Casein Kinase 2 dependent phosphorylation of eIF4B regulates BACE1 expression in Alzheimer's disease

Cell Death Dis. 2021 Aug 4;12(8):769. doi: 10.1038/s41419-021-04062-3.


Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / metabolism*
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / metabolism*
  • Disease Models, Animal
  • Eukaryotic Initiation Factors / metabolism*
  • Gene Silencing
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation / drug effects
  • Presenilin-1 / metabolism
  • Protein Biosynthesis / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Up-Regulation / drug effects


  • Amyloid beta-Peptides
  • Eukaryotic Initiation Factors
  • Presenilin-1
  • Protein Kinase Inhibitors
  • eIF-4B
  • Casein Kinase II
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse