Inhibition of peroxisomal β-oxidation by thioridazine increases the amount of VLCFAs and Aβ generation in the rat brain

Neurosci Lett. 2012 Oct 18;528(1):6-10. doi: 10.1016/j.neulet.2012.08.086. Epub 2012 Sep 7.


Alzheimer's disease (AD) is characterized by the accumulation of the β-amyloid peptide (Aβ), which is generated from sequential cleavages of the amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. Fatty acid alterations in AD brains have recently received substantial attention. Because increased very long chain fatty acid (VLCFA) levels in AD brains imply that peroxisomal β-oxidation dysfunction may be associated with AD pathogenesis, we investigated the effects of impaired peroxisomal β-oxidation on Aβ generation in vivo and in vitro using thioridazine, a selective peroxisomal β-oxidation inhibitor. Under the experimental conditions, thioridazine caused VLCFA accumulation and increases in Aβ(40) content, APP immunoreactivity and APP(751+770) mRNA expressions in the rat cerebral cortex. A correlation analysis showed that the Aβ(40) levels were positively correlated with the cortex C(24:0) and C(26:0) levels. Additionally, the primary cerebral cortex neurons treated with this compound showed increases in APP(751+770) mRNA, APP protein, BACE1 mRNA and protein, and secreted Aβ40 levels. This work supports an emerging viewpoint that impaired peroxisomal function may play an important role in the progression of AD pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Antipsychotic Agents / pharmacology
  • Blotting, Western
  • Brain / drug effects
  • Brain / metabolism*
  • Chromatography, Gas
  • Enzyme-Linked Immunosorbent Assay
  • Fatty Acids / metabolism*
  • Immunohistochemistry
  • Male
  • Oxidation-Reduction / drug effects
  • Peroxisomes / drug effects
  • Peroxisomes / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thioridazine / pharmacology


  • Amyloid beta-Peptides
  • Antipsychotic Agents
  • Fatty Acids
  • Thioridazine