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

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 Aβ40 content, APP immunoreactivity and APP751+770 mRNA expressions in the rat cerebral cortex. A correlation analysis showed that the Aβ40 levels were positively correlated with the cortex C24:0 and C26:0 levels. Additionally, the primary cerebral cortex neurons treated with this compound showed increases in APP751+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.

► Thioridazine, an inhibitor of peroxisomal β-oxidation, increased brain VLCFA levels.
► Inhibited peroxisomal β-oxidation increased Aβ40 level and APP expressions.
► Aβ40 level was positively correlated with cortex C24:0 and C26:0 levels respectively.
► Thioridazine increased APP and BACE1 expressions in primary cortex neurons.
► Impaired peroxisomal functions may contribute to the pathogenesis of AD.