Neurosci Lett. 2012 Sep 7;
Shi R, Zhang Y, Shi Y, Shi S, Jiang L
Abstract
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.
PMID: 22985512
What is interesting about this article is that a typical antipsychotic medication – Thioridazine – impairs Peroxisomal Beta-Oxidation of fatty acids, impairing degradation of fatty acid chains too long to be handled by mitochondria. This leads to an increase in Beta-Amyloid formation.
I wonder if the adverse effects of typical antipsychotics – via acetylcholine antagonism and impairment of peroxisomal beta-oxidation – accelerates the development of the negative symptoms or dementia precox of schizophrenia. This argues against their use since the negative psychotic symptoms are the most treatment resistant symptoms and are the most disabling symptoms of schizophrenia.