한빛사논문
- 조회3,235
Hongwon Kim,1 Junsang Yoo,1 Jaein Shin,1 Yujung Chang,1 Junghyun Jung,2 Dong-Gyu Jo,3 Janghwan Kim,4,5 Wonhee Jang,2 Christopher J. Lengner,6 Byung-Soo Kim7 and Jongpil Kim1,*
1 Laboratory of Stem Cells and Cell reprogramming, Department of Biomedical Engineering (BK21 plus team), Dongguk University, Seoul, 100-715, Republic of Korea
2 Department of Life Science, Dongguk University, Seoul 100-715, Republic of Korea
3 School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
4 Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBBB), Daejeon 305-806, Republic of Korea
5 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
6 Department of Biomedical Sciences, School of Veterinary Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
7 School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
*Correspondence to: Jongpil Kim, PhD
Associate Professor Department of Biomedical Engineering Dongguk University, Seoul, Korea
Abstract
The recent generation of induced neurons by direct lineage conversion holds promise for in vitro modelling of sporadic Alzheimer’s disease. Here, we report the generation of induced neuron-based model of sporadic Alzheimer’s disease in mice and humans, and used this system to explore the pathogenic mechanisms resulting from the sporadic Alzheimer’s disease risk factor apolipoprotein E (APOE) 3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE ?3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-β42 and hyperphosphorylation of tau. Importantly, we demonstrate that APOE 3/4 patient induced neuron culture models can faithfully recapitulate molecular signatures seen in APOE 3/4-associated sporadic Alzheimer’s disease patients. Moreover, analysis of the gene network derived from APOE 3/4 patient induced neurons reveals a strong interaction between APOE 3/4 and another Alzheimer’s disease risk factor, desmoglein 2 (DSG2). Knockdown of DSG2 in APOE 3/4 induced neurons effectively rescued defective APP processing, demonstrating the functional importance of this interaction. These data provide a direct connection between APOE 3/4 and another Alzheimer’s disease susceptibility gene and demonstrate in proof of principle the utility of induced neuron-based modelling of Alzheimer’s disease for therapeutic discovery.
Keywords: Alzheimer’s disease, amyloid-β, neuroprotection, APP, APOE
논문정보
- Research article
- 2017년 07월 (BRIC 등록일 2017-07-06)
- 국내(교신)+국외 연구진
- 생명과학 > 신경생물학
댓글 작성 로그인
팝업 닫기관련 링크
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
