Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease

Mol Psychiatry. 2014 Apr;19(4):511-8. doi: 10.1038/mp.2013.23. Epub 2013 Mar 12.

Abstract

5-Lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD) and in vivo modulates the amyloidotic phenotype of amyloid precursor protein transgenic mice. However, no data are available on the effects that 5LO has on synaptic function, integrity and cognition. To address this issue, we used a genetic and a pharmacological approach by generating 3 × Tg mice deficient for 5LO and administering 3 × Tg mice with a 5LO inhibitor. Compared with controls, we found that even before the development of overt neuropathology, both animals manifested significant memory improvement, rescue of their synaptic dysfunction and amelioration of synaptic integrity. In addition, later in life, these mice had a significant reduction of Aβ and tau pathology. Our findings support a novel functional role for 5LO in regulating synaptic plasticity and memory. They establish this protein as a pleiotropic contributor to the development of the full spectrum of the AD phenotype, making it a valid therapeutic target for the treatment of AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Alzheimer Disease / complications*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Arachidonate 5-Lipoxygenase / genetics
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Brain / pathology*
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Fear / psychology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • Hydroxyurea / analogs & derivatives
  • Hydroxyurea / pharmacology
  • Hydroxyurea / therapeutic use
  • In Vitro Techniques
  • Lipoxygenase Inhibitors / pharmacology
  • Lipoxygenase Inhibitors / therapeutic use
  • Memory Disorders / etiology
  • Memory Disorders / therapy*
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Presenilin-1 / genetics
  • Synapses / drug effects
  • Synapses / genetics
  • Synapses / physiology*
  • tau Proteins / genetics

Substances

  • Amyloid beta-Protein Precursor
  • Lipoxygenase Inhibitors
  • PSEN1 protein, human
  • Presenilin-1
  • tau Proteins
  • Arachidonate 5-Lipoxygenase
  • zileuton
  • Hydroxyurea