Is it possible to improve memory function by upregulation of the cholesterol 24S-hydroxylase (CYP46A1) in the brain?

PLoS One. 2013 Jul 16;8(7):e68534. doi: 10.1371/journal.pone.0068534. Print 2013.

Abstract

We previously described a heterozygous mouse model overexpressing human HA-tagged 24S-hydroxylase (CYP46A1) utilizing a ubiquitous expression vector. In this study, we generated homozygotes of these mice with circulating levels of 24OH 30-60% higher than the heterozygotes. Female homozygous CYP46A1 transgenic mice, aged 15 months, showed an improvement in spatial memory in the Morris water maze test as compared to the wild type mice. The levels of N-Methyl-D-Aspartate receptor 1, phosphorylated-N-Methyl-D-Aspartate receptor 2A, postsynaptic density 95, synapsin-1 and synapthophysin were significantly increased in the hippocampus of the CYP46A1 transgenic mice as compared to the controls. The levels of lanosterol in the brain of the CYP46A1 transgenic mice were significantly increased, consistent with a higher synthesis of cholesterol. Our results are discussed in relation to the hypothesis that the flux in the mevalonate pathway in the brain is of importance in cognitive functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / enzymology*
  • Brain / physiology*
  • Cholesterol 24-Hydroxylase
  • Female
  • Humans
  • Memory / physiology*
  • Mice
  • Mice, Transgenic
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism*

Substances

  • Steroid Hydroxylases
  • Cholesterol 24-Hydroxylase

Grant support

This work was supported by grants from Swedish Brain Power, Strategic Neuroscience Programme, Swedish Science Council, Swedish Alzheimer’s Foundation, Old Servant’s Foundation, Gun och Bertil Stonhes Foundation, and the Swedish Brain Foundation. S.M. was partially supported by the Italian Blanceflor Boncompagni-Ludovisi Foundation. E.P. was supported by Ramon Areces Foundation (Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.