Antidepressants modulate intracellular amyloid peptide species in N2a neuroblastoma cells.
It is estimated that 30%-50% of Alzheimer's disease (AD) patients are diagnosed with major or minor depression. Research that addresses the relationship between these two diseases will benefit patients who suffer from depression comorbid with AD and allow further understanding of the neuroanatomy of depression. A clinical study showed that the use of the antidepressant fluoxetin concomitantly with the FDA-approved AD drug rivastigmine provided an improvement in the daily activities and the overall functioning in the patients with cognitive impairment. In an attempt to understand the underlying mechanism for the antidepressant's beneficial effect in AD patients, we evaluated the effects of different classes of antidepressants on the amyloid-β peptide (Aβ) species in N2a neuroblastoma cells overexpressing amyloid-β protein precursor. The effect of increasing antidepressant concentrations on the intracellular and secreted Aβ species is investigated by Western blotting. The tested antidepressants include fluoxetine, paroxetine, maprotiline, and imipramine. Fluoxetine and paroxetine at 10 μM significantly decreased the intracellular level of Aβ oligomers and increased the level of Aβ monomers. However, imipramine and maprotiline increased the intracellular amount of Aβ monomers without affecting Aβ oligomers. Based on these results, it is possible that fluoxetine and paroxetine could be beneficial to AD patients via reducing the level of the cytotoxic oligomers and keeping the Aβ peptide in the monomeric form. These data could explain some of the beneficial effects of antidepressants in AD patients observed in clinical studies.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
Marwa
M
Aboukhatwa
Yuan
Y
Luo
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000704:Analysis of Variance; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects*; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D000077191:Wortmannin
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000730:Androstadienes; D000928:Antidepressive Agents; D010726:Phosphodiesterase Inhibitors; D000077191:Wortmannin