaptic loss, and impaired neural network. Serum exposure increases A β and p‐Tau levels through inducing beta‐secretase 1 (BACE) and glycogen synthase kinase‐3 alpha / beta (GSK3 α / β ) levels, respectively. In addition, single‐cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid‐based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future.
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“To mimic BBB leakage-induced sporadic AD, human induced pluripotent stem cell (hiPSC)-derived brain organoids (BOs, composed of neurons and astrocytes) were exposed to serum to recapitulate AD-like pathologies (Figure 3I).31”
From Reverse the progression of Alzheimer’s disease through Nano-ERASER-based adult neuroregeneration (2026) · cites this paper as [31]
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Metadata
- Authors
- Chen, X., Sun, G., Tian, E., Zhang, M., Davtyan, H., Beach, T. G., Reiman, E. M., Blurton‐Jones, M., Holtzman, D. M., & Shi, Y.
- Affiliations
- City Of Hope National Medical Center (US)
- University of California, Irvine (US)
- Banner Sun Health Research Institute (US)
- Banner Alzheimer’s Institute (US)
- Department of Neurobiology & Behavior Institute for Memory Impairments & Neurological Disorders and Sue & Bill Gross Stem Cell Research Center University of California Irvine Irvine CA 92697 USA
- Washington University in St. Louis (US)
- Corresponding author
- Shi, Yanhong
- ORCID
- Venue
- Advanced Science
- Publisher
- Wiley
- Published
- 2021-08-02
- Volume
- 8
- Issue
- 18
- Pages
- e2101462-e2101462
- ISSN
- 2198-3844 (ISSN-L)
- PMC
- PMC8456220
- OpenAlex
- W3190034604
- Cited by
- 200
- References
- 71
- Citations by year
- 2026: 32 · 2025: 49 · 2024: 48 · 2023: 44 · 2022: 24 · 2021: 3
- FWCI
- 18.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Advanced Science (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (R01AG056305, P30AG019610, RF1AG061794, R56AG061171, P30AG066519, R01AG056303)
- National Institute on Drug Abuse (RF1DA048813)
- National Cancer Institute (P30CA033572)
- National Institute of Neurological Disorders and Stroke (U24NS072026)
- Louise and Herb Horvitz Charitable Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- sporadic Alzheimer's disease, brain organoids, human induced pluripotent stem cells, serum exposure, blood-brain barrier disruption, amyloid-beta, tau phosphorylation, beta-secretase 1, glycogen synthase kinase-3, synaptic loss, disease modeling, single-cell transcriptomics
- MeSH terms
- Alzheimer Disease, Brain, Humans, Organoids, Induced Pluripotent Stem Cells
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