Page 122 - ebook

[A. Biochemistry/Molecular Biology] A-61

Aberrant role of pyruvate kinase M2 in the regulation of

gamma-secretase and memory deficits in Alzheimer’s disease

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Jonghee Han¹,² , Junho Hyun¹ , Jaesang Park¹, Sunmin Jung¹, Yoonseo Oh¹, Youbin Kim³, Shin-Hyeon
Ryu¹, Seo-Hyun Kim¹, Eunil Jeong¹, Dong-Gyu Jo⁴, Sung-Hye Park⁵, Yong-Keun Jung¹*

¹School of Biological Science, Seoul National University, Seoul 08826, Korea, ²Department of Neuroscience,

University of Texas Southwestern Medical Center, Dallas 75390, USA, ³Interdisciplinary Program in Neuroscience,
Seoul National University, Seoul 08826, Korea, ⁴School of Pharmacy, Sungkyunkwan University, Gyunggi-do 16419,

Korea, ⁵Department of Pathology, eoul National University College of Medicine, Seoul 03080, Korea

Toxic amyloid beta (Ab) 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 Abeta 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 Abeta and exacerbates the impairment of spatial and

recognition memory. Taken together, these findings indicate that PKM2 is an important gamma-secretase regulator
that promotes Abeta production and memory impairment under hypoxia.