Deletion of asparagine endopeptidase reduces anxiety- and depressive-like behaviors and improves abilities of spatial cognition in mice

Brain Res Bull. 2018 Sep;142:147-155. doi: 10.1016/j.brainresbull.2018.07.010. Epub 2018 Jul 17.


Mammalian asparagine endopeptidase (AEP) is a lysosomal cysteine protease that cleaves protein substrates on the C-terminal side of asparagine. The expression and activity of AEP are closely related to many pathological conditions that include cancer, atherosclerosis and inflammation. It has been validated that the level of AEP is elevated in aged human and neurodegenerative diseases like Alzheimer's disease (AD). Mood disorder is one of the most emotional symptoms that can be seen in AD patients, which leads us to assume that AEP can modulate affective behaviors. AEP knockout (AEP KO) and wildtype (WT) mice were used in this study, and a series of behavioral tests were performed to establish a potential link between AEP and psychiatric disorders. It was demonstrated that AEP KO mice displayed lower anxiety-like behavior and more advance exploratory behavior in open-field and hole-board tests. AEP KO mice reduced depressive-like behaviors in the forced swim and tail suspension tests. Morris water maze (MWM) test showed that the abilities of spatial learning and memory were elevated in AEP-deletion mice compared with those of WT mice. Furthermore, the enhanced synaptic plasticity (LTP and DPT) as well as the increased expressions of SYP and PSD-95 proteins in hippocampus were showed in AEP KO mice. Otherwise, the level of BDNF protein was reduced and the level of NF-κB p65 protein was increased in hippocampus and frontal cortex of AEP KO mice. These data highlight the importance of studying AEP in the anxiety and depression behaviors and the spatial learning and memory.

Keywords: AEP; Anxiety; Depression; Learning and memory; Mice; Synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / enzymology*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cognition / physiology
  • Cysteine Endopeptidases / deficiency*
  • Cysteine Endopeptidases / genetics
  • Depression / enzymology*
  • Disks Large Homolog 4 Protein / metabolism
  • Excitatory Postsynaptic Potentials / physiology
  • Exploratory Behavior / physiology*
  • Frontal Lobe / enzymology
  • Hippocampus / enzymology
  • Male
  • Maze Learning / physiology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Neuronal Plasticity / physiology
  • Spatial Memory / physiology*
  • Synaptophysin / metabolism


  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • NF-kappa B
  • Synaptophysin
  • Syp protein, mouse
  • Cysteine Endopeptidases
  • asparaginylendopeptidase