2. Academic Validation
  3. Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease

Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease

  • Cell Rep. 2021 Dec 7;37(10):110102. doi: 10.1016/j.celrep.2021.110102.
Jonghee Han 1,  Junho Hyun 2,  Jaesang Park 2,  Sunmin Jung 2,  Yoonseo Oh 2,  Youbin Kim 3,  Shin-Hyeon Ryu 2,  Seo-Hyun Kim 2,  Eun Il Jeong 2,  Dong-Gyu Jo 4,  Sung-Hye Park 5,  Yong-Keun Jung 6
Affiliations

Affiliations

  • 1 School of Biological Science, Seoul National University, Seoul 08826, Korea; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 School of Biological Science, Seoul National University, Seoul 08826, Korea.
  • 3 Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Korea.
  • 4 School of Pharmacy, Sungkyunkwan University, Gyunggi-do 16419, Korea.
  • 5 Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea.
  • 6 School of Biological Science, Seoul National University, Seoul 08826, Korea. Electronic address: ykjung@snu.ac.kr.
PMID: 34879266 DOI: 10.1016/j.celrep.2021.110102
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.

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