TY - JOUR
T1 - Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure
AU - Chen, Xianwei
AU - Sun, Guoqiang
AU - Tian, E.
AU - Zhang, Mingzi
AU - Davtyan, Hayk
AU - Beach, Thomas G.
AU - Reiman, Eric M.
AU - Blurton-Jones, Mathew
AU - Holtzman, David M.
AU - Shi, Yanhong
N1 - Funding Information:
The authors thank Drs. Xiwei Wu, Jinhui Wang, and Hyejin Cho at City of Hope Integrative Genomics Core Facility for their help of scRNA-seq and analysis, and Drs. Zhuo Li and Ricardo Zerda at City of Hope Electron Microscopy Core Facility for their help of electron microscopy. The authors thank the Michael Amini Transfusion Medicine Center of City of Hope for providing anonymous blood specimens. This work was supported by the Louise and Herbert Horvitz Charitable Foundation, the Sidell Kagan Foundation, the Christopher Family Endowed Innovation Fund, and the National Institute of Aging of the National Institutes of Health R01 AG056305, RF1 AG061794, and R56 AG061171 to Y.S., P30 AG019610 to E.M.R., RF1 DA048813, R01 AG056303, and P30 AG066519 to M.B.J. The authors are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human brain tissues. The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
The authors thank Drs. Xiwei Wu, Jinhui Wang, and Hyejin Cho at City of Hope Integrative Genomics Core Facility for their help of scRNA‐seq and analysis, and Drs. Zhuo Li and Ricardo Zerda at City of Hope Electron Microscopy Core Facility for their help of electron microscopy. The authors thank the Michael Amini Transfusion Medicine Center of City of Hope for providing anonymous blood specimens. This work was supported by the Louise and Herbert Horvitz Charitable Foundation, the Sidell Kagan Foundation, the Christopher Family Endowed Innovation Fund, and the National Institute of Aging of the National Institutes of Health R01 AG056305, RF1 AG061794, and R56 AG061171 to Y.S., P30 AG019610 to E.M.R., RF1 DA048813, R01 AG056303, and P30 AG066519 to M.B.J. The authors are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human brain tissues. The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05‐901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH
PY - 2021/9/22
Y1 - 2021/9/22
N2 - 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 (Aβ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3α/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.
AB - 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 (Aβ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3α/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.
KW - brain organoids
KW - disease modeling
KW - induced pluripotent stem cells
KW - serum exposure
KW - sporadic Alzheimer's disease
UR - http://www.scopus.com/inward/record.url?scp=85111849699&partnerID=8YFLogxK
U2 - 10.1002/advs.202101462
DO - 10.1002/advs.202101462
M3 - Article
C2 - 34337898
AN - SCOPUS:85111849699
SN - 2198-3844
VL - 8
JO - Advanced Science
JF - Advanced Science
IS - 18
M1 - 2101462
ER -