한빛사 논문
Jonghee Han,1,2,6 Junho Hyun,1,6 Jaesang Park,1 Sunmin Jung,1 Yoonseo Oh,1 Youbin Kim,3 Shin-Hyeon Ryu,1 Seo-Hyun Kim,1 Eun Il Jeong,1 Dong-Gyu Jo,4 Sung-Hye Park,5 and Yong-Keun Jung1,7,*
1School of Biological Science, Seoul National University, Seoul 08826, Korea 2Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 3Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Korea 4School of Pharmacy, Sungkyunkwan University, Gyunggi-do 16419, Korea 5Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea 6These authors contributed equally 7Lead contact
*Correspondence
Abstract
Toxic amyloid beta (Aβ) species cause synaptic dysfunction and neurotoxicity in Alzheimer’s disease (AD). As of yet, however, there are no reported regulators for gamma-secretase, which links a risky environment to amyloid accumulation in AD. Here, we report that pyruvate kinase M2 (PKM2) is a positive regulator of gamma-secretase under hypoxia. From a genome-wide functional screen, we identify PKM2 as a gamma-secretase activator that is highly expressed in the brains of both patients and murine models with AD. PKM2 regulates Aβ production and the amount of active gamma-secretase complex by changing the gene expression of aph-1 homolog. Hypoxia induces PKM2 expression, thereby promoting gamma-secretase activity. Moreover, transgenic expression of PKM2 in 3xTg AD model mice enhances hippocampal production of Aβ and exacerbates the impairment of spatial and recognition memory. Taken together, these findings indicate that PKM2 is an important gamma-secretase regulator that promotes Aβ production and memory impairment under hypoxia.
논문정보
관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기