Improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase

PLoS One. 2009;4(2):e4590. doi: 10.1371/journal.pone.0004590. Epub 2009 Feb 25.


Background: Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-beta (Abeta) degradation. The aim of our study was to explore the impact of NEP deficiency on the initial development of dementia-like symptoms in mice.

Methodology/principal findings: We found that while endogenous Abeta concentrations were elevated in the brains of NEP-knockout mice at all investigated age groups, immunohistochemical analysis using monoclonal antibodies did not detect any Abeta deposits even in old NEP knockout mice. Surprisingly, tests of learning and memory revealed that the ability to learn was not reduced in old NEP-deficient mice but instead had significantly improved, and sustained learning and memory in the aged mice was congruent with improved long-term potentiation (LTP) in brain slices of the hippocampus and lateral amygdala. Our data suggests a beneficial effect of pharmacological inhibition of cerebral NEP on learning and memory in mice due to the accumulation of peptides other than Abeta degradable by NEP. By conducting degradation studies and peptide measurements in the brain of both genotypes, we identified two neuropeptide candidates, glucagon-like peptide 1 and galanin, as first potential candidates to be involved in the improved learning in aged NEP-deficient mice.

Conclusions/significance: Thus, the existence of peptides targeted by NEP that improve learning and memory in older individuals may represent a promising avenue for the treatment of neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Amygdala / physiology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Dementia / prevention & control
  • Galanin / pharmacology
  • Glucagon-Like Peptide 1 / pharmacology
  • Hippocampus / physiology
  • Learning / drug effects*
  • Long-Term Potentiation / drug effects
  • Memory / drug effects*
  • Mice
  • Neprilysin / antagonists & inhibitors
  • Neprilysin / deficiency*
  • Neprilysin / physiology
  • Peptide Fragments / pharmacology


  • Amyloid beta-Peptides
  • Peptide Fragments
  • Galanin
  • Glucagon-Like Peptide 1
  • Neprilysin