Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer's disease

FASEB J. 2011 Sep;25(9):2911-20. doi: 10.1096/fj.11-182873. Epub 2011 May 18.


The purpose of this work was to test whether brain-penetrating angiotensin-converting enzyme (ACE) inhibitors (e.g., perindopril), as opposed to non-brain-penetrating ACE inhibitors (e.g., enalapril and imidapril), may reduce the cognitive decline and brain injury in Alzheimer's disease (AD). We first compared the effect of perindopril, enalapril, and imidapril on cognitive impairment and brain injury in a mouse model of AD induced by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)₁₋₄₀. Perindopril, with significant inhibition of hippocampal ACE, significantly prevented cognitive impairment in this AD mouse model. This beneficial effect was attributed to the suppression of microglia/astrocyte activation and the attenuation of oxidative stress caused by iNOS induction and extracellular superoxide dismutase down-regulation. In contrast, neither enalapril nor imidapril prevented cognitive impairment and brain injury in this AD mouse. We next examined the protective effects of perindopril on cognitive impairment in PS2APP-transgenic mice overexpressing Aβ in the brain. Perindopril, without affecting brain Aβ deposition, significantly suppressed the increase in hippocampal ACE activity and improved cognition in PS2APP-transgenic mice, being associated with the suppression of hippocampal astrocyte activation and attenuation of superoxide. Our data demonstrated that the brain-penetrating ACE inhibitor perindopril, as compared to non-brain-penetrating ACE inhibitors, protected against cognitive impairment and brain injury in experimental AD models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / chemically induced
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / toxicity
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Disease Models, Animal
  • Enalapril / therapeutic use
  • Hippocampus / metabolism
  • Imidazolidines / therapeutic use
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidative Stress
  • Peptide Fragments / toxicity
  • Peptidyl-Dipeptidase A / metabolism
  • Perindopril / therapeutic use*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism


  • Amyloid beta-Peptides
  • Angiotensin-Converting Enzyme Inhibitors
  • Imidazolidines
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • Enalapril
  • imidapril
  • Nitric Oxide Synthase Type II
  • Superoxide Dismutase
  • Peptidyl-Dipeptidase A
  • Perindopril