APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids

Jing Zhao; Yuan Fu; Yu Yamazaki; Yingxue Ren; Mary D. Davis; Chia Chen Liu; Wenyan Lu; Xue Wang; Kai Chen; Yesesri Cherukuri; Lin Jia; Yuka A. Martens; Lucy Job; Francis Shue; Thanh Thanh Nguyen; Steven G. Younkin; Neill R. Graff-Radford; Zbigniew K. Wszolek; David A. Brafman; Yan W. Asmann; Nilüfer Ertekin-Taner; Takahisa Kanekiyo; Guojun Bu

doi:10.1038/s41467-020-19264-0

APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids

Jing Zhao, Yuan Fu, Yu Yamazaki, Yingxue Ren, Mary D. Davis, Chia Chen Liu, Wenyan Lu, Xue Wang, Kai Chen, Yesesri Cherukuri, Lin Jia, Yuka A. Martens, Lucy Job, Francis Shue, Thanh Thanh Nguyen, Steven G. Younkin, Neill R. Graff-Radford, Zbigniew K. Wszolek, David A. Brafman, Yan W. AsmannNilüfer Ertekin-Taner, Takahisa Kanekiyo, Guojun Bu

Engineering, Ira A. Fulton Schools of (IAFSE)

Research output: Contribution to journal › Article › peer-review

158 Scopus citations

Abstract

APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.

Original language	English (US)
Article number	5540
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19264-0
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1038/s41467-020-19264-0

Cite this

Zhao, J., Fu, Y., Yamazaki, Y., Ren, Y., Davis, M. D., Liu, C. C., Lu, W., Wang, X., Chen, K., Cherukuri, Y., Jia, L., Martens, Y. A., Job, L., Shue, F., Nguyen, T. T., Younkin, S. G., Graff-Radford, N. R., Wszolek, Z. K., Brafman, D. A., ... Bu, G. (2020). APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids. Nature communications, 11(1), Article 5540. https://doi.org/10.1038/s41467-020-19264-0

Zhao, J, Fu, Y, Yamazaki, Y, Ren, Y, Davis, MD, Liu, CC, Lu, W, Wang, X, Chen, K, Cherukuri, Y, Jia, L, Martens, YA, Job, L, Shue, F, Nguyen, TT, Younkin, SG, Graff-Radford, NR, Wszolek, ZK, Brafman, DA, Asmann, YW, Ertekin-Taner, N, Kanekiyo, T & Bu, G 2020, 'APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids', Nature communications, vol. 11, no. 1, 5540. https://doi.org/10.1038/s41467-020-19264-0

@article{8bbf19cb510d485492e3edcd464e34d3,

title = "APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer{\textquoteright}s disease patient iPSC-derived cerebral organoids",

abstract = "APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer{\textquoteright}s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.",

author = "Jing Zhao and Yuan Fu and Yu Yamazaki and Yingxue Ren and Davis, {Mary D.} and Liu, {Chia Chen} and Wenyan Lu and Xue Wang and Kai Chen and Yesesri Cherukuri and Lin Jia and Martens, {Yuka A.} and Lucy Job and Francis Shue and Nguyen, {Thanh Thanh} and Younkin, {Steven G.} and Graff-Radford, {Neill R.} and Wszolek, {Zbigniew K.} and Brafman, {David A.} and Asmann, {Yan W.} and Nil{\"u}fer Ertekin-Taner and Takahisa Kanekiyo and Guojun Bu",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-19264-0",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids

AU - Zhao, Jing

AU - Fu, Yuan

AU - Yamazaki, Yu

AU - Ren, Yingxue

AU - Davis, Mary D.

AU - Liu, Chia Chen

AU - Lu, Wenyan

AU - Wang, Xue

AU - Chen, Kai

AU - Cherukuri, Yesesri

AU - Jia, Lin

AU - Martens, Yuka A.

AU - Job, Lucy

AU - Shue, Francis

AU - Nguyen, Thanh Thanh

AU - Younkin, Steven G.

AU - Graff-Radford, Neill R.

AU - Wszolek, Zbigniew K.

AU - Brafman, David A.

AU - Asmann, Yan W.

AU - Ertekin-Taner, Nilüfer

AU - Kanekiyo, Takahisa

AU - Bu, Guojun

PY - 2020/12/1

Y1 - 2020/12/1

N2 - APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.

AB - APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=85094882845&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85094882845&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-19264-0

DO - 10.1038/s41467-020-19264-0

M3 - Article

C2 - 33139712

AN - SCOPUS:85094882845

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5540

ER -

APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this