APOE ε4-dependent effects on the early amyloid pathology in induced neurons of patients with Alzheimer’s disease  

作　　者：Hongwon Kim Siyoung Kim Byounggook Cho Jaein Shin Jongpil Kim 

机构地区：[1]Department of Biomedical Engineering,Dongguk University,Pildong-ro 1-gil 30,Jung-Gu,Seoul 04620,Republic of Korea [2]Laboratory of Stem Cells&Gene Editing,Department of Chemistry,Dongguk University,Pildong-ro 1-gil 30,Jung-Gu,Seoul 04620,Republic of Korea.

出　　处：《Translational Neurodegeneration》2022年第1期248-261,共14页转化神经变性病（英文）

基　　金：Ministry of Science and ICT,and Ministry of Health and Welfare(2021M3E5E5096464,Republic of Korea);Basic Science Research Program of the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2022R1A6A1A03053343).

摘　　要：Background: The ε4 allele of apolipoprotein E (APOE ε4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD), associated with amyloid pathogenesis. However, it is not clear how APOE ε4 accelerates amyloid-beta (Aβ) deposition during the seeding stage of amyloid development in AD patient neurons. Methods: AD patient induced neurons (iNs) with an APOE ε4 inducible system were prepared from skin fibroblasts of AD patients. Transcriptome analysis was performed using RNA isolated from the AD patient iNs expressing APOE ε4 at amyloid-seeding and amyloid-aggregation stages. Knockdown of IGFBP3 was applied in the iNs to investigate the role of IGFBP3 in the APOE ε4-mediated amyloidosis. Results: We optimized amyloid seeding stage in the iNs of AD patients that transiently expressed APOE ε4. Remarka-bly, we demonstrated that Aβ pathology was aggravated by the induction of APOE ε4 gene expression at the amyloid early-seeding stage in the iNs of AD patients. Moreover, transcriptome analysis in the early-seeding stage revealed that IGFBP3 was functionally important in the molecular pathology of APOE ε4-associated AD. Conclusions: Our findings suggest that the presence of APOE ε4 at the early Aβ-seeding stage in patient iNs is critical for aggravation of sporadic AD pathology. These results provide insights into the importance of APOE ε4 expression for the progression and pathogenesis of sporadic AD.

关 键 词：Alzheimer’s disease Direct conversion Apolipoprotein E Induced neuron AMYLOID PRESENILIN 

分 类 号：R749.16[医药卫生—神经病学与精神病学]