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

Jonghee Han, Junho Hyun, Jaesang Park, Sunmin Jung, Yoonseo Oh, Youbin Kim, Shin Hyeon Ryu, Seo Hyun Kim, Eun Il Jeong, Dong Gyu Jo, Sung Hye Park, Yong Keun Jung

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number110102
JournalCell Reports
Volume37
Issue number10
DOIs
StatePublished - Dec 7 2021

Keywords

  • Alzheimer's disease
  • amyloid beta
  • gamma-secretase
  • hypoxia
  • pyruvate kinase M2

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease'. Together they form a unique fingerprint.

Cite this