A popular antidepressant drug and its metabolite induce toxicity via beta-amyloid and a serotonin transporter-dependent mechanism

Depression increases the risk of Alzheimer disease (AD); however, some of this risk might be associated with the type of antidepressant drug used to treat the depression. Indeed, a significant risk has been associated with selective serotonin reuptake inhibitors (SSRIs). SSRIs increase synaptic serotonin levels by inhibiting the serotonin transporter (SERT). It has been reported that SERT can transport molecules other than serotonin. One such molecule is the 14 kDa protein α-synuclein (a protein which accumulates in the Parkinson disease brain). Therefore, it is possible that the AD-related, 4 kDa beta-amyloid (Aβ), may also be transported by SERT, and the inhibition of SERT by SSRIs could inadvertently result in the intracellular accumulation of Aβ and, ultimately, cell death and plaque formation (a hallmark of AD pathology). Caenorhabditis elegans (C. elegans) and mammalian cell culture were used to study the effects of selected SSRIs, i.e. Fluoxetine and its major metabolite, nor-Fluoxetine, on the accumulation of Aβ. The expression of Aβ1-42 in our transgenic C. elegans strain is under the control of the muscle promoter and is therefore specific to the muscle. Any accumulation causes a loss of motility/paralysis phenotype. Both Fluoxetine and nor-Fluoxetine exacerbated paralysis in C. elegans expressing Aβ1-42. To confirm a role for the worm analogue of SERT, MOD-5, in this effect, a worm was generated that carried the Aβ1-42 peptide on a truncated MOD-5 background. Paralysis was also exacerbated in this cross-bred worm strain (versus the parental strain that just expressed the Aβ1-42 peptide), even in the absence of SSRI treatment. The degree of paralysis in a worm that carried the Aβ1-42 peptide on a TPH-1 (tryptophan hydroxylase) null background (thus, inhibiting the synthesis of serotonin) was similar to that in the parental strain that just expressed the Aβ1-42 peptide. Thus, any paralysis in this worm model was not dependent on any change in in serotonin availability. The experiments based on mammalian cell cultures, although showing promise, were not as conclusive and need further optimization. Given the increased practice of prescribing SSRIs for off-label purposes, a significant number of individuals could be unknowingly put at risk for AD through a mechanism based on inhibition of SERT-mediated transport and intracellular accumulation of Aβ peptides. These observations will hopefully lead to a change in prescription practices