The NAAG'ing Concerns of Modeling Human Alzheimer's Disease in Mice

J Alzheimers Dis. 2019;68(3):939-945. doi: 10.3233/JAD-181251.

Abstract

Studies over the past two decades report significant reductions in brain N-acetylaspartyl glutamate (NAAG) levels in neurodegenerative diseases with associated cognitive impairment, including Alzheimer's disease (AD). Because NAAG is cleaved by glutamate carboxypeptidase II (GCPII), restoration of brain NAAG levels via GCPII inhibition is a potential therapeutic strategy for AD. Herein, studies were conducted to identify an appropriate murine model of AD that recapitulates human brain NAAG changes in order to preclinically evaluate the therapeutic benefit of GCPII inhibition. Our opposing findings of brain NAAG changes in human and mouse AD highlights the limited predictive value of AD mouse models.

Keywords: Alzheimer’s disease; animal models; drug discovery; mass spectrometry.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Animals
  • Antigens, Surface / metabolism
  • Brain / metabolism*
  • Brain Chemistry
  • Dipeptides / analysis
  • Dipeptides / metabolism*
  • Disease Models, Animal*
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Glutamate Carboxypeptidase II / antagonists & inhibitors
  • Glutamate Carboxypeptidase II / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL

Substances

  • Antigens, Surface
  • Dipeptides
  • isospaglumic acid
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II