APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer\u2019s disease patient iPSC-derived cerebral organoids

Jing Zhao,Yuan Fu,Chia-Chen Liu,Nilüfer Ertekin-Taner,Xue Wang,Kai Chen,Lucy Job,Wenyan Lü ,Yesesri Cherukuri,Zbigniew K Wszołek ,Mary Dabney Davis ,David A Brafman,Thanh Thanh L Nguyen ,Lin Ji ,Steven G Younkin,Yuka A Martens,Yan W Asmann,Yingxue Ren,Takahisa Kanekiyo,Neill R Graff‐Radford ,Yu Yamazaki,Francis Shue,Guojun Bu

doi:10.1038/s41467-020-19264-0

Jing Zhao, Yuan Fu + Show 21 more

Open Access

https://doi.org/10.1038/s41467-020-19264-0

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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.

Highlights

APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD)
amyloid precursor protein (APP) β-actin associated with lower levels of full-length APP (Fig. 3g, h). These results suggest that amyloid-β peptides (Aβ) clearance mechanism rather than APP processing is altered in cerebral organoids from AD patients regardless of APOE4 status, resulting in enhanced Aβ accumulation and increased Aβ42/Aβ40 ratio
Patients with or without APOE4. cerebral organoids simulate intrinsic spatial patterning, and display acquisition of cell identity in a timed manner that closely mimics the temporal patterning with sequential neuronal layer formation, accompanied with matured astrocytes[21,22,33]

Summary

Introduction

APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). Our study using human iPSC-organoids recapitulates APOE4related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis. The induced pluripotent stem cells (iPSCs) derived from human somatic cells with AD-linked mutations or risk alleles are promising in vitro models by recapitulating the earliest molecular and pathological changes in age-related disorders[13,14,15,16,17]. Elevated levels of Aβ and phosphorylated tau, as well as increased cellular stress markers have been reported in iPSC-derived neurons from AD patients[14,15,16,18]. In addition to altered APP processing, an increase in levels of total and phosphorylated tau is observed in iPSC-derived neurons from AD patients carrying the APP p.V717I mutation or APOE4 risk allele[18,19]. In this study, we utilize a large number of human iPSC lines from healthy subjects and AD patients carrying APOE ε3/ε3 or ε4/ε4 genotype, and investigate

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