@article{75a510b44e7d4ca59c429bfa214ce05c,
title = "Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease",
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.",
keywords = "Alzheimer's disease, amyloid beta, gamma-secretase, hypoxia, pyruvate kinase M2",
author = "Jonghee Han and Junho Hyun and Jaesang Park and Sunmin Jung and Yoonseo Oh and Youbin Kim and Ryu, {Shin Hyeon} and Kim, {Seo Hyun} and Jeong, {Eun Il} and Jo, {Dong Gyu} and Park, {Sung Hye} and Jung, {Yong Keun}",
note = "Funding Information: The authors would like to thank Dr. T. Tomita (University of Tokyo, Japan) for providing the anti-PEN2 antibody and Dr. W. Araki (National Institute of Neuroscience, Japan) for providing SH-SY5Y-APPswe cells. Alzheimer's disease tissue samples were provided by the Harvard Brain Tissue Resource Center of McLean Hospital (MA, USA) and by the Brain Bank of Seoul National University Hospital Biomedical Research Institute. J. Hyun was supported by the Brain Korea 21 program. This work was supported by a CRI grant (no. 2019R1A2B5B03070352) from the National Research Foundation of Korea (NRF), the Bio & Medical Technology Development Program of the National Research Foundation (NRF-2017M3A9G7073521) funded by the Korea government (MSIT), and by a grant (to Y.-K.J.) funded by the Alzheimer's Association (USA). J. Han, J. Hyun, and Y.-K.J. conceived the study; J. Han, J. Hyun, J.P. S.J. S.-H.K. Y.O. Y.K. S.-H.R. S.-H.P. D.-G.J. and E.I.J. carried out the experiments; J. Han, J. Hyun, and Y.-K.J. designed experiments; J. Han, J. Hyun, and Y.-K.J. wrote the manuscript with input from all other authors. All authors approved the manuscript. The authors declare no competing interests, and the material in this study is original research and has not been either previously published or submitted for publication elsewhere while under consideration. Funding Information: The authors would like to thank Dr. T. Tomita (University of Tokyo, Japan) for providing the anti-PEN2 antibody and Dr. W. Araki (National Institute of Neuroscience, Japan) for providing SH-SY5Y-APP swe cells. Alzheimer{\textquoteright}s disease tissue samples were provided by the Harvard Brain Tissue Resource Center of McLean Hospital (MA, USA) and by the Brain Bank of Seoul National University Hospital Biomedical Research Institute. J. Hyun was supported by the Brain Korea 21 program. This work was supported by a CRI grant (no. 2019R1A2B5B03070352 ) from the National Research Foundation of Korea (NRF), the Bio & Medical Technology Development Program of the National Research Foundation ( NRF-2017M3A9G7073521 ) funded by the Korea government (MSIT), and by a grant (to Y.-K.J.) funded by the Alzheimer{\textquoteright}s Association (USA). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = dec,
day = "7",
doi = "10.1016/j.celrep.2021.110102",
language = "English (US)",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}